KR20230005221A - Non-Aqueous Topical Formulation - Google Patents

Abstract

The present disclosure is directed to various forms (e.g., concentrates) for cosmetic use, applications to address dermatological conditions, and/or use to alleviate the appearance of time- and/or environmentally induced skin aging. , serums, chemical exfoliation solutions, rinse-off masks, creams, emulsions, etc.). The present disclosure discloses that non-aqueous topical formulations include 1) a stabilized vitamin C formulation, 2) a vitamin C chemical exfoliation formulation, 3) a vitamin C and sugar alcohol formulation, 4) an urea anhydrous emulsion, and 5) an azelaic acid anhydrous formulation. , which is described in more detail below. These topical formulations come in a variety of forms (e.g., concentrated water, serum, chemical exfoliation solution, rinse-off mask, cream, emulsion, etc.).

Description

Non-Aqueous Topical Formulation

Cross reference of related applications

This application is filed on April 16, 2020 U.S. Provisional Application No. 63/010,878, filed on April 16, 2020 63/010,881, filed on April 16, 2020 63/010,884, 2020 It claims the benefit of 63/010,888, filed on April 16, and 63/010,889, filed on April 16, 2020, the disclosures of which are incorporated herein by reference in their entirety.

technology field

The present disclosure relates to stable compositions and methods for treating, preventing, or ameliorating dermatocosmetic conditions, including reducing the appearance of skin aging. The present disclosure also relates to stable compositions and methods for accelerating and enhancing wound healing.

Ascorbic acid (commonly known as vitamin C) is a powerful antioxidant and is widely used in topical compositions to treat or prevent a variety of cosmetic and/or dermatological conditions as well as over time and/or environmentally induced skin aging. , such as facial fine lines and wrinkles, dyschromia/uneven pigmentation, and dark circles under the eyes). In addition, vitamin C can help neutralize the damaging effects of free radicals and serves to stimulate the growth and shedding of collagen, which is important for maintaining skin elasticity.

Tyrosinase is a copper-containing enzyme that catalyzes the production of melanin and other pigments by oxidation from tyrosine. It is reported that the antioxidant activity of ascorbic acid mediates the rate of melanogenesis and thereby reduces (inhibits) the rate of melanogenesis. See YK Choi et al, Int J Dermatol . Vol. 49, p. 218-26 (2010)].

The "gold standard" in cosmetic dermatology for skin lightening/brightening is hydroquinone (HQ). However, HQ can have side effects including mild burning sensation, stinging, erythema (redness), and dry skin. Vitamin C is also used to lighten the appearance of skin, including, for example, dark circles under the eyes, and has a more favorable safety profile (ie fewer side effects). See, eg, LE Espinal-Perez et al, Int J Dermatol . Vol. 43, p. 604-7 (2004) (93% improvement from use of 4% HQ versus 62.5% improvement from use of 5% Vitamin C; however, 68.7% side effects from HQ versus from Vitamin C). 6.2% of side effects).

The scientific and patent literature describes vitamin C topical products, especially water containing formulations, as "unstable". Research and development efforts in the search for more stable topical vitamin C formulations are carried out by using anhydrous carrier systems, adding antioxidants or other ingredients to vitamin C formulations, and buffering vitamin V formulations to a low pH to obtain esterified derivatives (e.g., , magnesium ascorbyl phosphate (“MAP”) and ascorbyl-6-palmitate). Representative prior art approaches and their drawbacks are discussed below.

There is a need for stabilized formulations containing higher concentrations of vitamin C and methods for preparing such formulations.

In topical compositions, the use of urea (and substituted ureas) is known, including for retention of moisture (as a humectant), keratolytic activity as well as enhancement of penetration both by itself and other active ingredients. At concentrations less than about 10%, urea acts as a humectant. At higher concentrations, up to about 10-40%, urea is used to treat dry/rough skin conditions including ichthyosis and psoriasis.

It is also known in the art that the inclusion of effective concentrations of urea in aqueous topical compositions poses formulation problems. Urea undergoes sustained hydrolysis to produce ammonia and other amines, compounds that not only have an unpleasant odor but also tend to increase the pH. Moreover, hydrolysis of urea in an aqueous composition can result in discoloration or other degradation of the product, including phase separation.

Urea (also commonly referred to as carbamide) is a powerful humectant, emollient, and keratolytic agent, and is widely used in topical compositions to treat dry, scaly skin, such as dermatitis, psoriasis, xerostomia ( xerosis), ichthyosis, eczema, keratosis, and keratosis pilaris. See M Pan et al, Dermatology Online Journal Vol. 19 (2013)].

Research suggests that topical urea's keratolytic and hydrating effects are due to dissolution of hydrogen bonds in the stratum corneum, loosening of epidermal keratin, and increased water-binding sites. See M Gloor et al., Skin Pharmacol. Appl. Skin Physiol. Vol. 15 (2002)]. Uses of urea (and substituted ureas) in topical compositions are well known, including for retaining moisture (as a humectant), for keratolytic activity, as well as for enhancing penetration both by itself and other active ingredients. At concentrations less than about 10%, urea acts as a humectant. At higher concentrations, up to about 10-40%, urea is used to treat dry/rough skin conditions including ichthyosis and psoriasis.

Azelaic acid (also commonly known as nonanedioic acid) is a dicarboxylic acid that is naturally present in many whole grains and is widely used in topical compositions to treat or prevent a variety of cosmetic and/or dermatological conditions (listed below). as well as reducing the appearance of color abnormalities/uneven pigmentation. Non-limiting examples of such dermatological conditions that can be ameliorated by topical application of the compositions of the present invention include melasma, inflammatory dermatoses (including acne, rosacea, melasma, psoriasis).

Additionally, the scientific and patent literature describes azelaic acid as being difficult to solubilize. See, eg, US Patent No. 5,925,679. Azelaic acid is slightly soluble in water, cosmetic oil, and alcohol, but each of these solvents has serious limitations. Water will only slightly dissolve the azelaic acid so that it contains up to about 0.24% by weight (w/w) azelaic acid, which is unlikely to be sufficient for a water and azelaic acid solution to be effective. Azelaic acid is sparingly or not soluble in cosmetic oils. Alcohol is an excellent solvent, but high amounts of alcohol, such as isopropyl alcohol, in topical compositions are unsatisfactory because they have the undesirable side effect of drying the skin and reducing the stability of azelaic acid in the composition. In fact, some alcohols, such as ethyl alcohol, make azelaic acid unstable at normal temperatures, resulting in an entirely ineffective composition. Korean Patent KR100861978B1 identifies the problem of solubilizing clinically effective amounts of azelaic acid.

There has been a need for non-oily/non-oily topical formulations that contain and retain high concentrations of ingredients such as vitamin C and/or effective amounts of urea and/or azelaic acid without degradation and concomitant reduction in biological activity, and there is still a need. situation exists. These needs are met by the concentrates of the present disclosure.

The present disclosure is directed to various forms (e.g., concentrates) for cosmetic use, applications to address dermatological conditions, and/or use to alleviate the appearance of time- and/or environmentally induced skin aging. , serums, chemical exfoliation solutions, rinse-off masks, creams, emulsions, etc.).

In one aspect of the present disclosure, a topical formulation of L -ascorbic acid dissolved in a combination of a urea agent and a non-aqueous skin compatible solvent is provided. The formulation is shelf stable for extended periods of time without significant degradation of the L -ascorbic acid in the composition and has desirable physical properties. Topical formulations may include high concentrations of L -ascorbic acid. Topical formulations may include cinnamic acid or a derivative thereof as a penetration enhancer and stabilizing component of ascorbic acid. The topical compositions of the present disclosure find use in the treatment or prevention of a variety of cosmetic and/or dermatological conditions as well as in reducing the appearance of age-related and/or environmentally induced skin aging.

In another aspect of the present disclosure, a topical formulation of an anhydrous emulsion consisting of a urea compound, a non-aqueous skin compatible solvent, and a silicone compound is provided. The formulations are storage stable in non-aqueous solutions for extended periods of time without significant degradation of the urea in the composition, and have desirable physical properties. Topical formulations may include urea concentrations of 1 to 30% by weight. Topical compositions of the present disclosure find use in treating or preventing a variety of cosmetic and/or dermatological conditions.

In another aspect of the present disclosure, a topical formulation of L -ascorbic acid dissolved in a combination of urease and a non-aqueous skin compatible solvent is provided. The formulation is shelf stable for extended periods of time without significant degradation of the L -ascorbic acid in the composition and has desirable physical properties. Topical formulations may include chemical exfoliants and may be used as chemical exfoliation solutions. The present disclosure provides a topical composition comprising a combination of ascorbic acid and urease and a chemical exfoliant dissolved in a non-aqueous solvent. The compositions of the present disclosure are liquid compositions that are stable to both the ascorbic acid component and the urea component. Topical formulations may include high concentrations of L -ascorbic acid, from 10 to 28% by weight. The topical compositions of the present disclosure find use in the treatment or prevention of a variety of cosmetic and/or dermatological conditions as well as in reducing the appearance of age-related and/or environmentally induced skin aging. In some embodiments, the topical composition finds use, for example, as a chemical exfoliation solution that promotes the exfoliation of the top layer of skin cells after topical application.

In another aspect of the present disclosure, a topical formulation of azelaic acid dissolved in a combination of urease and a non-aqueous skin compatible solvent is provided. Topical formulations can include high concentrations of azelaic acid, from 1% to 20% by weight. Topical compositions of the present disclosure find use in treating or preventing a variety of cosmetic and/or dermatological conditions.

The inventors of the present disclosure have discovered that certain amounts of azelaic acid and urea compositions can be added to a non-aqueous solvent to provide various desired concentration levels of solubilized azelaic acid and urea. Solubilized azelaic acid is expected to be much less irritating to the skin because azelaic acid in a dissolved state is much more readily absorbed by the skin than the undissolved state found in a dispersion. Better absorption means less azelaic acid needs to be present in the formulation to be effective, thereby lowering the risk of irritation to the skin.

The inventors of the present disclosure have discovered that low concentrations and concentrations greater than 2-5% of azelaic acid can be added to a non-aqueous solvent to provide solubilized azelaic acid that eliminates burning, itching, and/or numbness upon topical application. .

The present disclosure provides non-aqueous topical formulations comprising 1) a stabilized vitamin C formulation, 2) a vitamin C chemical exfoliation formulation, 3) a vitamin C and sugar alcohol formulation, 4) an urea anhydrous emulsion, and 5) an azelaic acid anhydrous formulation. Describes various categories of , which are described in more detail below. These topical formulations come in a variety of forms (e.g., concentrated water, serum, chemical exfoliation solution, rinse-off mask, cream, emulsion, etc.).

In the following description, additional details of the various categories of non-aqueous topical formulations are provided first, then the various ingredients or components of the formulations are described, and finally, exemplary examples of each category of non-aqueous topical formulations are provided. The numbering mode is described.

The present disclosure provides topical formulations of L -ascorbic acid dissolved in a combination of urease and a non-aqueous skin compatible solvent. The formulation is shelf stable for extended periods of time without undesirable discoloration or significant degradation of the L -ascorbic acid in the composition. The present disclosure provides specific topical formulations that have been developed and optimized to provide skin compatibility and desirable physical properties.

Topical compositions of the present disclosure may be used for the treatment or prevention of a variety of cosmetic and/or dermatological conditions as well as for the treatment or prevention of time- and/or environmentally induced skin aging, such as facial fine lines and wrinkles, discoloration or uneven pigmentation, and It finds use in reducing the appearance of dark circles under the eyes. Non-limiting examples of cosmetic conditions that can be ameliorated by topical application of the compositions of the present disclosure include keratosis, melasma, lentigine, age spots, inflammatory dermatoses (including eczema, acne, psoriasis), and xerosis (dry skin). Also known in the art as cutaneous or pruritus). Topical application can be achieved with the use of a biocompatible gel that can be provided in the form of a patch or the use of a cream, foam or the like. Several gels, patches, creams, foams, etc. are suitable for application to wounds.

In some embodiments, a formulation of the present disclosure comprises: (i) 5 to 28% by weight of ascorbic acid; and (ii) urease; (iii) cinnamic acid, and (iv) one or more optional additional ingredients, and (v) a non-aqueous skin compatible solvent in which to dissolve said ingredients.

In some embodiments, a formulation of the present disclosure comprises: (i) 1% to 20% by weight of azelaic acid; (ii) 1% to 20% by weight of urease, (iii) one or more optional additional ingredients, and (iv) a non-aqueous skin compatible solvent in which to dissolve said ingredients.

The inventors of the present disclosure have discovered that certain amounts of azelaic acid and urea compositions can be added to a non-aqueous solvent to provide various desired concentration levels of solubilized azelaic acid and urea. Solubilized azelaic acid is expected to be much less irritating to the skin because azelaic acid in a dissolved state is much more readily absorbed by the skin than the undissolved state found in a dispersion. Better absorption means less azelaic acid needs to be present in the formulation to be effective, thereby lowering the risk of irritation to the skin.

The inventors of the present disclosure have discovered that low concentrations and concentrations greater than 2-5% of azelaic acid can be added to a non-aqueous solvent to provide solubilized azelaic acid that eliminates burning, itching, and/or numbness upon topical application. .

In some embodiments, a formulation of the present disclosure comprises: (i) 5% to 28% ascorbic acid, (ii) 1% to 20% by weight sugar alcohol agent, (iii) one or more optional additional ingredients, (iv) a non-aqueous skin compatible solvent for dissolving the ingredients.

In some embodiments, a formulation of the present disclosure comprises: (i) 5% to 28% ascorbic acid, (ii) 5% to 20% urease, (iii) 2% to 20% by weight of a chemical keratolytic agent, (iv) one or more optional additional ingredients, and (v) a non-aqueous skin compatible solvent that dissolves the ingredients.

The inventors have discovered that the ascorbic acid formulations of the present disclosure provide a basis for enhancing and accelerating topical wound healing. Accordingly, the inventors have found that the formulation promotes wound healing when applied topically.

The inventors have discovered that urease dissolved in non-aqueous solvents provides improved solubility and penetration of ascorbic acid in non-aqueous solvents.

The inventors have found that cinnamic acid or its derivatives, such as ferulic acid, in addition to ascorbic acid and urea in non-aqueous solvents provide an enhanced stabilizing effect in the formulations of the present disclosure. Thus, the incorporation of cinnamic acid and its derivatives is a penetration enhancer providing improved stability of ascorbic acid and urease in non-aqueous formulations.

In some embodiments, a formulation of the present disclosure comprises: (i) 1% to 30% by weight of urease; (ii) one or more optional additional ingredients, (iii) a non-aqueous skin compatible solvent that dissolves said ingredients. The present disclosure provides topical formulations of urea dissolved in a non-aqueous skin compatible solvent combined with a silicone agent as an emulsifying agent. The formulation is storage stable in non-aqueous solutions for extended periods of time without undesirable odor change or significant degradation of the urea in the composition. The present disclosure provides specific topical formulations that have been developed and optimized to provide skin compatibility and desirable physical properties. In some embodiments, a formulation of the present disclosure comprises: (i) 1% to 30% by weight of urease; (ii) a non-aqueous skin compatible solvent for dissolving the above ingredients; (iii) silicone agent combined with the above components to form an emulsion.

Hydrolysis of urea in an aqueous composition can result in discoloration or other degradation of the product, including phase separation. The inventors of the present disclosure have found that by incorporating a substantially anhydrous first phase (eg, internal phase) containing urea and a non-aqueous solvent, the obtained first phase (eg, internal phase) is hydrolyzed was found to solubilize urea.

The inventors of the present disclosure have discovered that by incorporating a non-aqueous solution of urea into the emulsion, the resulting composition provides for exclusion of water and thus prevents urea degradation. Urea undergoes sustained hydrolysis to produce ammonia and other amines, compounds that not only have an unpleasant odor but also tend to increase the pH. The inventors have found that emulsions containing a homogeneous non-aqueous solution of urea prevent discoloration and unpleasant odors caused by decomposition of urea; It has been found to stabilize the pH of the composition.

The inventors of the present disclosure have discovered that a certain amount of urease can be added to a non-aqueous solvent to provide a stable urea solution at various desired concentration levels.

The inventors of the present disclosure have found that by incorporating a homogeneous non-aqueous solution of urea into the emulsion, the resulting composition relieves skin irritation.

The inventors of the present disclosure have found that by incorporating a homogeneous non-aqueous solution of urea into the emulsion, the resulting composition is storage stable in non-aqueous solution.

Topical compositions of the present disclosure find use in treating or preventing a variety of cosmetic and/or dermatological conditions. Non-limiting examples of dermatological conditions that can be ameliorated by topical application of the compositions of the present disclosure include inflammatory dermatoses (including eczema, acne, psoriasis), and xerosis (also known in the art as dry skin or pruritus). include

ascorbic acid

In some embodiments, the present disclosure is a combination of certain amounts of urea in a non-aqueous skin compatible solvent that together can provide for dissolution of the specified amount of ascorbic acid, and wherein the ascorbic acid results in a skin compatible liquid composition that is substantially stable to degradation. It provides a formulation containing. In some embodiments, the amount of ascorbic acid that is stably dissolved in the composition is greater than would be possible without the particular combination of ingredients provided by the present disclosure.

The terms "ascorbic acid", " L -ascorbic acid", and "vitamin C" are used interchangeably herein and refer to a naturally occurring vitamin of CAS registry number 50-81-7. Any conventional form of ascorbic acid can be used in the subject formulations. In some embodiments, the ascorbic acid used in the high potency vitamin C concentrates of the present disclosure is a powder.

In certain embodiments, the ascorbic acid material used to prepare the subject composition consists of granular particles. Such particulate powders have a particle size (e.g., average particle size) of less than about 25 microns, such as less than about 20 microns and more preferably less than about 12.5 microns, for example, as measured by the Hagman gauge. have In some embodiments, all ascorbic acid powders used to prepare a subject composition can pass through standard test procedures used by the US Pharmacopoeia, number 100 US standard sieve. In some embodiments, at least 80% (eg, at least 90% or 100%) of the ascorbic acid powder used to prepare the subject composition can be passed through a No. 325 US Standard sieve. For example, one powder that meets the above criteria is ascorbic acid ultrafine powder from DSM Nutritional Products LLC, Parsippany, NJ. Previously, this product was available from Roche Vitamins and Fine Chemicals under product code number 6045653.

In some embodiments, the amount of ascorbic acid in a subject composition is at least about 5% by weight, such as at least about 10%, at least about 12%, at least about 15%, at least about 20%, or at least about 25% by weight. . In some embodiments, the subject composition comprises about 28% by weight or less, such as about 25% by weight or less of ascorbic acid in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of ascorbic acid in a subject composition is from about 10% to about 20%, or from about 12% to about 28%, such as from about 15% to about 28%, or from about 20% to about 20% by weight. It is about 28% by weight. In some embodiments, the amount of ascorbic acid in the subject composition is about 5%, about 10%, about 15%, about 20%, or about 25% by weight.

In certain embodiments, the amount of ascorbic acid in a subject composition is from about 10% to about 20% by weight (e.g., about 10%, about 15%, or about 20%), and the ratio of ascorbic acid to urease (by weight % ratio) is a ratio of 1.8 to 2.2, such as 2 (ie 2:1).

In certain embodiments, the amount of ascorbic acid in a subject composition is from about 25% to about 28% (e.g., about 25%, about 26%, about 27%, or about 28%) by weight of ascorbic acid relative to urease. The ratio of (wt% ratio) is from 1.0 to 1.3, such as a ratio of 1.25 (ie 1.25:1) or a ratio of 1.0 (ie 1:1).

Generally, the amount of ascorbic acid in a composition is calculated for a solution phase based on a non-aqueous solvent. See Formulations 1, 3, 4, 6, and 7 in Table 3. However, the amount of ascorbic acid and other components relative to the emulsion composition as a whole can be easily calculated by one skilled in the art. Formulations 2 and 5 of Table 3 represent exemplary emulsion compositions, where the weight percent values presented are relative to the total emulsion composition. In some cases, these concentrate solutions with specific amounts of ascorbic acid may be combined with immiscible ingredients (eg, oil components) and emulsifiers to create emulsion compositions (eg, as described below). It is understood that

urease

The formulations of the present disclosure include urease in an amount sufficient to enhance the solubility of ascorbic acid in non-aqueous skin compatible solvents and to provide a stable solution. The inventors have discovered that a certain amount of urease can be added to a non-aqueous solvent to provide stable ascorbic acid solutions at various desired concentration levels. The amounts of these ureases are selected based on observations regarding the maximum amount of ascorbic acid that can be stably dissolved in a particular non-aqueous solvent and the minimum amount of urease that must be included to provide a stable ascorbic acid solution.

Ureas of interest include, but are not limited to, ureas and substituted ureas, such as alkyl substituted ureas, and more particularly mono- or di-substituted alkyl ureas (eg, hydroxyalkyl ureas). In some embodiments, the urease is a hydroxyalkyl urea, such as hydroxyethyl urea. The urease component used in the subject formulation may be a combination of urea and/or substituted urea. For example, urease can be a combination of urea and hydroxyethyl urea. In certain embodiments, the urease is urea. In certain embodiments, the urease is hydroxyethyl urea.

In some embodiments, the amount of urea in a high potency vitamin C composition of the present disclosure is defined as a function of the concentration of L-ascorbic acid ("AA"). For AA concentrations above the maximum solubility (Z%) of ascorbic acid in neat non-aqueous solvent, as a first step, subtract Z from the desired amount of AA in the concentrate solution. do. As a second step, the difference from the first step is multiplied by 1.25. The minimum amount (wt %) of urease to be included in a non-aqueous solvent based composition can be calculated by the equation: {Concentration of AA - Z} * 1.25.

In some embodiments, for compositions based on 1,3-propanediol as the solvent, a maximum solubility of ascorbic acid (AA) in neat 1,3-propanediol was observed to be 12% by weight. Thus, for AA concentrations greater than 12%, as a first step, subtract 12 from the desired amount of AA in the concentrate. As a second step, the difference from the first step is multiplied by 1.25. The minimum amount (% by weight) of urease to be included in a 1,3-propanediol based composition can be calculated by the equation: {Concentration of AA - 12} * 1.25. See Table 1.

For example, for a composition comprising 15% by weight ascorbic acid, at least about 4% urea is included in the 1,3-propanediol solvent. For a composition comprising 20% by weight ascorbic acid, at least about 10% urea is included in the 1,3-propanediol solvent. For a composition comprising 25% by weight ascorbic acid, at least about 16% urea is included in the 1,3-propanediol solvent. In some embodiments, an additional amount of urease may be included up to a maximum amount of 20% by weight to provide desirable physical properties in combination with additional optional minor ingredients.

In some embodiments, the subject composition comprises about 13 to 19 weight percent ascorbic acid, about 2 to 9 weight percent urease, and 1,3-propanediol. In some embodiments, a subject composition comprises about 15% by weight ascorbic acid, about 2 to about 9% by weight urease (e.g., about 4%, about 5%, about 6%, about 7%, or about 8% ), and 1,3-propanediol. In certain embodiments, the subject composition comprises about 15% by weight ascorbic acid, about 8% by weight urease, and 1,3-propanediol.

In some embodiments, the subject composition comprises about 20 to 24 weight percent ascorbic acid, about 10 to about 15 weight percent urease, and 1,3-propanediol. In some embodiments, a subject composition comprises about 20% by weight ascorbic acid, about 10 to about 15% by weight urease (e.g., about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%), and 1,3-propanediol. In certain embodiments, the subject composition comprises about 20% by weight ascorbic acid, about 10% by weight urease, and 1,3-propanediol.

In some embodiments, the subject composition comprises about 25 to 28 weight percent ascorbic acid, about 16 to about 20 weight percent urease, and 1,3-propanediol. In some embodiments, a subject composition comprises about 25% by weight ascorbic acid, about 16% to about 20% by weight urease (e.g., about 16%, about 17%, about 18%, about 19%, or about 20% ), and 1,3-propanediol. In certain embodiments, the subject composition comprises about 25% by weight ascorbic acid, about 20% by weight urease, and 1,3-propanediol.

Ureas of interest include, but are not limited to, ureas and substituted ureas, such as alkyl substituted ureas, and more particularly mono- or di-substituted alkyl ureas (eg, hydroxyalkyl ureas). In some embodiments, the urease is a hydroxyalkyl urea, such as hydroxyethyl urea. The urease component used in the subject formulation may be a combination of urea and/or substituted urea. For example, urease can be a combination of urea and hydroxyethyl urea. In certain embodiments, the urease is urea. In certain embodiments, the urease is hydroxyethyl urea.

In certain embodiments, the urease used to prepare the subject compositions is in crystalline form prior to dissolution in a solvent. In some embodiments, the crystalline form of urea has a particle size (eg For example, the average particle size).

In some embodiments, the amount of urease in a subject composition is at least about 5% by weight, such as at least about 6% by weight, at least about 7% by weight, at least 8% by weight, at least about 9% by weight, at least about 10% by weight, at least about 11% by weight at least about 12%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20% , at least about 21%, at least about 22%, at least about 23%, at least about 24%, or at least about 25%. In some embodiments, the subject composition comprises about 28% by weight or less, such as about 25% by weight or less of urease in a non-aqueous solvent solution.

In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of urease in a subject composition is from about 10% to about 20%, or from about 12% to about 28%, such as from about 15% to about 28%, or from about 20% to about 28% by weight. In some embodiments, the amount of urease in a subject composition is about 5%, about 10%, about 15%, about 20%, or about 25% by weight.

Generally, the amount of urease in a composition is calculated for a solution phase based on a non-aqueous solvent. However, the amount of urease and other components relative to the emulsion composition as a whole can be easily calculated by one skilled in the art. In some cases, these concentrate solutions with certain amounts of urease are believed to be capable of being combined with immiscible ingredients (eg, oil components) and emulsifiers to create emulsion compositions (eg, as described below). I understand.

For example, for a composition comprising 15% by weight urease, at least about 4% urea is included in the 1,3-propanediol solvent. For a composition comprising 20% by weight urease, at least about 10% urea is included in the 1,3-propanediol solvent. For a composition comprising 25% urease by weight, at least about 16% urea is included in the 1,3-propanediol solvent.

In some embodiments, the subject composition is about 1 to 30% by weight (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8% , about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%) urease and a non-aqueous solvent . In some embodiments, a subject composition comprises 5 to 10 weight percent, about 10 to 15 weight percent, or about 15 to 20 weight percent of urease and a non-aqueous solvent. In certain embodiments, the subject composition comprises about 5% by weight of urease and a non-aqueous solvent. In certain embodiments, a subject composition comprises about 15% by weight urease and a non-aqueous solvent. In certain embodiments, the subject composition comprises about 20% by weight urease and a non-aqueous solvent.

In some embodiments, a subject composition comprises about 5 to 7 weight percent urease and a non-aqueous solvent. In some embodiments, a subject composition comprises about 7 to 9 weight percent urease and a non-aqueous solvent. In certain embodiments, a subject composition comprises about 9 to 11 weight percent urease and a non-aqueous solvent. In certain embodiments, a subject composition comprises about 11 to 13 weight percent urease and a non-aqueous solvent. In certain embodiments, a subject composition comprises about 13 to 15 weight percent urease and a non-aqueous solvent. In certain embodiments, a subject composition comprises about 15 to 17 weight percent urease and a non-aqueous solvent. In certain embodiments, a subject composition comprises about 17 to 19 weight percent urease and a non-aqueous solvent. In certain embodiments, a subject composition comprises about 19 to 21 weight percent urease and a non-aqueous solvent. In certain embodiments, a subject composition comprises about 21 to 23 weight percent urease and a non-aqueous solvent. In certain embodiments, a subject composition comprises about 23 to 25 weight percent urease and a non-aqueous solvent.

In some embodiments, the first phase (eg, inner phase) of the subject composition comprises about 5 to 50% by weight of urease. In some embodiments, the first phase (e.g., inner phase) of the subject composition comprises about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, About 10% or more, about 11% or more, about 12% or more, about 13% or more, about 14% or more, about 15% or more, about 16% or more, about 17% or more, about 18 At least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26% or more, about 27% by weight or more, about 28% by weight or more, about 29% by weight or more, about 30% by weight or more, about 31% by weight or more, about 32% by weight or more, about 33% by weight or more, about 34% by weight or more, About 35% or more, about 36% or more, about 37% or more, about 38% or more, about 39% or more, about 40% or more, about 41% or more, about 42% or more, about 43 at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, or at least about 50% urease .

Cinnamic acid and its derivatives

In some embodiments, formulations of the present disclosure also include cinnamic acid and a source thereof, which are known to work synergistically with ascorbic acid to provide additional antioxidant protection to the skin. Cinnamic acids of interest and sources thereof include, but are not limited to, ferulic acid, caffeic acid, and coumaric acid. In some embodiments, the cinnamic acid is ferulic acid. The cinnamic acid component used in the subject formulation may be a combination of ferulic acid and/or substituted cinnamic acids. For example, cinnamic acid can be a combination of ferulic acid and caffeic acid.

In some embodiments, the subject composition comprises from about 0.1% to about 2% by weight (e.g., about 0.1%, about 0.5%, about 1%, about 1.5%, or about 2%) of cinnamic acid.

Formulations of the present disclosure include cinnamic acid and its derivatives (e.g., ferulic acid, caffeic acid, coumaric acid, cinapic acid, and other phenolic cinnamic acids), its cis and trans isomers, its salts, and its equivalents. .

In some embodiments, a composition of the present disclosure comprises at least 0.1% by weight of cinnamic acid or a derivative thereof. In some embodiments, the composition comprises 0.1% to 5.0% by weight of cinnamic acid or a derivative thereof. In some embodiments, the composition is at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, 1.0% 1.1% or more, 1.2% or more, 1.3% or more, 1.4% or more, 1.5% or more, 1.6% or more, 1.7% or more, 1.8% or more, 1.9% or more, or 2.0% or more % or more of cinnamic acid or its derivatives. In some embodiments, the composition comprises about 0.1 to 5.0% by weight of cinnamic acid or a derivative thereof (eg, 0.1% to 0.5%, 0.5% to 1.0%, 1.0% to 1.5%, 1.5% by weight to 2.0%, 2.0% to 2.5%, 2.5% to 3.0%, 3.0% to 3.5%, 3.5% to 4.0%, 4.0% to 4.5%, or 4.5% to 4.5%. 5.0% by weight of cinnamic acid or a derivative thereof).

Suitable cinnamic acids or derivatives thereof that may be used in the compositions of the present disclosure are found in US Pat. No. US6596761, incorporated herein by reference in its entirety.

The term "derivatives of caffeic acid, coumaric acid, ferulic acid" should be understood to mean those as described above for their cosmetically or pharmacologically acceptable esters, salts, and base adducts, especially cinnamic acid derivatives. do.

Ferulic acid and its derivatives

In some embodiments, the cinnamic acid derivative is ferulic acid. Ferulic acid is an antioxidant that increases the photoprotective effect of AA on the skin. The inventors have found that ferulic acid can stabilize and solubilize AA in non-aqueous systems. In some embodiments, a composition of the present disclosure includes ferulic acid and derivatives thereof. In some embodiments, ferulic acid is E-ferulic acid. In some embodiments, ferulic acid is Z-ferulic acid. In some embodiments, ferulic acid is a mixture of E-ferulic acid and Z-ferulic acid.

Ferulic acid can protect vitamin A and vitamin C when combined with vitamin C and/or vitamin A to improve the photoprotective action of these vitamins. In combination with vitamin C, ferulic acid helps to minimize the harmful effects (e.g., erythema or sunburn cell formation) caused by ultraviolet radiation by providing 2 to 4 times more photoprotection against ultraviolet radiation. can Ferulic acid can also improve the chemical stability of vitamin C and vitamin E, enhancing the synergistic and longer lasting photoprotective effect.

In some embodiments, ferulic acid is readily soluble in non-aqueous solvents. In some embodiments, the non-aqueous solvent is one or more of 1,3 propanediol, 1,2 propanediol, 1,3 butanediol, and dimethyl isosorbide. In some embodiments, isosorbide can increase the effectiveness of ferulic acid by enhancing skin penetration.

In some embodiments, a composition of the present disclosure comprises at least 0.1% by weight of ferulic acid or a derivative thereof. In some embodiments, the composition is at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, 1.0% 1.1% or more, 1.2% or more, 1.3% or more, 1.4% or more, 1.5% or more, 1.6% or more, 1.7% or more, 1.8% or more, 1.9% or more, or 2.0% or more % or more ferulic acid or its derivatives. In some embodiments, the composition comprises about 0.1 to 5.0% by weight of cinnamic acid or a derivative thereof (eg, 0.1% to 0.5%, 0.5% to 1.0%, 1.0% to 1.5%, 1.5% by weight to 2.0%, 2.0% to 2.5%, 2.5% to 3.0%, 3.0% to 3.5%, 3.5% to 4.0%, 4.0% to 4.5%, or 4.5% to 4.5%. 5.0% by weight of ferulic acid or a derivative thereof).

In certain embodiments, the composition contains 2% or less by weight ferulic acid, such as 1.5% or less, 1.0% or less (eg, about 1% by weight), or 0.5% or less (eg, about 0.5% by weight) ferrule. contains acid

In some embodiments, ferulic acid (e.g., 4-hydroxy-3-methoxy-cinnamic acid, caffeic acid 3-methyl ether) is characterized by the structure

Caffeic acid and its derivatives

In some embodiments, the cinnamic acid derivative is caffeic acid. Caffeic acid is an antioxidant that increases the photoprotective effect of AA on the skin. It can also stabilize AA in aqueous systems. In some embodiments, a composition of the present disclosure includes caffeic acid and its derivatives.

In some embodiments, caffeic acid is readily soluble in non-aqueous solvents. In some embodiments, the non-aqueous solvent is one or more of 1,3 propanediol, 1,2 propanediol, 1,3 butanediol, and dimethyl isosorbide. In some embodiments, isosorbide can increase the effectiveness of caffeic acid by enhancing skin penetration.

In some embodiments, a composition of the present disclosure comprises at least 0.1% by weight of caffeic acid or a derivative thereof. In some embodiments, the composition is at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, 1.0% 1.1% or more, 1.2% or more, 1.3% or more, 1.4% or more, 1.5% or more, 1.6% or more, 1.7% or more, 1.8% or more, 1.9% or more, or 2.0% or more % or more caffeic acid or a derivative thereof. In some embodiments, the composition comprises about 0.1 to 5.0% by weight of caffeic acid or a derivative thereof (eg, 0.1% to 0.5%, 0.5% to 1.0%, 1.0% to 1.5%, 1.5% by weight to 2.0%, 2.0% to 2.5%, 2.5% to 3.0%, 3.0% to 3.5%, 3.5% to 4.0%, 4.0% to 4.5%, or 4.5% to 4.5%. 5.0% by weight of caffeic acid or a derivative thereof).

In some embodiments, caffeic acid comprises the structure:

In some embodiments, the cinnamic acid derivative is a combination of ferulic acid and caffeic acid. In some embodiments, the cinnamic acid derivatives are trans-ferulic acid and caffeic acid.

Coumaric acid and its derivatives

In some embodiments, the cinnamic acid derivative is coumaric acid. Coumaric acid is an antioxidant that increases the photoprotective effect of AA on the skin. It can also stabilize AA in aqueous systems. In some embodiments, a composition of the present disclosure includes coumaric acid and derivatives thereof. In some embodiments, the coumaric acid includes p-coumaric acid.

In some embodiments, coumaric acid is readily soluble in non-aqueous solvents. In some embodiments, the non-aqueous solvent is one or more of 1,3 propanediol, 1,2 propanediol, 1,3-butanediol, and dimethyl isosorbide. In some embodiments, isosorbide can increase the effectiveness of coumaric acid by enhancing skin penetration.

In some embodiments, a composition of the present disclosure comprises at least 0.1% by weight of coumaric acid or a derivative thereof. In some embodiments, the composition is at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, 1.0% 1.1% or more, 1.2% or more, 1.3% or more, 1.4% or more, 1.5% or more, 1.6% or more, 1.7% or more, 1.8% or more, 1.9% or more, or 2.0% or more % or more of coumaric acid or a derivative thereof. In some embodiments, the composition comprises about 0.1 to 5.0% by weight of coumaric acid or a derivative thereof (eg, 0.1% to 0.5%, 0.5% to 1.0%, 1.0% to 1.5%, 1.5% by weight to 2.0%, 2.0% to 2.5%, 2.5% to 3.0%, 3.0% to 3.5%, 3.5% to 4.0%, 4.0% to 4.5%, or 4.5% to 4.5%. 5.0% by weight of coumaric acid or a derivative thereof).

Cinapic acid (eg hydroxycinnamic acid) and its derivatives

In some embodiments, the cinnamic acid derivative is cinapic acid or a derivative thereof. Cinapic acid is an antioxidant that increases the photoprotective effect of AA on the skin. It can also stabilize AA in aqueous systems. In some embodiments, a composition of the present disclosure includes sinapinic acid and derivatives thereof.

In some embodiments, sinapinic acid is readily soluble in non-aqueous solvents. In some embodiments, the non-aqueous solvent is one or more of 1,3 propanediol, 1,2 propanediol, 1,3 butanediol, and dimethyl isosorbide. In some embodiments, isosorbide can increase the effectiveness of sinapinic acid and its derivatives by enhancing skin penetration.

In some embodiments, a composition of the present disclosure comprises at least 0.1% by weight of cinapic acid or a derivative thereof. In some embodiments, the composition is at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, 1.0% 1.1% or more, 1.2% or more, 1.3% or more, 1.4% or more, 1.5% or more, 1.6% or more, 1.7% or more, 1.8% or more, 1.9% or more, or 2.0% or more % or more of cinapic acid or a derivative thereof. In some embodiments, the composition comprises about 0.1 to 5.0% by weight of cinapic acid or a derivative thereof (eg, 0.1% to 0.5%, 0.5% to 1.0%, 1.0% to 1.5%, 1.5% by weight to 2.0%, 2.0% to 2.5%, 2.5% to 3.0%, 3.0% to 3.5%, 3.5% to 4.0%, 4.0% to 4.5%, or 4.5% to 4.5%. 5.0% by weight of sinapinic acid or a derivative thereof).

In some embodiments, sinapinic acid has the general formula:

and/or an effective amount of a cinnamic acid derivative of the formula:

In the above formula, groups X, Y, R which may be independently selected from the group consisting of H and branched and unbranched alkyl having 1 to 18 C atoms, such as 1 to 6 C atoms, may be used.

chemical exfoliants

In some embodiments, formulations of the present disclosure include a chemical exfoliant. Chemical exfoliants are additives that can promote the shedding of the top layer of skin cells. Chemical exfoliants can be small organic molecules containing carboxylic acid groups and hydroxyl groups. The present disclosure provides a topical composition comprising a combination of ascorbic acid and urease and a chemical exfoliant dissolved in a non-aqueous solvent. The compositions of the present disclosure are liquid compositions that are stable to both the ascorbic acid component and the urea component.

In some embodiments, the chemical exfoliant is an alpha hydroxy acid or a beta hydroxy acid. The acid may be an alkyl carboxylic acid or a benzoic acid (eg, a hydroxy substituted benzoic acid). A hydroxyl group can be a phenol or an alkyl alcohol. In certain embodiments, the chemical exfoliant is an alpha-hydroxy carboxylic acid. In certain embodiments, the chemical exfoliant contains 2 to 12 carbon atoms, such as 2 to 6 or 2 to 4 carbons. Chemical exfoliants of interest include glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, phenol, gluconolactone, lactobionic acid, maltobionic acid, and combinations thereof, but Not limited. In some embodiments, the chemical exfoliant is salicylic acid.

In some embodiments, the amount of chemical exfoliant in the subject composition is 2% to 50% by weight of the chemical exfoliant, such as 2% to 3%, 3% to 4%, 4% to 5%, 2% to 5%, 5% to 10%, 5% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% % to 35%, 35% to 40%, 40% to 45%, or 45% to 50% chemical exfoliant. In some embodiments, the amount of chemical exfoliant in the subject composition ranges from 2% to 30% by weight.

In some embodiments, the amount of chemical exfoliant in a subject composition is at least about 2%, such as at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 12%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less, of a chemical exfoliant in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of chemical exfoliant in a subject composition is about 10% to about 20%, or about 12% to about 28%, such as about 15% to about 28%, or about 20% by weight. to about 28% by weight. In some embodiments, the amount of chemical exfoliant in the subject composition is about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% %, about 40%, about 45%, or about 50%.

In some embodiments, the chemical exfoliant is glycolic acid. In some embodiments, the amount of glycolic acid in the subject composition is 2% to 50% by weight of glycolic acid, such as 2% to 3%, 3% to 4%, 4% to 5%, 2% by weight % to 5 wt%, 5 wt% to 10 wt%, 5 wt% to 15 wt%, 15 wt% to 20 wt%, 20 wt% to 25 wt%, 25 wt% to 30 wt%, 30 wt% to 35 wt%, 35 wt% to 40 wt%, 40 wt% to 45 wt%, or 45 wt% to 50 wt% glycolic acid.

In some embodiments, the amount of glycolic acid in a subject composition is at least about 2% by weight, such as at least about 3% by weight, at least about 4% by weight, at least about 5% by weight, at least about 10% by weight, at least about 12% by weight, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less, of glycolic acid in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of glycolic acid in a subject composition is from about 10% to about 20%, or from about 12% to about 28%, such as from about 15% to about 28%, or from about 20% to It is about 28% by weight. In some embodiments, the amount of glycolic acid in the subject composition is about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% by weight %, about 40%, about 45%, or about 50%.

In some embodiments, the chemical exfoliant is lactic acid. In some embodiments, the amount of lactic acid in the subject composition is between 2% and 50% by weight of lactic acid, such as between 2% and 3%, 3% and 4%, 4% and 5%, 2% and 2%. 5 wt%, 5 wt% to 10 wt%, 5 wt% to 15 wt%, 15 wt% to 20 wt%, 20 wt% to 25 wt%, 25 wt% to 30 wt%, 30 wt% to 35 wt% %, 35% to 40%, 40% to 45%, or 45% to 50% lactic acid.

In some embodiments, the amount of lactic acid in a subject composition is at least about 2% by weight, such as at least about 3% by weight, at least about 4% by weight, at least about 5% by weight, at least about 10% by weight, at least about 12% by weight, at least about 15 wt%, at least about 20 wt%, at least about 25 wt%, at least about 30 wt%, at least about 35 wt%, at least about 40 wt%, at least about 45 wt%, or at least about 50 wt%. In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less of lactic acid in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of lactic acid in a subject composition is from about 10% to about 20%, or from about 12% to about 28%, such as from about 15% to about 28%, or from about 20% to about 28% by weight. In some embodiments, the amount of lactic acid in the subject composition is about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% by weight. , about 40%, about 45%, or about 50% by weight.

In some embodiments, the chemical exfoliant is mandelic acid. In some embodiments, the amount of mandelic acid in a subject composition is between 2% and 50% by weight of lactic acid, such as between 2% and 3%, 3% and 4%, 4% and 5%, 2% by weight. to 5% by weight, 5% to 10% by weight, 5% to 15% by weight, 15% to 20% by weight, 20% to 25% by weight, 25% to 30% by weight, 30% to 35% by weight %, 35% to 40%, 40% to 45%, or 45% to 50% mandelic acid.

In some embodiments, the amount of mandelic acid in a subject composition is at least about 2% by weight, such as at least about 3% by weight, at least about 4% by weight, at least about 5% by weight, at least about 10% by weight, at least about 12% by weight, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less, of mandelic acid in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of mandelic acid in a subject composition is from about 10% to about 20%, or from about 12% to about 28%, such as from about 15% to about 28%, or from about 20% to about 20% by weight. It is about 28% by weight. In some embodiments, the amount of mandelic acid in the subject composition is about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% by weight %, about 40%, about 45%, or about 50%.

In some embodiments, the chemical exfoliant is salicylic acid. In some embodiments, the amount of salicylic acid in the subject composition is between 2% and 50% salicylic acid by weight, such as between 2% and 3%, 3% and 4%, 4% and 5%, 2% and 2% by weight. 5 wt%, 5 wt% to 10 wt%, 5 wt% to 15 wt%, 15 wt% to 20 wt%, 20 wt% to 25 wt%, 25 wt% to 30 wt%, 30 wt% to 35 wt% %, 35% to 40%, 40% to 45%, or 45% to 50% salicylic acid.

In some embodiments, the amount of salicylic acid in a subject composition is at least about 2% by weight, such as at least about 3% by weight, at least about 4% by weight, at least about 5% by weight, at least about 10% by weight, at least about 12% by weight, at least about 15 wt%, at least about 20 wt%, at least about 25 wt%, at least about 30 wt%, at least about 35 wt%, at least about 40 wt%, at least about 45 wt%, or at least about 50 wt%. In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less, of salicylic acid in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of salicylic acid in a subject composition is from about 10% to about 20%, or from about 12% to about 28%, such as from about 15% to about 28%, or from about 20% to about 28% by weight. In some embodiments, the amount of salicylic acid in the subject composition is about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% by weight. , about 40%, about 45%, or about 50% by weight.

In some embodiments, the chemical exfoliant is capryloyl salicylic acid. In some embodiments, the amount of capryloyl salicylic acid in the subject composition is 2% to 50% salicylic acid by weight, such as 2% to 3%, 3% to 4%, 4% to 5%, 2% by weight 5 wt% to 5 wt%, 5 wt% to 10 wt%, 5 wt% to 15 wt%, 15 wt% to 20 wt%, 20 wt% to 25 wt%, 25 wt% to 30 wt%, 30 wt% to 35%, 35% to 40%, 40% to 45%, or 45% to 50% capryloyl salicylic acid.

In some embodiments, the amount of capryloyl salicylic acid in a subject composition is at least about 2% by weight, such as at least about 3% by weight, at least about 4% by weight, at least about 5% by weight, at least about 10% by weight, at least about 12% by weight , at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% . In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less, of capryloyl salicylic acid in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of caproloyl salicylic acid in a subject composition is about 10% to about 20%, or about 12% to about 28%, such as about 15% to about 28%, or about 20% by weight. % to about 28% by weight. In some embodiments, the amount of capryloyl salicylic acid in the subject composition is about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight.

In some embodiments, the chemical exfoliant is salicyloyl phytosphingosine. In some embodiments, the amount of salicyloyl phytosphingosine in a subject composition is 2% to 50% by weight of phytosphingosine salicylate, such as 2% to 3%, 3% to 4%, 4% to 4% by weight. 5 wt%, 2 wt% to 5 wt%, 5 wt% to 10 wt%, 5 wt% to 15 wt%, 15 wt% to 20 wt%, 20 wt% to 25 wt%, 25 wt% to 30 wt% %, 30% to 35%, 35% to 40%, 40% to 45%, or 45% to 50% salicyloyl phytosphingosine.

In some embodiments, the amount of salicyloyl phytosphingosine in a subject composition is at least about 2% by weight, such as at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 12% by weight wt%, at least about 15 wt%, at least about 20 wt%, at least about 25 wt%, at least about 30 wt%, at least about 35 wt%, at least about 40 wt%, at least about 45 wt%, or at least about 50 wt% %to be. In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less, of salicyloyl phytosphingosine in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of salicyloyl phytosphingosine in a subject composition is about 10% to about 20% by weight, or about 12% to about 28% by weight, such as about 15% to about 28% by weight, or about 20% to about 28% by weight. In some embodiments, the amount of salicyloyl phytosphingosine in the subject composition is about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30% by weight. , about 35%, about 40%, about 45%, or about 50% by weight.

In some embodiments, the chemical exfoliant is phenol. In some embodiments, the amount of phenol in the subject composition is from 2% to 50% by weight of salicylic acid, such as from 2% to 3%, 3% to 4%, 4% to 5%, 2% to 2% by weight. 5 wt%, 5 wt% to 10 wt%, 5 wt% to 15 wt%, 15 wt% to 20 wt%, 20 wt% to 25 wt%, 25 wt% to 30 wt%, 30 wt% to 35 wt% %, 35% to 40%, 40% to 45%, or 45% to 50% phenol.

In some embodiments, the amount of phenol in the subject composition is at least about 2%, such as at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 12%, at least about 15 wt%, at least about 20 wt%, at least about 25 wt%, at least about 30 wt%, at least about 35 wt%, at least about 40 wt%, at least about 45 wt%, or at least about 50 wt%. In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less of phenol in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of phenol in a subject composition is from about 10% to about 20%, or from about 12% to about 28%, such as from about 15% to about 28%, or from about 20% to about 28% by weight. In some embodiments, the amount of phenol in the subject composition is about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% , about 40%, about 45%, or about 50% by weight.

In some embodiments, the chemical exfoliant is gluconolactone. In some embodiments, the amount of gluconolactone in a subject composition is 2% to 50% by weight of gluconolactone, such as 2% to 3%, 3% to 4%, 4% to 5%, 2% to 5%, 5% to 10%, 5% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% % to 35%, 35% to 40%, 40% to 45%, or 45% to 50% gluconolactone.

In some embodiments, the amount of gluconolactone in a subject composition is at least about 2%, such as at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 12%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less of gluconolactone in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of gluconolactone in a subject composition is about 10% to about 20%, or about 12% to about 28%, such as about 15% to about 28%, or about 20% by weight. to about 28% by weight. In some embodiments, the amount of gluconolactone in a subject composition is about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% %, about 40%, about 45%, or about 50%.

In some embodiments, the chemical exfoliant is lactobionic acid. In some embodiments, the amount of lactobionic acid in a subject composition is 2% to 50% by weight of lactobionic acid, such as 2% to 3%, 3% to 4%, 4% to 5%, 2% to 5%, 5% to 10%, 5% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% % to 35%, 35% to 40%, 40% to 45%, or 45% to 50% lactobionic acid.

In some embodiments, the amount of lactobionic acid in a subject composition is at least about 2%, such as at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 12%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less of lactobionic acid in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of lactobionic acid in a subject composition is about 10% to about 20%, or about 12% to about 28%, such as about 15% to about 28%, or about 20% by weight. to about 28% by weight. In some embodiments, the amount of lactobionic acid in the subject composition is about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% %, about 40%, about 45%, or about 50%.

In some embodiments, the chemical exfoliant is maltobionic acid. In some embodiments, the amount of maltobionic acid in a subject composition is 2% to 50% by weight of maltobionic acid, such as 2% to 3%, 3% to 4%, 4% to 5%, 2% to 5%, 5% to 10%, 5% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% % to 35%, 35% to 40%, 40% to 45%, or 45% to 50% maltobionic acid.

In some embodiments, the amount of maltobionic acid in a subject composition is at least about 2%, such as at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 12%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less of maltobionic acid in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of maltobionic acid in a subject composition is from about 10% to about 20%, or from about 12% to about 28%, such as from about 15% to about 28%, or about 20% by weight. to about 28% by weight. In some embodiments, the amount of maltobionic acid in the subject composition is about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% %, about 40%, about 45%, or about 50%.

In some embodiments, the chemical exfoliant is a combination of two or more of glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, phenol, gluconolactone, lactobionic acid, and maltobionic acid. . In some embodiments, the amount of two or more of glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, phenol, gluconolactone, lactobionic acid, and maltobionic acid in a subject composition is 2 weight % to 50% by weight of at least two of glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, phenol, gluconolactone, lactobionic acid, and maltobionic acid, such as 2% by weight to 3% by weight, 3% to 4% by weight, 4% to 5% by weight, 2% to 5% by weight, 5% to 10% by weight, 5% to 15% by weight, 15% to 20% by weight 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, or 45% to 50% by weight % of glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, phenol, gluconolactone, lactobionic acid, and maltobionic acid.

In some embodiments, the amount of two or more of glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, phenol, gluconolactone, lactobionic acid, and maltobionic acid in a subject composition is at least about 2 wt%, such as at least about 3 wt%, at least about 4 wt%, at least about 5 wt%, at least about 10 wt%, at least about 12 wt%, at least about 15 wt%, at least about 20 wt%, at least about 25 wt% %, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In some embodiments, the subject composition comprises about 2% by weight or less, such as about 25% by weight or less glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, phenol in a non-aqueous solvent solution. , gluconolactone, lactobionic acid, and maltobionic acid. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of two or more of glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, phenol, gluconolactone, lactobionic acid, and maltobionic acid in a subject composition is about 10 wt% to about 20 wt%, or about 12 wt% to about 28 wt%, such as about 15 wt% to about 28 wt%, or about 20 wt% to about 28 wt%. In some embodiments, the amount of two or more of glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, phenol, gluconolactone, lactobionic acid, and maltobionic acid in a subject composition is about 2 About 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight.

azelaic acid

The present disclosure together provides a formulation comprising a combination of certain amounts of urea in a non-aqueous skin compatible solvent that is capable of providing dissolution of a certain amount of azelaic acid, wherein the azelaic acid results in a skin compatible liquid composition that is substantially stable to degradation. provides In some embodiments, the amount of azelaic acid that is stably dissolved in the composition is greater than would be possible without the particular combination of ingredients provided by the present disclosure.

The terms “azelaic acid” and “nonandioic acid” refer to naturally occurring dicarboxylic acids of CAS registry number 123-99-9. Any conventional form of azelaic acid can be used in the subject formulations. In some embodiments, the azelaic acid used in the formulations of the present disclosure is a powder.

In certain embodiments, the azelaic acid material used to prepare the subject composition consists of granular particles. Such particulate powders have a particle size (eg average particle size) of less than about 25 microns, such as less than about 20 microns and more preferably less than about 12.5 microns, for example measured by the Hagman Gauge. In some embodiments, all azelaic acid powders used to prepare subject compositions can pass through standard test procedures used by the US Pharmacopoeia, number 100 US standard sieve. In some embodiments, at least 80% (eg, at least 90% or 100%) of azelaic acid powder used to prepare a subject composition can be passed through a No. 325 US Standard sieve.

In some embodiments, the amount of azelaic acid in a subject composition is at least 1 wt%, at least 2 wt%, at least 4 wt%, or at least about 5 wt%, such as at least about 10 wt%, at least about 12 wt%, at least about 15 wt% %, at least about 20%, or at least about 25%. In some embodiments, the subject composition comprises about 28% by weight or less, such as about 25% by weight or less of azelaic acid in a non-aqueous solvent solution. In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of azelaic acid in a subject composition is from about 1% to about 12%, or from about 4% to about 8%, or from about 8% to about 12% by weight. In some embodiments, the amount of azelaic acid in the subject composition is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8% by weight %, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18% %, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%.

In certain embodiments, the amount of azelaic acid in a subject composition is from about 1% to about 20% by weight (e.g., about 1%, about 5%, about 10%, about 15%, or about 20%), and urease The ratio of azelaic acid to (weight % ratio) is from 0.8 to 9, such as a ratio of 2 (i.e., 2:1). In some embodiments, the ratio of azelaic acid to urease (wt % ratio) is 0.5 to 9.5, such as 0.5 to 4.5, 0.8 to 1.2, 1.2 to 1.6, 1.4 to 2.0, 2.0 to 2.4, 2.4 to 2.8, 2.8 to 3.2 , 3.2 to 3.6, 3.6 to 4.0, 4.0 to 4.4, 4.4 to 4.8, 4.8 to 5.2, 5.2 to 5.6, 5.6 to 6.0, 6.0 to 6.4, 6.4 to 6.8, 6.8 to 7.2, 7.2 to 7.6, 7.6 to 8.0, 8.0 to 8.4, 8.4 to 8.8, 8.8 to 9.2, or 9.2 to 9.5.

In certain embodiments, the amount of azelaic acid in a subject composition is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8% by weight %, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18% %, about 19% by weight, about 20% by weight, and the ratio of azelaic acid to urease (wt% ratio) is 1.0 (i.e., 1:1) or more, 1.25 or more, 1.50 or more, 1.75 or more, 2.0 or more, 2.5 or more , 3.0 or more, 3.25 or more, 3.50 or more, 3.75 or more, 4.0 or more, 4.25 or more, 4.50 or more, 4.75 or more, 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more.

Generally, the amount of azelaic acid in a composition is calculated for a solution phase based on a non-aqueous solvent. See formulations in Tables 11-16. However, the amount of azelaic acid and other components relative to the emulsion composition as a whole can be easily calculated by one skilled in the art. The formulations in Tables 11-16 represent exemplary emulsion compositions, where the weight percentage values presented are relative to the total emulsion composition. In some cases, these concentrate solutions having certain amounts of azelaic acid can be combined with immiscible ingredients (eg, oil ingredients) and emulsifiers to create emulsion compositions (eg, as described below). It is understood that

In some embodiments, the amount of azelaic acid in a subject composition is at least 1%, 2%, 3%, or about 4%, such as at least about 6%, at least about 8%, at least about 10%, or at least about 12% by weight. In certain embodiments, the non-aqueous solvent is 1,3-propanediol.

In some cases, these concentrate solutions with certain amounts of azelaic acid can be combined with immiscible ingredients (eg, oil components) and emulsifiers to create emulsion compositions (eg, as described herein). is understood to be

sugar alcohol agent

In some embodiments, formulations of the present disclosure include a sugar alcohol agent in an amount sufficient to enhance the solubility of ascorbic acid in non-aqueous skin compatible solvents and provide a stable solution. The inventors have discovered that a certain amount of sugar alcohol agent can be added to a non-aqueous solvent to increase the maximum amount of ascorbic acid that can be dissolved without recrystallization. Additionally, these formulations provide a stabilized ascorbic acid solution at various desired concentration levels.

Sugar alcohol refers to an additive comprising a sugar alcohol or a sugar alcohol derivative, ie, a sugar alcohol linked to a sugar through one of its alcohol groups (eg, through an ether linkage). In some embodiments, the sugar alcohol is an acyclic C4 to C6 polyalcohol compound, for example, with the formula HOCH ₂ (CHOH) _n CH ₂ OH, where n is 2 to 4. In some embodiments, the sugar alcohol agent comprises a C4 to C6 sugar alcohol, for example a C5 to C6 sugar alcohol. In some embodiments, the sugar alcohol is a C4 to C6 sugar alcohol, such as a C5 to C6 sugar alcohol.

A sugar alcohol derivative refers to a compound comprising a sugar alcohol linked to a second moiety. In some embodiments, sugar alcohol derivatives include those wherein the sugar alcohol is linked (eg, via an ether linkage) to a sugar (eg, monosaccharide or disaccharide) through one of its alcohol groups. Sugar alcohol derivatives of interest include, but are not limited to, xylitylglucoside, anhydroxylitol, and the like.

Sugar alcohols of interest include xylitol and xylitol derivatives such as xylitylglucoside and anhydroxylitol; sorbitol; lactitol; mantitol; erythritol; and mannitol, but is not limited thereto. In certain embodiments, the sugar alcohol agent is xylitol. The sugar alcohol component used in the subject formulation may be a combination of sugar alcohols. For example, the sugar alcohol agent can be a combination of xylitol and erythritol. In the non-skincare industry, xylitol can be used to reduce or eliminate the growth of bacteria such as staphylococci. For example, xylitol is known to prevent demineralization of teeth and bones, otitis media infections, airway infections, inflammation, and cancer progression.

Causes that lead to microbiome growth on the skin include pH, moisture, pores, and nutrients in the skin that promote bacterial growth, such as sweat. The present inventors found that xylitol inhibits pathogenic bacteria such as Staphylococcus aureus found on the skin and regulates the skin-microflora balance due to its selective effect, while providing protection against the growth of pathogenic bacteria. (SE) can be used in topical compositions of the present disclosure to maintain the integrity of healthy skin microflora. In addition, the combination of ascorbic acid and xylitol regulates the pH of the skin and increases hydration, thereby reducing the amount of harmful pathogenic microorganisms present on the skin's surface.

In some embodiments, the weight percent amount of sugar alcohol agent in a composition of the present disclosure is an amount sufficient to solubilize ascorbic acid in a non-aqueous solvent. In some embodiments, the amount of sugar alcohol agent in a composition of the present disclosure is defined as a function of the concentration of ascorbic acid ([AA]). For concentrations of AA that alone exceed the maximum solubility of ascorbic acid ([Xs]) in unadulterated non-aqueous solvents, as a first step, [Xs] is subtracted from the desired concentration of AA in the concentrate solution. Thus, ([Xs]) is the maximum concentration of ascorbic acid that can be dissolved in an undissolved non-aqueous solvent. As a second step, the difference from the first step is multiplied by (Y). The minimum amount (wt %) (S) of a sugar alcohol included in a non-aqueous solvent based composition can be calculated by the equation:

([AA] - [Xs])* (Y).

In some embodiments, (Y) is 0.5 ± 0.2. In some embodiments, (Y) is 1.0 ± 0.5. In some embodiments, (Y) is 1.5 ± 0.5. In some embodiments, (Y) is 2.0 ± 0.5. In some embodiments, (Y) is 2.5 ± 0.5. In some embodiments, (Y) is 3.0 ± 0.5. In some embodiments, (Y) is 4.0 ± 0.5. In some embodiments, (Y) is 4.5 ± 0.5. In some embodiments, (Y) is 5.0 ± 0.5. In some embodiments, (Y) is 5.5 ± 0.5. In some embodiments, (Y) is 5.5 ± 0.5. In some embodiments, (Y) is 6.0 ± 0.5. In some embodiments, (Y) is 6.5 ± 0.5. In some embodiments, (Y) is 7 ± 0.5. In some embodiments, (Y) is 7.5 ± 0.5. In some embodiments, (Y) is 8.0 ± 0.5. In some embodiments, (Y) is 8.5 ± 0.5. In some embodiments, (Y) is 9.0 ± 0.5. In some embodiments, (Y) is 9.5 ± 0.5. In some embodiments, (Y) is 10.0 ± 0.5. In some embodiments, (Y) is 1.0 or greater, such as 1.5 or greater, 2.0 or greater, 2.5 or greater, 3.0 or greater, 3.5 or greater, 4.0 or greater, 4.5 or greater, 5.0 or greater. 5.5 or more, 6.0 or more, 6.5 or more, 7.0 or more, 7.5 or more, 8.0 or more, 8.5 or more, 9.0 or more, 9.5 or more, or 10.0 or more.

In some embodiments, the sugar alcohol is dissolved at a concentration that is at least ([AA]-[Xs])*(1.25) or greater, where [AA] is the concentration of ascorbic acid in weight percent and [Xs] is nothing Maximum solubility (% by weight) of ascorbic acid in unmixed non-aqueous solvent.

In some embodiments, the sugar alcohol is dissolved at a concentration that is at least ([AA]-[Xs])*(1.50) or greater, where [AA] is the concentration of ascorbic acid in weight percent and [Xs] is nothing Maximum solubility (% by weight) of ascorbic acid in unmixed non-aqueous solvent.

In some embodiments, the amount of sugar alcohol agent in the subject composition is at least about 5% by weight, such as at least about 6% by weight, at least about 7% by weight, at least 8% by weight, at least about 9% by weight, at least about 10% by weight, at least About 11%, at least about 12%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20% %, at least about 21%, at least about 22%, at least about 23%, at least about 24%, or at least about 25%. In some embodiments, the subject composition comprises about 28% or less, such as about 25% or less, by weight sugar alcohol agent in a non-aqueous solvent solution.

In certain embodiments, the non-aqueous solvent is 1,3-propanediol. In certain embodiments, the amount of sugar alcohol agent in a subject composition is about 10% to about 20%, or about 12% to about 28%, such as about 15% to about 28%, or about 20% by weight. to about 28% by weight. In some embodiments, the amount of sugar alcohol agent in the subject composition is about 5%, about 10%, about 15%, about 20%, or about 25% by weight.

In some embodiments, the subject composition is about 1 to 30% by weight (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8% , about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%) sugar alcohols and non-aqueous solvents include In some embodiments, the subject composition comprises 5 to 10 weight percent, about 10 to 15 weight percent, or about 15 to 20 weight percent sugar alcohol agent. In certain embodiments, the subject composition comprises about 5% by weight sugar alcohol and non-aqueous solvent. In certain embodiments, the subject composition comprises about 15% by weight sugar alcohol and non-aqueous solvent. In certain embodiments, the subject composition comprises about 20% by weight sugar alcohol and non-aqueous solvent.

In some embodiments, the subject composition comprises about 5 to 7 weight percent sugar alcohol and non-aqueous solvent. In some embodiments, the subject composition comprises about 7 to 9 weight percent sugar alcohol and non-aqueous solvent. In certain embodiments, the subject composition comprises about 9 to 11 weight percent sugar alcohol and non-aqueous solvent. In certain embodiments, the subject composition comprises about 11 to 13 weight percent sugar alcohol and non-aqueous solvent. In certain embodiments, the subject composition comprises about 13 to 15 weight percent sugar alcohol and non-aqueous solvent. In certain embodiments, the subject composition comprises about 15 to 17 weight percent sugar alcohol and non-aqueous solvent. In certain embodiments, the subject composition comprises about 17 to 19 weight percent sugar alcohol and non-aqueous solvent. In certain embodiments, the subject composition comprises about 19 to 21 weight percent sugar alcohol and non-aqueous solvent. In certain embodiments, the subject composition comprises about 21 to 23 weight percent sugar alcohol and non-aqueous solvent. In certain embodiments, the subject composition comprises about 23 to 25 weight percent sugar alcohol and non-aqueous solvent.

In some embodiments, the sugar alcohol is xylitylglucoside. In some embodiments, the amount of xylitylglucoside in a subject composition is at least about 5%, such as at least about 6%, at least about 7%, at least 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, or at least about 25%. In some embodiments, the subject composition comprises about 28% or less by weight of xylitylglucoside, such as about 25% by weight or less, in a non-aqueous solvent solution.

In some embodiments, the sugar alcohol is anhydroxylitol. In some embodiments, the amount of anhydroxylitol in a subject composition is at least about 5% by weight, such as at least about 6% by weight, at least about 7% by weight, at least 8% by weight, at least about 9% by weight, at least about 10% by weight, at least About 11%, at least about 12%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20% %, at least about 21%, at least about 22%, at least about 23%, at least about 24%, or at least about 25%. In some embodiments, the subject composition comprises about 28% by weight or less, such as about 25% by weight or less of anhydroxylitol in a non-aqueous solvent solution.

In some embodiments, the sugar alcohol is sorbitol. In some embodiments, the amount of sorbitol in a subject composition is at least about 5% by weight, such as at least about 6% by weight, at least about 7% by weight, at least 8% by weight, at least about 9% by weight, at least about 10% by weight, at least about 11% by weight at least about 12%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20% , at least about 21%, at least about 22%, at least about 23%, at least about 24%, or at least about 25%. In some embodiments, the subject composition comprises about 28% by weight or less, such as about 25% by weight or less of sorbitol in a non-aqueous solvent solution.

In some embodiments, the sugar alcohol is lactitol. In some embodiments, the amount of lactitol in a subject composition is at least about 5%, such as at least about 6%, at least about 7%, at least 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20% %, at least about 21%, at least about 22%, at least about 23%, at least about 24%, or at least about 25%. In some embodiments, the subject composition comprises about 28% by weight or less, such as about 25% by weight or less of lactitol in a non-aqueous solvent solution.

In some embodiments, the sugar alcohol is maltitol. In some embodiments, the amount of maltitol in a subject composition is at least about 5% by weight, such as at least about 6% by weight, at least about 7% by weight, at least 8% by weight, at least about 9% by weight, at least about 10% by weight, at least about 11% by weight at least about 12%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20% , at least about 21%, at least about 22%, at least about 23%, at least about 24%, or at least about 25%. In some embodiments, the subject composition comprises about 28% or less, such as about 25% or less, by weight of maltitol in a non-aqueous solvent solution.

In some embodiments, the sugar alcohol is erythritol. In some embodiments, the amount of erythritol in a subject composition is at least about 5% by weight, such as at least about 6% by weight, at least about 7% by weight, at least 8% by weight, at least about 9% by weight, at least about 10% by weight, at least about 11% by weight. at least about 12%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20% , at least about 21%, at least about 22%, at least about 23%, at least about 24%, or at least about 25%. In some embodiments, the subject composition comprises about 28% by weight or less, such as about 25% by weight or less of erythritol in a non-aqueous solvent solution.

In some embodiments, the sugar alcohol is mannitol. In some embodiments, the amount of mannitol in a subject composition is at least about 5% by weight, such as at least about 6% by weight, at least about 7% by weight, at least 8% by weight, at least about 9% by weight, at least about 10% by weight, at least about 11% by weight at least about 12%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20% , at least about 21%, at least about 22%, at least about 23%, at least about 24%, or at least about 25%. In some embodiments, the subject composition comprises about 28% by weight or less, such as about 25% by weight or less of mannitol in a non-aqueous solvent solution.

In some embodiments, the sugar alcohol is a combination of xylitol and erythritol. In some embodiments, the amount of the combination of xylitol and erythritol in the subject composition is at least about 5%, such as at least about 6%, at least about 7%, at least 8%, at least about 9%, at least about 10% by weight. , at least about 11%, at least about 12%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, or at least about 25%. In some embodiments, the subject composition comprises about 28% by weight or less, such as about 25% by weight or less of a combination of xylitol and erythritol in a non-aqueous solvent solution.

Non-aqueous skin compatible solvent

In addition to urease and cinnamic acid (eg, as described herein), the high potency vitamin C formulations of the present disclosure contain as essential ingredients at least one non-aqueous skin compatible solvent. A skin compatible solvent is a solvent that does not cause irritation or sensitization when applied topically to the skin. Non-aqueous skin compatible solvents of interest include polyols, C(1-6) alkanediols, glycol ethers, dimethyl ethers, and combinations thereof.

In some embodiments, the solvent is a skin compatible polyol. Polyols are organic alcohol solvents with two or more hydroxyl groups. In some embodiments, the polyol solvent is a C(3-6)polyol. In some embodiments, the polyol solvent is a polyether polyol. In some embodiments, the polyol solvent is a polyester polyol. Skin compatible polyols of interest include glycerol (1,2,3-propanetriol); diglycerol; propylene glycol (1,2-propanediol); dipropylene glycol; 1,3-propanediol; butylene glycol (1,3-butanediol); 1,2-butanediol; pentylene glycol (1,2-pentanediol); 1,5-pentanediol; 1,2-hexanediol; 1,6-hexanediol; 1,2,3-hexanetriol, 1,2,6-hexanetriol; ethoxydiglycol; and dimethyl isosorbide, but is not limited thereto. In some embodiments, the solvent is a glycol ether, dimethyl ether, or a combination thereof. A preferred skin compatible solvent is 1,3-propanediol commercially available from DuPont Tate & Lyle BioProducts LLC under the tradename ZEMEA®. In some embodiments, the solvent is a mixture of 1,3 propanediol and 1,2 hexanediol.

In some embodiments, the solvent is a skin compatible polyol. Polyols are organic alcohol solvents with two or more hydroxyl groups. In some embodiments, the polyol solvent is a C(3-612)polyol, such as a C(3-6)polyol. In some embodiments, the polyol solvent is a C(2-6) alkanediol. In some embodiments, the polyol solvent is a polyether polyol. In some embodiments, the polyol solvent is a polyester polyol. Skin compatible polyols of interest include glycerol (1,2,3-propanetriol); diglycerol; propylene glycol (1,2-propanediol); dipropylene glycol; 1,3-propanediol; butylene glycol (1,3-butanediol); 1,2-butanediol; pentylene glycol (1,2-pentanediol); 1,5-pentanediol; 1,2-hexanediol; 1,6-hexanediol; 1,2,3-hexanetriol, 1,2,6-hexanetriol; ethoxydiglycol; and dimethyl isosorbide, but is not limited thereto. In some embodiments, the solvent is a glycol ether, dimethyl ether, or a combination thereof. A preferred skin compatible solvent is 1,3-propanediol commercially available from DuPont Tate & Lyle BioProducts LLC under the tradename ZEMEA®. In some embodiments, the solvent is a mixture of 1,3 propanediol and 1,2 hexanediol. In some embodiments, a subject composition comprises about 1 to 20 weight percent urease, about 1 to 20 weight percent azelaic acid, and 1,3-propanediol.

In some embodiments, the subject composition is about 10 to 80% by weight (e.g., about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%) of the non-aqueous skin Contains a compatible solvent. In some embodiments, the subject composition comprises about 1 to 25% by weight of azelaic acid (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, About 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20 %, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%); About 1 to 25% by weight of urease (about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23% , about 24%, or about 25%); and/or about 1 to 28% by weight of an ascorbic acid agent (about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, About 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, or about 28%); and 10 to 80% by weight of a polyol. In some embodiments, a subject composition comprises 5 to 10%, about 10 to 15%, about 15 to 20%, about 20 to 25%, or about 25 to 30% by weight of azelaic acid (e.g., About 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13 %, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%); About 1 to 5%, about 5 to 10%, about 10 to 15%, or about 15 to 20% by weight of urease (e.g., about 1%, about 2%, about 3%, about 4% , about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29% , or about 30%); and/or about 1 to 28% by weight of an ascorbic acid agent (about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22% , about 23%, about 24%, about 25%, about 26%, about 27%, or about 28%); and polyols. In certain embodiments, the subject composition comprises about 5 weight percent urease and 10 to 80 weight percent polyol.

In some embodiments, the subject composition comprises about 5 to 30% by weight of azelaic acid (e.g., about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, About 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24 %, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%); About 5 to 30% by weight of urease (e.g., about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26% , about 27%, about 28%, about 29%, or about 30%); and/or about 5 to 30% by weight of ascorbic acid (e.g., about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25% , about 26%, about 27%, about 28%, about 29%, or about 30%); and a non-aqueous solvent selected from the group consisting of C(1-6) alkanediols, glycol ethers, dimethyl ethers, or combinations thereof. In some embodiments, the skin compatible non-aqueous solvent is a combination of propanediol and dimethyl ether. In some embodiments, the skin compatible non-aqueous solvent is a combination of propanediol and hexanediol.

In some embodiments, the ratio of azelaic acid to urea in the liquid composition is between 1.5 and 3.0. In some embodiments, the ratio of azelaic acid to urea in the liquid composition is between 2.0 and 3.0. In some embodiments, the ratio of azelaic acid to urea in the liquid composition is between 2.0 and 2.5. In some embodiments, the ratio of azelaic acid to urea in the liquid composition is between 2.0 and 2.5, and the weight percent of azelaic acid dissolved in a solvent component composed of one or more C(2-6) alkanediols is greater than or equal to 8%, such as 10 % or more (eg, 10% to 15%, or 10% to 12% azelaic acid). In some embodiments, the solvent component is 1,3-propanediol or a mixture of 1,3 propanediol and 1,2 hexanediol. In some embodiments, the ratio of azelaic acid to urea in the liquid composition is 2.0.

In some embodiments, the ratio of ascorbic acid to urea in the liquid composition is between 1.5 and 3.0. In some embodiments, the ratio of ascorbic acid to urea in the liquid composition is between 2.0 and 3.0. In some embodiments, the ratio of ascorbic acid to urea in the liquid composition is between 2.0 and 2.5. In some embodiments, the ratio of ascorbic acid to urea in the liquid composition is from 2.0 to 2.5, and the weight percent of azelaic acid dissolved in the solvent component consisting of one or more C(2-6) alkanediols is greater than or equal to 8%, such as 10%. % or more (eg, 10% to 15%, or 10% to 12% azelaic acid). In some embodiments, the solvent component is 1,3-propanediol or a mixture of 1,3 propanediol and 1,2 hexanediol. In some embodiments, the ratio of azelaic acid to urea in the liquid composition is 2.0.

Additional Ingredients

The formulation may contain one or more (optional) additional ingredients. Any conventional ingredient known in the art to provide cosmetic/aesthetic benefits may be used in the subject formulation. These cosmetic/aesthetic benefits include reducing the appearance of fine lines/wrinkles, improving skin barrier function (by reducing the rate/degree of transepidermal water loss), making skin feel smoother/more elastic/more supple, but is not limited to producing the appearance of a more uniform skin tone (reducing chromatic aberration) and/or "glow"/radiance (also described in the art as "brightness"). .

In some embodiments, the composition further comprises one or more optional additional ingredients (eg, as described herein). In some embodiments, the one or more optional additional ingredients are tocopherols, tocotrienols (e.g., alpha, beta, delta, and gamma tocopherols or alpha, beta, delta, and gamma tocotrienols), azelaic acid, hydroxy acids (e.g., , salicylic acid), panthenol, pinus pinaster bark extract, emulsifier, hyaluronic acid complex, madecassoside, acetyl gingerone, bakuchiol, and bis ethylhexyl hydroxydimethoxy benzylmalonate do.

In some embodiments, the optional additional ingredient is salicylic acid. In some embodiments, the amount of salicylic acid in the subject composition is between 0.1% and 5% salicylic acid by weight, such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2% to 3%, 3% to 4%, 4% to 5%, 2% to 5% salicylic acid.

Each optional additional component (e.g., as described herein) is present in an amount of 10% or less, such as 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, by weight of the composition. 4 wt% or less, 3 wt% or less, 2 wt% or less, 1 wt% or less. In some embodiments, the total amount of one or more optional additional components (eg, as described herein) in the composition is 10% or less, such as 9% or less, 8% or less, 7% or less, 6% or less by weight. Below, 5% by weight or less, 4% by weight or less, 3% by weight or less, 2% by weight or less, and 1% by weight or less.

In some embodiments, the composition further comprises one or more optional additional ingredients selected from antioxidants, skin lightening agents, and humectants in a total weight of up to 10.

Tocopherols or tocotrienol agents

In some embodiments, the composition further comprises an optional additional component that is a tocopherol or tocotrienol agent. In some embodiments, the tocopherol or tocotrienol is a form of vitamin E selected from alpha, beta, delta, and gamma tocopherols and alpha, beta, delta, and gamma tocotrienols, and combinations thereof. In some embodiments, the tocopherol or tocotrienol is alpha-tocopherol.

In some embodiments, the tocopherol or tocotrienol agent is present in the composition in an amount of 2% by weight or less, such as 1.5% by weight or less, 1% by weight or less, or 0.5% by weight or less.

In some embodiments of any one of the formulations described herein, the formulation excludes a tocopherol or tocotrienol agent, eg, or a precursor thereof having vitamin E activity. In certain embodiments of any one of the formulations described herein, the formulation excludes vitamin E acetate.

antioxidant

In some embodiments, one or more additional ingredients are antioxidants.

In certain embodiments, the formulation contains a secondary antioxidant (i.e., other than optional additive vitamin C, or optional additives tocopherols or tocotrienols) or a primary antioxidant (i.e., without optional vitamin C, or optional additives tocopherols or tocotrienols). contain

Preferred secondary antioxidants are cinnamic acid derivatives (eg ferulic acid, caffeic acid, or coumaric acid), terpenoid antioxidants, and benzoic acid derivatives (eg p-hydroxy benzoic acid, gallic acid, or protocate). Chuic acid) is included. Pine maritime pine bark/bud extract (available under the tradename Pycnogenol® from DKSH North America, Inc. or under the tradename Pantrofina® Skin360 from Res Pharma Industriale) contains these cinnamic acid derivatives and benzoic acid derivatives, and therefore is a preferred primary or secondary Tea is an antioxidant.

In some embodiments, the secondary antioxidant is zingerone or acetyl zingerone. In some embodiments, the secondary antioxidant is bakuchiol (10309-37-2), a natural terpenoid antioxidant. In some embodiments, the secondary antioxidant is bis-ethylhexyl hydroxydimethoxy benzylmalonate (HDBM).

Secondary antioxidants, when included, preferably 0.1 to 3% by weight of the composition, more preferably 0.1 to 2% by weight, such as 0.1 to 1% by weight, 0.1 to 0.5% by weight, for example about 0.2% by weight. , about 0.3%, about 0.4%, or about 0.5% by weight. In some embodiments, the secondary antioxidant is acetyl zingerone.

In some embodiments, the secondary primary or secondary antioxidant is zingerone or acetyl zingerone. In some embodiments, the primary or secondary antioxidant is bakuchiol (10309-37-2), a natural terpenoid antioxidant. In some embodiments, the secondary antioxidant is bis-ethylhexyl hydroxydimethoxy benzylmalonate (HDBM).

In some embodiments, the primary or secondary antioxidant is vitis vinifera (grape) seed extract, camellia sinensis leaf extract, quercus robur wood extract ), an antioxidant formulation containing Pine maritime pine bark extract.

Secondary antioxidants, when included, preferably 0.1 to 3% by weight of the composition, more preferably 0.1 to 2% by weight, such as 0.1 to 1% by weight, 0.1 to 0.5% by weight, for example about 0.2% by weight. , about 0.3%, about 0.4%, or about 0.5% by weight. In some embodiments, the primary or secondary antioxidant is acetyl zingerone.

Primary or secondary antioxidants, when included, are preferably 0.1 to 5%, 0.1 to 3%, more preferably 0.1 to 2%, such as 0.1 to 1%, 0.1 to 0.5% by weight of the composition. %, such as about 0.2%, about 0.3%, about 0.4%, or about 0.5%.

In some embodiments, antioxidants are suitable for enhancing photoprotection from UVA radiation. Additional non-limiting examples of antioxidants include polydatin, phloretin, resveratrol, ferulic acid, and mixtures thereof. In some embodiments, an antioxidant may be combined with one or more UV filters, such as organic UV filters, in a cosmetically acceptable carrier. The UV filter(s) can be UVB filters, UVA filters (UVA1 and/or UVA2 filters), and/or inorganic UV filters (UVA and/or UVB filters).

skin lightener

In certain embodiments, the formulation contains a secondary skin lightening agent (eg, as described herein) (ie, other than vitamin C). Skin lightening agents that may be included in the compositions of the present disclosure include hydroquinone and its derivatives including, for example, its monomethyl and monobenzyl ethers; licorice root (Glycyrrhiza glabra) extract; azelaic acid; kojic acid; arbutin; retinoids (including all trans retinoic acid, adapalene, and tazarotene); alpha hydroxy acids, especially citric acid, lactic acid, and glycolic acid; ellagic acid; gluconic acid; gentisic acid (2,5-dihydrobenzoic acid); 4-hydroxy benzoic acid; salts and esters of the aforementioned acids including ammonium lactate and sodium lactate; N-acetyl glucosamine; aloesin, a hydroxymethyl chromone isolated from aloe vera; Vitamin B3 compounds or derivatives thereof—including but not limited to niacin, nicotinic acid, and niacinamide. epigallocatecin 3-O-gallate (EGCG) and other catechin constituents of tea extracts, especially green tea; an extract of soybean oil (dol soybean) containing isoflavones; hydroxystilbene; butyl hydroxy anisole; and butyl hydroxy toluene can also be used as skin lightening agents. In some embodiments, the additional skin lightening agent is azelaic acid or arbutin.

The skin lightening agent, when included, is preferably in an amount ranging from 0.1 to 10%, more preferably from 0.2 to 5%, such as from 0.2 to 4%, from 0.2 to 3%, or from 0.2 to 2% by weight of the composition. exists as In certain embodiments, the secondary skin lightening agent is soluble and can be added directly to the high vitamin C (>15%) concentrate of the present invention. Secondary skin lightening agents may also be encapsulated using techniques known to those skilled in the art.

hydroxy acid

In some embodiments, the formulation contains a hydroxy acid, such as a carboxylic acid and a small molecule compound comprising a hydroxy group. The acid may be an alkyl carboxylic acid or benzoic acid. A hydroxyl group can be a phenol or an alkyl alcohol. In certain embodiments, the hydroxy acid is an alpha-hydroxy carboxylic acid. In certain embodiments, hydroxy acids contain 2 to 12 carbon atoms, such as 2 to 6 or 2 to 4 carbons. Hydroxy acids of interest include, but are not limited to, glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, gluconolactone, lactobionic acid, maltobionic acid, and combinations thereof. don't

anti-inflammatory

In some embodiments, the formulation contains an anti-inflammatory agent as an additional ingredient. In some embodiments, the anti-inflammatory agent is madecassoid or madecassic acid. When included, the anti-inflammatory agent is preferably present in an amount ranging from 0.1 to 2%, more preferably from 0.1 to 1%, such as from 0.1 to 0.5%, or from 0.1 to 0.2% by weight of the composition. In some embodiments, madecassoide is included in an amount ranging from 0.1 to 0.5% by weight, such as about 0.1% or about 0.2% by weight.

Exemplary Topical Formulations

In some embodiments, the topical composition comprises a) 5% to 28% by weight dissolved in a non-aqueous skin compatible solvent selected from polyols, C(1-6) alkanediols, glycol ethers, dimethyl ethers, or combinations thereof. % ascorbic acid; and b) 5% to 20% by weight of urease, wherein the ratio of ascorbic acid to urease is from about 1.0 to about 3.5. Generally, ascorbic acid is dissolved at a concentration (AA) that is greater than its maximum concentration (X) in solvent alone, and urea is dissolved at a concentration that is at least about (AA-X)*1.25. In some embodiments, urea is dissolved at a concentration that is about (AA-X)*1.25. In some embodiments, the urea is dissolved at a concentration that is about (AA-X)*1.25 ± 1% by weight, such as (AA-X)*1.25 ± 0.5% by weight.

In some embodiments, the ratio of ascorbic acid to urease in the composition is between 1.8 and 2.2. In some embodiments, the topical composition comprises about 15% by weight ascorbic acid; About 8% by weight of urease; and a solvent containing 1,3-propanediol and/or 1,2-hexanediol; and one or more optional additional ingredients. In certain embodiments, the one or more optional additional ingredients include acetyl zingerone. In certain embodiments, the one or more optional additional ingredients are tocopherols or tocotrienols (eg, as described herein).

In some embodiments, the ratio of ascorbic acid to urease in the composition is between 1.8 and 2.2. In some embodiments, the topical composition comprises about 20% by weight ascorbic acid; about 10% by weight of urease; and a solvent that is 1,3-propanediol; and one or more optional additional ingredients.

In some embodiments, the ratio of ascorbic acid to urease in the composition is between 1.8 and 2.2. In some embodiments, the topical composition comprises about 10% by weight ascorbic acid; about 5% by weight of urease; and a solvent that is 1,3-propanediol; and one or more optional additional ingredients. In certain embodiments, the one or more optional additional ingredients include Pine maritime pine bark extract. In some embodiments, the composition comprises no more than 2% by weight of Pine maritime pine bark extract, such as no more than 1.5%, no more than 1%, or no more than 0.5% (eg, about 0.5% by weight) of Pine maritime bark extract. include

In some embodiments, the ratio of ascorbic acid to urease in the composition is between 1.0 and 1.3, such as 1.25. In some embodiments, the topical composition comprises about 25% by weight ascorbic acid; About 20% by weight of urease; and a solvent that is 1,3-propanediol; and one or more optional additional ingredients. In certain embodiments, the one or more optional additional ingredients are hydroxy acids such as glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, gluconolactone, lactobionic acid, maltobionic acid, and combinations thereof. In some embodiments, the hydroxy acid is salicylic acid. In some embodiments, the composition comprises 3% by weight or less of a hydroxy acid, such as 2% or less or 1% or less (eg, about 2% by weight) of a hydroxy acid.

In some embodiments, the ratio of ascorbic acid to urease in the composition is about 1 (eg, 1:1). In some embodiments, the topical composition comprises about 5% by weight ascorbic acid; about 5% by weight of urease; and a solvent that is 1,3-propanediol; and one or more optional additional ingredients. In certain embodiments, the one or more optional additional ingredients include panthenol. In some embodiments, the composition comprises 10% or less by weight panthenol, such as 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less (e.g., about 4% by weight) of panthenol. . In some embodiments, the composition comprises about 1% to about 6% by weight of panthenol, such as about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% by weight. of panthenol. In certain embodiments, the one or more optional additional ingredients include a hyaluronic acid complex. In some embodiments, the composition comprises no more than 2% by weight of the hyaluronic acid complex, such as no more than 1.5%, no more than 1%, or no more than 0.5% (eg, about 1% by weight) of the hyaluronic acid complex.

In some embodiments, formulations of the present disclosure are generally free of silicone and are “substantially free” concentrates of water. "Substantially free" of water means that (i) no water is intentionally added to the concentrate, and (ii) the amount of water in the concentrate is less than about 2%, preferably less than 1%, more preferably less than 1% by weight of the concentrate. preferably less than about 0.5% by weight, and even more preferably less than about 0.1% by weight. In certain embodiments, the concentrate is also free of oils or lipids.

emulsion composition

Any non-aqueous liquid composition having a specific amount of ascorbic acid (eg, as described herein) can be combined with an immiscible phase or component (eg, an oil component) to create an emulsion composition. It is understood that In some embodiments, the non-aqueous liquid composition that makes up the first phase of the emulsion composition is referred to as a concentrate. The liquid concentrate may be mixed with one or more additional ingredients (eg, an immiscible oil phase or ingredient, and an optional emulsifier). A variety of methods and components for making emulsions are available and can be used in the subject emulsion composition.

In some embodiments, an emulsion composition of the present disclosure is referred to as a gel.

Any conventional oils and lipids may be used for the oil component of the subject emulsion. An oil component or oil phase refers to any phase that is immiscible with the non-aqueous liquid composition. In some embodiments, the oil component is silicone-based and includes, for example, silicone polymers. In some embodiments, the oil component includes a silicone oil or silicone elastomer, such as a polyorganosiloxane. In some embodiments, the silicone polymer has dual properties and can be used as an emulsion and/or can serve as the continuous/dispersed phase of an emulsion composition.

Oils and lipids of interest include silicone oil, linseed oil, camellia oil, macadamia nut oil, corn oil, mink oil, olive oil, avocado oil, sandalwood oil, castor oil, safflower oil, apricot oil, cinnamon oil, jojoba oil, grape oil , Sunflower Oil, Almond Oil, Rapeseed Oil, Sesame Oil, Wheat Germ Oil, Rice Germ Oil, Rice Bran Oil, Cottonseed Oil, Soybean Oil, Peanut Oil, Tea Seed Oil, Evening Primrose Oil, Eggyoke Oil, Neetsfoot Oil ), cod liver oil, triglycerin, glycerin trioctanate, pentaerythritol tetraoctanate, glycerin triisopalmitate, cholesterol, free fatty acids, and combinations thereof.

Any conventional emulsifier or emulsion is used in the preparation of the subject emulsion to stabilize the composition and prevent separation of the oil component from the solvent solution (eg, non-aqueous liquid composition). Exemplary emulsifiers include, but are not limited to, polysorbate, laureth-4, potassium cetyl sulfate, and silicone and silicone-elastomer based emulsions and emulsion blends. In some embodiments, small amounts of surfactants such as monoglycerides, sorbitan fatty acid esters or polyglycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid ethers are added thereto, and the stability is further improved.

Any conventional emulsifier or emulsifier is used to prepare the emulsion of interest to stabilize the composition and to separate the oil component from the solvent solution (e.g., a non-aqueous liquid composition of a first phase (e.g., inner phase) solution) prevent

In some embodiments, a formulation of the present disclosure comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12% by weight , about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight , about 23%, about 24%, or about 25% by weight emulsifier. In some embodiments, a formulation of the present disclosure is about 4% to about 6%, about 6% to about 8%, about 8% to about 10%, about 10% to about 12% about 14% , about 14% to about 16%, about 16% to about 18%, about 18% to about 20%, about 20% to about 22%, about 22% to about 24%, about 24% by weight to about 26%, about 26% to about 28%, or about 28% to about 30% by weight of an emulsifier.

In some embodiments, the emulsifier is a silicone-compatible additive.

In some embodiments, exemplary emulsifiers include, but are not limited to, polysorbate, laureth-4, potassium cetyl sulfate, and silicone and silicone-elastomer based emulsions and emulsion blends. In some embodiments, a small amount of a surfactant such as a monoglyceride, sorbitan fatty acid ester or polyglycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid ether, or a combination thereof is added thereto, and stability is further Improved. In some embodiments, an emulsifier is added to a formulation in an effective amount to improve the stability of the formulation.

In some embodiments, the emulsifier is sorbitan laurate, sorbitan palmitate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan stearate, sorbitan oleate, sorbitan bitan monoisostearate, sorbitan triisostearate, sorbitan trioleate, sorbitan tristearate; Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Cocoate, Glyceryl Erucate, Glyceryl Hydroxystearate, Glyceryl Isostearate, Glyceryl Lanolate, Glyceryl Laurate, Glyceryl Linoleate, Glyceryl Myristate, Glyceryl Oleate, Glyceryl Palmitate Lactate, Glyceryl Sesquioleate, Glyceryl Stearate, Glyceryl Stearate Citrate, glyceryl stearate lactate; Polyglyceryl-4-isostearate, polyglyceryl-3 oleate, polyglyceryl-2 sesquioleate, triglyceryl diisostearate, diglyceryl monooleate, tetraglyceryl monooleate, glycol Distearate, Glycol Hydroxystearate, Glycol Oleate, Glycol Ricinoleate, Glycol Stearate, Propylene Glycol Isostearate, Propylene Glycol Hydroxystearate, Propylene Glycol Laurate, Propylene Glycol Myristate, Propylene Glycol Oleate , propylene glycol ricinoleate, propylene glycol stearate; sucrose cocoate, sucrose laurate; methyl glucose sesquistearate, methyl glucose dioleate; PEG-20 methyl glucose sesquistearate; or mixtures thereof, but is not limited thereto.

made of silicone

In some embodiments, the emulsifier of a formulation of the present disclosure contains one or more silicone emulsions (eg, silicone agents). In some embodiments, a first phase (eg, inner phase) solution containing urease and a non-aqueous solvent (eg, a non-aqueous liquid composition) is a second phase (eg, an inner phase) containing one or more silicone emulsifiers (eg, a non-aqueous liquid composition). eg, external phase) is mixed with a solution to form an emulsion formulation. In some embodiments, the emulsion prevents degradation of urease. In some embodiments, the emulsion prevents precipitation of urease. In some embodiments, the emulsion prevents oxygen or air from degrading the urease within the emulsion. In some embodiments, the emulsion prevents moisture from degrading the urease within the emulsion. In some embodiments, the emulsion prevents absorption of water from degrading the urease within the emulsion.

In some embodiments, the emulsion increases the half-life of the emulsion containing urease. In some embodiments, the half-life of the emulsion is 6 weeks to 8 weeks, 2 months 4 months, 4 months to 6 months, 6 months to 1 year, 1 to 1.5 years, 1.5 to 2 years, 2 to 2.5 years, 2.5 to 3 years years, 3 to 3.5 years, or 3.5 to 4 years. In some embodiments, the half-life is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 1 year, at least about 1.5 years, at least about 2 years or more, or about 2.5 years or more.

Silicone agents of interest include dimethicone, adimethicone, cyclopentasiloxane, dimethicone/PEG-10/15 crosspolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, PEG-3 dimethicone, PEG-10 dimethicone. Thicone, PEG-9 Methyl Ether Dimethicone, Polyglyceryl-3 Polydimethylsiloxyethyl Dimethicone, PEG/PPG-18/18 Dimethicone, PEG-15/Lauryl Dimethicone Crosspolymer, PEG-15/Lauryl polydimethylsiloxyethyl dimethicone crosspolymer, dimethicone/polyglycerin-3 crosspolymer, and dimethicone/vinyl amethicone crosspolymer.

In some embodiments, a formulation of the present disclosure comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12% by weight , about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight , about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% by weight of one or more silicone agents. In some embodiments, a formulation of the present disclosure comprises about 1 to 5%, 5 to 10%, 10% to 15%, 15 to 20%, 20 to 25%, or 25 to 30% by weight. range of one or more silicone agents.

In some embodiments, a composition of the present disclosure includes a second phase (eg, an outer phase) comprising a silicone agent. In some embodiments, the second phase (eg, outer phase) comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11% by weight. %, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% of one or more Contains a silicone agent. In some embodiments, the second phase (eg, outer phase) is about 1 to 10%, 10 to 20%, 20 to 30%, 30 to 40%, 40 to 50%, 50 to 50% by weight. 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100% by weight of one or more silicone agents. In some embodiments, the second phase (eg, outer phase) is about 1 to 5%, 5 to 10%, 10 to 15%, 15 to 20%, 20 to 25%, 25 to 30% by weight. 30 to 35% by weight 35 to 40% by weight, 40 to 45% by weight, 45 to 50% by weight, 50 to 55% by weight, 55 to 60% by weight, 60 to 65% by weight, 65 to 70% by weight, 70 to 75%, 75 to 80%, 80 to 85%, 85 to 90%, 90 to 95%, or 95 to 100% by weight of one or more silicone agents.

In some embodiments, the second phase (eg, outer phase) includes a non-silicone oil agent in addition to one or more silicone agents. In some embodiments, the second phase (e.g., outer phase) contains, in addition to one or more silicones, 0.5 to 1%, 1 to 1.5%, 1.5 to 2%, 2 to 2.5%, 2.5 to 2.5% by weight. 3 wt%, 3 to 3.5 wt%, 3.5 to 4 wt%, 4 to 4.5 wt%, 4.5 to 5 wt%, 5 to 5.5 wt%, 6 to 6.5 wt%, 6.5 to 7 wt%, 7 to 7.5 wt% %, 8 to 8.5%, 8.5% to 9%, 9 to 9.5%, or 9.5 to 10% by weight of a non-silicone oil agent. In some embodiments, the second phase (eg, outer phase) is about 1 to 5%, 5 to 10%, 10 to 15%, 15 to 20%, 20 to 25%, 25 to 30% by weight. 30 to 35 wt%, 35 to 40 wt%, 40 to 45 wt%, 45 to 50 wt%, 50 to 55 wt%, 55 to 60 wt%, 60 to 65 wt%, 65 to 70 wt%, one or more silicone agents in the range of 70 to 75%, 75 to 80%, 80 to 85%, 85 to 90%, 90 to 95%, or 95 to 100% by weight; and 0.5 to 1%, 1 to 1.5%, 1.5 to 2%, 2 to 2.5%, 2.5 to 3%, 3 to 3.5%, 3.5 to 4%, 4 to 4.5%, 4.5 to 5%, 5 to 5.5%, 6 to 6.5%, 6.5 to 7%, 7 to 7.5%, 8 to 8.5%, 8.5% to 9%, 9 to 9.5%, or An amount of non-silicone oil agent in the range of 9.5 to 10% by weight.

In some embodiments, the silicone agent is dimethicone. In some embodiments, the silicone agent contains dimethicone in combination with dimethicone/PEG-10/15 crosspolymer. In some embodiments, the silicone agent contains dimethicone in combination with dimethicone/PEG-10/15 crosspolymer and lauryl PEG-9 polydimethylsiloxyethyl dimethicone.

In some embodiments, the silicone agent is about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15% %, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, About 28%, about 29%, or about 30% of dimethicone alone or in combination with dimethicone/PEG-10/15 crosspolymer and lauryl PEG-9 polydimethylsiloxyethyl. In some embodiments, the silicone agent is about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15% %, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% dimethicone; About 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17 %, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% dimethicone/PEG-10/15 crosspolymer; and/or about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16% , about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% lauryl PEG-9 polydimethylsiloxyethyl.

In some embodiments, a subject composition comprises a ratio of a first phase (eg, inner phase) to a second phase (eg, outer phase). In certain embodiments, the ratio of the first phase (eg, inner phase) to the second phase (eg, outer phase) is 1 to 5, such as 1.0 (i.e., 1:1), 1.25, 1.50, 1.75, 2.0 (i.e., 2:1), 2.25, 2.50, 2.75, 3.0, 3.25, 3.50, 3.75, 4.0, 4.25, 4.50, 4.75, 5. In certain embodiments, the ratio of the first phase (e.g., the inner phase) to the second phase (e.g., the outer phase) is between 1 and 20, such as 1 (i.e., 1:1), 2, 3, ranges of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, the ratio of the first phase (eg, inner phase) to the second phase (eg, outer phase) is between 1.8 and 2.2, such as a ratio of 2. In certain embodiments, the ratio of the first phase (eg, inner phase) to the second phase (eg, outer phase) is between 1.0 and 1.3, such as a ratio of 1.25 or a ratio of 1.0. In some embodiments, the ratio of the first phase (eg, inner phase) to the second phase (eg, outer phase) is at most 19 (eg, 19:1). In some embodiments, the ratio of the first phase (eg, inner phase) to the second phase (eg, outer phase) ranges from 1 to 19. In some embodiments, the ratio of the first phase (eg, inner phase) to the second phase (eg, outer phase) is 9 (ie, 9:1). In some embodiments, the ratio of the first phase (eg, inner phase) to the second phase (eg, outer phase) is 19 (ie, 1 9:1).

In some embodiments, the first phase is an internal phase and the second phase is an external phase. In some embodiments, droplets of an internal phase (eg, solvent phase) are contained within an external phase (eg, silicon phase).

storage stability

The high potency vitamin C formulations of the present disclosure are capable of retaining at least 90% of the starting ascorbic acid content when the concentrate is stored at room temperature for 12 months or more.

The amount of ascorbic acid content in a composition can be determined using a wide range of techniques including, but not limited to, titration, spectrophotometry, electrochemistry, fluorescence, enzymatic, and chromatography. Methods for determining ascorbic acid content in topical formulations can be complicated/confounded by the presence of excipients or other antioxidants (eg, vitamin C stabilizers) as well as degradation products. Among the methods listed above, high-performance liquid chromatography is preferred. AM Maia et al., "Validation of HPLC stability-indicating method for Vitamin C in semisolid pharmaceutical/cosmetic preparations …" Talanta Vol. 71, pp. 71; 639-643 (2007).

In some embodiments, the storage stable composition of the present disclosure is stored in a sealed container at 40°C ± 2°C for at least 6 weeks (e.g., at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 18 weeks, at least 24 weeks). decomposition of less than 10 mol% of ascorbic acid after storage for at least 1 week, or even more), such as less than 9 mol%, less than 8 mol%, less than 7 mol%, 6 mol% of ascorbic acid initially present in the composition prior to storage Less than mol%, less than 5 mol%, less than 4 mol%, less than 3 mol%, less than 2 mol% degradation.

In some embodiments, the storage stable composition of the present disclosure is stored in a sealed container at 45°C ± 2°C for at least 4 weeks (e.g., at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 18 weeks). After storage for at least 24 weeks, or even longer), decomposition of less than 10 mol% of ascorbic acid, such as less than 9 mol%, less than 8 mol%, less than 7 mol of ascorbic acid initially present in the composition prior to storage %, less than 6 mol%, less than 5 mol%, less than 4 mol%, less than 3 mol%, less than 2 mol% degradation.

In some embodiments, the storage stable compositions of the present disclosure are stored for at least 6 months (eg, at least 8 months, at least 10 months, at least 12 months, at least 18 months at 25 ° C ± 2 ° C in a sealed container or multi-purpose container). decomposition of less than 10 mol% of ascorbic acid after storage for at least, or even more), such as less than 9 mol%, less than 8 mol%, less than 7 mol% of ascorbic acid initially present in the composition before storage after storage, Less than 6 mol%, less than 5 mol%, less than 4 mol%, less than 3 mol%, less than 2 mol% degradation. In certain embodiments, the composition is stored in a hermetically sealed container. In certain embodiments, the composition is stored in a multi-use container.

In some embodiments, a storage stable composition of the present disclosure is provided in a sealed container or multi-purpose container at 25°C ± 2°C for at least 12 months (eg, at least 18 months, at least 24 months, or even longer) After storage, decomposition of less than 20 mol% of ascorbic acid, such as less than 15 mol%, less than 12 mol%, less than 10 mol%, less than 8 mol%, less than 6 mol% of ascorbic acid initially present in the composition before storage, Shows less than 6 mol%, less than 4 mol%, less than 3 mol%, less than 2 mol% degradation. In certain embodiments, the composition is stored in a hermetically sealed container. In certain embodiments, the composition is stored in a multi-use container.

Formulations of the present disclosure are capable of retaining a starting urea content of at least 90% when the concentrate is stored in a non-aqueous solution for at least 12 months at room temperature.

Urea content in a composition can be determined using a wide range of known techniques including, but not limited to, enzymatic methods, colorimetric assays, and diacetyl monoxime (DAM) techniques.

In some embodiments, the storage stable composition of the present disclosure is stored in a sealed container at 40°C ± 2°C for at least 6 weeks (e.g., at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 18 weeks, at least 24 weeks). decomposition of less than 10 mol% of urea after storage for weeks or more, or even more), such as less than 9 mol%, less than 8 mol%, less than 7 mol%, 6 mol% of urea initially present in the composition prior to storage Less than 5 mol%, less than 4 mol%, less than 3 mol%, less than 2 mol% degradation.

In some embodiments, a storage stable composition of the present disclosure is provided in a sealed container or multi-purpose container at 25°C ± 2°C for at least 12 months (eg, at least 18 months, at least 24 months, or even longer) Decomposition of less than 20 mol% of urea after storage, such as less than 15 mol%, less than 12 mol%, less than 10 mol%, less than 8 mol%, less than 6 mol%, 6 mol of urea initially present in the composition prior to storage %, less than 4 mol%, less than 3 mol%, less than 2 mol% degradation. In certain embodiments, the composition is stored in a hermetically sealed container. In certain embodiments, the composition is stored in a multi-use container.

courage

In some embodiments, the high potency vitamin C concentrate of the present disclosure is administered with a second non-aqueous formulation (ie, an oil, ester, and/or silicone carrier). The two compositions are pre-filled in a "double-chamber" container - a pump container (where the two formulations are stored separately prior to dispensing), the high potency vitamin C concentrate of the present invention is placed in the first chamber and the non-aqueous formulation is pre-filled in the second chamber. Some dual chamber containers have two separate actuators/pumps, each with an orifice for dispensing one of the two formulations. Other dual chamber containers have two pumps and one actuator, and the two dosage forms are dispensed side by side (eg, through two orifices) or from a single shared orifice. A non-limiting example of a double chamber vessel is described in US Pat. No. 6,462,025.

Any container suitable for storing and/or dispensing the subject formulation may be adapted for use. The container can provide a sealed environment for holding the composition and isolation from the atmosphere. The container may prevent undesirable degradation during storage, for example from absorption of light and/or moisture from the atmosphere or ambient environment. A ready-to-use topical preparation of ascorbic acid in a multi-use container pre-filled with a storage stable topical composition (eg, as described herein) is provided.

Additional packaging materials for containers may be included. In some cases, the packaging material provides an additional barrier to prevent absorption of light and/or moisture from the atmosphere or ambient environment.

In some embodiments, e.g., in the case of a urea emulsion, the container can be used to solubilize both using a "time released" vehicle that will minimize potential irritation (e.g., for better delivery to the skin). for) a delivery system of urea that combines For example, a solubilized urea-containing polyol phase dispersed in small droplets inside a continuous silicone/oil outer phase can deliver urea in effective, but not all-at-a-time amounts.

manufacturing method

Subject formulations (e.g., as described herein), for example, by dissolving ascorbic acid in a non-aqueous solvent with urease and optionally one or more additional ingredients to provide a stable liquid composition that can be storage stable. ) is also provided by the present disclosure.

In some embodiments, the process

1. 1% to 20% by weight of a urease selected from urea, hydroxyethyl urea, and combinations thereof;

2. 10% to 94% by weight of a non-aqueous skin compatible solvent comprising a C _(3-6) polyol, ethoxydiglycol, dimethyl ether, or a combination thereof;

3. Up to 5% by weight (eg, 0.1 to 5%) of cinnamic acid or a derivative thereof; and

4. Optionally one or more additional agents

5. By combining with 5% to 28% by weight of ascorbic acid,

dissolving the ascorbic acid to produce a storage stable, non-aqueous, single phase clear liquid composition of ascorbic acid. In certain embodiments, one or more additional agents are combined and include 0.5% to 2% of Pine maritime pine bark extract. In certain embodiments, one or more additional agents are combined and include from 3% to 10% azelaic acid by weight.

In some embodiments, the process comprises combining 0.5% to 2% vitamin E and 1.5% to 5% emulsifier by weight to form a second liquid composition; and combining the second liquid composition with the liquid composition of ascorbic acid to create an emulsion. In some embodiments, the process comprises combining 0.5% to 2% by weight of a lipid component and 1.5% to 5% by weight of an emulsifier to form a second liquid composition; and combining the second liquid composition with the liquid composition of ascorbic acid to create an emulsion.

In some embodiments of the above process, one or more additional agents are combined and comprise from 0.5% to 2% by weight of a hydroxy acid. In certain embodiments, the hydroxy acid is selected from glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, gluconolactone, lactobionic acid, maltobionic acid, and combinations thereof.

Any of the subject formulations (eg, as described herein), for example, by dissolving azelaic acid in a non-aqueous solvent with urease and optionally one or more additional ingredients to provide a fully solubilized liquid composition. A solubilization process of azelaic acid comprising one preparation of is also provided by the present disclosure.

In some embodiments, the process

1. 1% to 20% by weight of a urease selected from urea, hydroxyethyl urea, and combinations thereof;

2. 10% to 94% by weight of a non-aqueous skin compatible solvent comprising a C(3-6) polyol, ethoxydiglycol, dimethyl ether, or a combination thereof; and

3. Optionally one or more additional agents

4. By combining with 4% to 20% azelaic acid,

dissolving the azelaic acid to produce a non-aqueous, single phase clear liquid composition of azelaic acid. In certain embodiments, one or more additional agents are combined, 0.1% to 2% madecassoside, 0.1 to 2% asiaticoside; and 0.5% to 2% of Pine maritime pine bark extract. In certain embodiments, one or more additional agents are combined and include from 3% to 10% azelaic acid by weight.

In some embodiments, the process comprises combining 0.5% to 2% vitamin E and 1.5% to 5% emulsifier by weight to form a second liquid composition; and combining the second liquid composition with the liquid composition of azelaic acid to create an emulsion. In some embodiments, the process comprises combining 0.5% to 2% by weight of a lipid component and 1.5% to 5% by weight of an emulsifier to form a second liquid composition; and combining the second liquid composition with the liquid composition of azelaic acid to create an emulsion.

In some embodiments of the above process, one or more additional agents are combined and comprise from 0.5% to 2% by weight of a hydroxy acid. In certain embodiments, the hydroxy acid is selected from glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, gluconolactone, lactobionic acid, maltobionic acid, and combinations thereof.

In some embodiments, the process

1. 1% to 20% by weight of xylitol and xylitol derivatives such as xylitylglucoside and anhydroxylitol; sorbitol; lactitol; maltitol; erythritol; a sugar alcohol agent selected from mannitol, and combinations thereof;

2. 10% to 94% by weight of a non-aqueous skin compatible solvent comprising a C(3-6) polyol, ethoxydiglycol, dimethyl ether, or a combination thereof; and

3. Optionally one or more additional agents

4. By combining with 5% to 28% by weight of ascorbic acid,

dissolving the ascorbic acid to produce a storage stable, non-aqueous, single phase clear liquid composition of ascorbic acid. In certain embodiments, one or more additional agents are combined, 0.5% to 2% ferulic acid; and 0.5% to 2% of Pine maritime pine bark extract. In certain embodiments, one or more additional agents are combined and include from 3% to 10% azelaic acid by weight.

In some embodiments, the process comprises combining 0.5% to 2% vitamin E and 1.5% to 5% emulsifier by weight to form a second liquid composition; and combining the second liquid composition with the liquid composition of ascorbic acid to create an emulsion. In some embodiments, the process comprises combining 0.5% to 2% by weight of a lipid component and 1.5% to 5% by weight of an emulsifier to form a second liquid composition; and combining the second liquid composition with the liquid composition of ascorbic acid to create an emulsion.

In some embodiments of the above process, one or more additional agents are combined and comprise from 0.5% to 2% by weight of a hydroxy acid. In certain embodiments, the hydroxy acid is selected from glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, gluconolactone, lactobionic acid, maltobionic acid, and combinations thereof. In some embodiments of the above process, one or more additional agents are combined and comprise from 0.1% to 5% by weight of a hydroxy acid. In certain embodiments, the hydroxy acid is selected from glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, gluconolactone, lactobionic acid, maltobionic acid, and combinations thereof.

For example, a subject formulation (e.g., as described herein) by dissolving urea in a non-aqueous solvent with one or more optionally additional ingredients in combination with a silicone component to provide a stable liquid composition that can be storage stable. A process for stabilizing urea for storage comprising the preparation of any one of (as described above) is also provided by the present disclosure.

In some embodiments, the process

1. 1% to 30% by weight of a urease selected from urea, hydroxyethyl urea, and combinations thereof;

2. 20% to 70% by weight of a non-aqueous skin compatible solvent comprising a C(3-6) polyol, ethoxydiglycol, dimethyl ether, or a combination thereof;

3. 4% to 35% by weight of a silicone agent;

4. Optionally combining one or more additional agents.

In some embodiments, the urease and the non-aqueous skin compatible solvent are first combined to a first phase (eg, internal phase) solution (eg, urea dissolved in the first phase (eg, internal phase) solvent). ), see, for example, the “polyol” phase of Tables 1-6. In some embodiments, the first phase (eg, internal phase) solution is a silicone/oil-phase (eg, external phase) solution (eg, the “silicone/oil phase/external phase” of Tables 1-6). ") to produce storage stable, non-aqueous, emulsion compositions of urea. In certain embodiments, one or more additional agents are combined into the second inner phase prior to the outer phase. In some embodiments, the one or more additional ingredients are 5% to 20% ascorbic acid; 0.5 to 2% ferulic acid; Vitamin E from 0.5% to 2%; 0.1 to 1% of bis-ethylhexyl hydroxydimethoxy benzylmalonate.

In some embodiments, one or more additional components of the process include 2% to 7% azelaic acid; 0.1 to 0.5% madecassoside; 0.1% to 1% of glycyrrhetinic acid; 0.5% to 1% of Pine maritime pine bark extract; 1% to 5% cholesterol ester; 0.5% to 1% bakuchiol; It also contains 0.1 to 1% retinol.

In some embodiments, the one or more additional ingredients include 5% azelaic acid, 0.1% madecassoside asiaticoside, 0.5% ferulic acid, 5% ascorbic acid, and diglycerin, and Pine maritime bark extract. do.

A storage stable product produced by a process according to any one of the embodiments described herein is also provided. In some embodiments, the process includes dispersing the internal phase components in propanediol. In some embodiments, the process further comprises mixing/stirring until the internal phase ingredients and propanediol are dissolved and the solution is clear.

After the inner phase ingredients are added, the process includes combining the outer phase ingredients into a closed vessel and mixing until combined. For example, the process includes slowly adding the mixture of the inner phase to the outer phase under high shear agitation and mixing until a uniform, viscous emulsion is formed.

In some embodiments, the final emulsion is slightly yellow translucent, highly viscous with a slightly ointment-like appearance.

For example, in a subject formulation (e.g., as described herein) by dissolving ascorbic acid in a non-aqueous solvent with urease and chemical exfoliant ingredients to provide a stable liquid composition that can be storage stable. A process for stabilizing ascorbic acid for storage comprising any one preparation is also provided by the present disclosure.

In some embodiments, the process

1. 1% to 20% by weight of a urease selected from urea, hydroxyethyl urea, and combinations thereof;

2. 10% to 94% by weight of a non-aqueous skin compatible solvent comprising a C(3-6) polyol, ethoxydiglycol, dimethyl ether, or a combination thereof;

3. 2% to 50% by weight of a chemical exfoliant; and

4. Optionally one or more additional agents

5. By combining with 5% to 28% by weight of ascorbic acid,

dissolving the ascorbic acid to produce a storage stable, non-aqueous, single phase clear liquid composition of ascorbic acid. In certain embodiments, one or more additional agents are combined, 0.5% to 2% ferulic acid; and 0.5% to 2% of Pine maritime pine bark extract. In certain embodiments, one or more additional agents are combined and include from 3% to 10% azelaic acid by weight.

In some embodiments, the process comprises combining 0.5% to 2% vitamin E and 1.5% to 5% emulsifier by weight to form a second liquid composition; and combining the second liquid composition with the liquid composition of ascorbic acid to create an emulsion. In some embodiments, the process comprises combining 0.5% to 2% by weight of a lipid component and 1.5% to 5% by weight of an emulsifier to form a second liquid composition; and combining the second liquid composition with the liquid composition of ascorbic acid to create an emulsion.

A storage stable product produced by a process according to any one of the embodiments described herein is also provided.

Justice

The following definitions are presented to illustrate and define the meaning and scope of terms used in this description.

It should be noted that the singular forms "a", "an", and "the" as used herein and in the appended claims include plural referents unless the context clearly dictates otherwise. For example, the term "primer" refers to one or more primers, ie, a single primer and multiple primers. It is further noted that the claims may be drawn to exclude any optional elements. Accordingly, this statement is intended to serve as antecedent basis for use of such exclusive terms as "solely", "only", etc., or use of a "negative" limitation in connection with the recitation of claim elements.

“At least one” means one or more, and includes individual components as well as mixtures/combinations.

It should be understood that numbers used to describe component amounts and/or reaction conditions are in all instances modified by the term "about." Unless otherwise specified, percentages and ratios are to be understood based on the total weight of the concentrate.

Numerical ranges are intended to include combinations of numbers within the recited ranges and subranges between the given ranges. For example, a range of 1 to 5 includes 1, 2, 3, 4, and 5 as well as subranges such as 2 to 5, 3 to 5, 2 to 3, 2 to 4, 1 to 4, and the like.

The terms "formulation" and "composition" are used interchangeably herein.

The term “non-aqueous” refers to compositions that are substantially anhydrous. Non-limiting examples of substantially anhydrous compositions include, for example, 1 wt% or less water, such as 0.5 wt% or less, 0.4 wt% or less, 0.3 wt% or less, 0.2 wt% or less, or 0.1 wt% or less water in the subject composition. includes

It should be understood that the teachings of this disclosure are not limited to the specific embodiments described and therefore may vary as a matter of course. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting as the scope of the present teachings will be limited only by the appended claims.

Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described in any way. Although the present teachings have been described with various embodiments, the present teachings are not intended to be limited to these embodiments. To the contrary, the present teachings cover various alternatives, modifications, and equivalents that will be recognized by those skilled in the art.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present teachings, some exemplary methods and materials are described herein.

Citation of any publication is for its disclosure prior to the filing date and is not to be construed as an admission that the claims are not entitled to antedate such publications by virtue of prior invention. In addition, the publication date provided may differ from the actual publication date, which may be independently ascertained. All patents and publications mentioned herein are expressly incorporated by reference.

Additional Embodiments

Additional embodiments of the present disclosure are described in the following aspects.

Now, further embodiments of the present disclosure include various categories of formulations and compositions, such as 1) stabilized vitamin C formulations, 2) vitamin C chemical exfoliation formulations, 3) vitamin C and sugar alcohol formulations, 4) anhydrous urea emulsions, and 5) azelaic anhydride formulations are described in more detail.

Stabilized Vitamin C Topical Formulations with Cinnamic Acid or Derivatives

Aspect 1. A storage stable topical composition comprising:

(a) 5% to 28% by weight of ascorbic acid;

(b) 5% to 20% urease;

(c) 0.1% to 5% by weight of cinnamic acid or a derivative thereof; and

less than 10% by weight of one or more optional additional components in total;

a non-aqueous skin compatible solvent comprising a polyol, C(2-6) alkanediol, glycol ether, dimethyl ether, or a combination thereof, which dissolves the above components; A storage stable topical composition, wherein ascorbic acid is dissolved at a concentration (AA) greater than its maximum concentration (X) in the solvent alone, and urea is dissolved at a concentration that is at least (AA-X)*1.25.

Embodiment 2. The storage stable topical composition of Embodiment 1, wherein the composition exhibits degradation of less than 10 mol% ascorbic acid after storage for 6 weeks at 40°C ± 2°C in a sealed container.

Embodiment 3. The storage stable topical composition of Embodiment 1, wherein the composition exhibits degradation of less than 5 mol % ascorbic acid after storage for 8 months at 40°C ± 2°C in a multipurpose container.

Embodiment 4. The storage stable topical composition of Embodiment 1, wherein the composition exhibits degradation of less than 10 mol % ascorbic acid after storage for 16 months at 40°C ± 2°C in a multipurpose container.

Aspect 5. The storage stable topical composition of any one of Aspects 1-4, wherein the urease is urea.

Aspect 6. The storage stable topical composition of any one of Aspects 1-4, wherein the urease is hydroxyethyl urea.

Embodiment 7. The storage stable topical composition of any one of Embodiments 1-4, wherein the urease is a mixture of urea and hydroxyethyl urea.

Aspect 8. The method of any one of Aspects 1-7, wherein the solvent is 1,3 propanediol, 1,2 propanediol, 1,3 butanediol, 1,5 pentanediol, 1,2 hexanediol, 1,6 hexane A storage stable topical composition selected from diols, 1,2 hexanediol, glycerol, diglycerol, ethoxydiglycol, dimethyl isosorbide, and combinations thereof.

Embodiment 9. The storage stable topical composition of Embodiment 8, wherein the solvent is 1,3 propanediol.

Aspect 10. The storage stable topical composition of Embodiment 8, wherein the solvent is a mixture of 1,3 propanediol and 1,2 hexanediol.

Embodiment 11. The method of any one of embodiments 1 to 10, wherein the one or more optional additional ingredients are tocopherols, tocotrienols (e.g., alpha, beta, delta, and gamma tocopherols or alpha, beta, delta, and gamma tocotrienols), Azelaic Acid, Hydroxy Acids (eg, Salicylic Acid), Panthenol, Pinus Marigold Bark Extract, Emulsifier, Hyaluronic Acid Complex, Madecassoside, Acetyl Gingerone, Bakuchiol, and Bis Ethylhexylhydroxydimethoxybenzyl A storage stable topical composition selected from malonates.

Aspect 12. The storage stable topical composition of any one of Aspects 1-11 comprising about 5% by weight of ascorbic acid.

Aspect 13. The storage stable topical composition of any one of Aspects 1-11 comprising from about 10% to about 20% by weight of ascorbic acid.

Aspect 14. The storage stable topical composition of aspect 13 comprising about 10% by weight of ascorbic acid.

Aspect 15. The storage stable topical composition of aspect 13 comprising about 15% by weight of ascorbic acid.

Aspect 16. The storage stable topical composition of aspect 13 comprising about 20% by weight of ascorbic acid.

Aspect 17. The storage stable topical composition of any one of Aspects 1-11 comprising about 25% by weight of ascorbic acid.

Embodiment 18. The storage stable topical composition of any one of Embodiments 13-16, wherein the ratio of ascorbic acid to urease is from 1.8 to 2.2.

Embodiment 19. The storage stable topical composition of embodiment 18, wherein the ratio of ascorbic acid to urease is from 2 to 1.

Embodiment 20. The storage stable topical composition of embodiment 18 or embodiment 19, wherein the optional additional ingredient comprises acetyl zingerone.

Embodiment 21. The storage stable topical composition of embodiment 20 comprising up to about 2% by weight of acetyl zingerone.

Embodiment 22. The storage stable topical composition of embodiment 21 comprising up to about 0.5% by weight of acetyl zingerone.

Embodiment 23. The storage stable topical composition of any one of Embodiments 1 to 19, wherein the cinnamic acid derivative is selected from ferulic acid, caffeic acid, coumaric acid, cinapic acid, and derivatives thereof.

Aspect 24. according to any one of aspects 15 and 18 to 23,

about 15% by weight ascorbic acid;

About 8% by weight of urease; and

about 1% by weight of ferulic acid;

A storage stable topical composition comprising a solvent comprising 1,3-propanediol which dissolves the above components.

Aspect 25. The storage stable topical composition of aspect 23 comprising from 0.1 to 2% by weight of ferulic acid.

Aspect 26. The storage stable topical composition of aspect 23 comprising 1% by weight or less of ferulic acid.

Aspect 27. The storage stable topical composition of aspect 26 comprising about 0.5% by weight ferulic acid.

Aspect 28. The storage stable topical composition of aspect 1 comprising 60% by weight of a solvent comprising propanediol.

Embodiment 29. The storage stable topical composition of embodiment 1 comprising 10% by weight of urea.

Embodiment 30. The storage stable topical composition of embodiment 1 comprising 0.5% by weight of diglycerin and Pine maritime pine bark extract.

Aspect 31. according to aspect 16 or aspect 23,

20% by weight of ascorbic acid;

10% by weight of urease;

0.5% by weight of ferulic acid;

60% by weight of propanediol; and

A storage stable topical composition comprising 0.5% by weight of diglycerin and Pine maritime pine bark extract.

Aspect 32. according to aspect 16 or aspect 23,

20% by weight of ascorbic acid;

10% by weight of urease; and

0.5% by weight of ferulic acid;

A storage stable topical composition comprising a solvent, which is 1,3-propanediol, which dissolves the above components.

Aspect 33. according to aspect 15 or aspect 23,

15% by weight of ascorbic acid;

8% by weight of urease; and

0.5% by weight of ferulic acid;

A storage stable topical composition comprising a solvent, which is 1,3-propanediol, which dissolves the above components.

Embodiment 34. The storage stable topical composition of embodiment 13 or embodiment 14, wherein the ratio of ascorbic acid to urease is from 3 to 3.5.

Aspect 35. The storage stable topical composition of any one of aspects 1-29, wherein the optional additional ingredient comprises azelaic acid.

Embodiment 36. The storage stable topical composition of embodiment 31 comprising from 3% to 10% azelaic acid by weight.

Embodiment 37. The storage stable topical composition of embodiment 31 comprising about 7.5% by weight azelaic acid.

Embodiment 38. The method of any one of Embodiment 14, Embodiment 23, and Embodiment 31,

about 10% by weight of ascorbic acid;

About 3% by weight of urease; and

about 0.5% to about 2% by weight ferulic acid;

A storage stable topical composition comprising a solvent, which is 1,3-propanediol, which dissolves the above components.

Embodiment 39. The storage stable topical composition of any one of Embodiments 1-38, wherein the one or more optional additional ingredients comprises Pine maritime pine bark extract.

Embodiment 40. The storage stable topical composition of embodiment 39 comprising no more than 2% by weight of Pine maritime pine bark extract.

Embodiment 41. The storage stable topical composition of embodiment 39 comprising about 0.5% by weight of Pine maritime pine bark extract.

Embodiment 42. The storage stable topical composition of any one of embodiments 1-41, wherein the one or more optional additional ingredients comprises madecassoside (eg, madecassoside asiaticoside).

Embodiment 43. The storage stable topical composition of any one of Embodiments 1-13, wherein the ratio of ascorbic acid to urease is from 1.0 to 1.3.

Embodiment 44. The storage stable topical composition of any one of Embodiments 1-13, wherein the ratio of ascorbic acid to urease is from 1.25 to 1.

Embodiment 45. The storage stable topical composition of any one of Embodiments 1-44, wherein the optional additional ingredient comprises a hydroxy acid.

Embodiment 46. The method of embodiment 45, wherein the hydroxy acid is selected from glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, gluconolactone, lactobionic acid, maltobionic acid, and combinations thereof storage stable topical composition.

Embodiment 47. The storage stable topical composition of embodiment 45, wherein the hydroxy acid is salicylic acid.

Aspect 48. The storage stable topical composition of aspect 45 comprising less than or equal to 3% by weight of a hydroxy acid.

Embodiment 49. The storage stable topical composition of embodiment 45 comprising about 2% by weight of a hydroxy acid.

Aspect 50. according to aspect 17,

about 25% by weight of ascorbic acid;

About 20% by weight of urease; and

about 0.5% to about 2% by weight ferulic acid;

A storage stable topical composition comprising a solvent, which is 1,3-propanediol, which dissolves the above components.

Embodiment 51. The storage stable topical composition of embodiment 1 wherein the ratio of ascorbic acid to urease is 1 to 1.

Embodiment 52. The storage stable topical composition of any one of embodiments 1-23, wherein the optional additional ingredient comprises panthenol.

Embodiment 53. The storage stable topical composition of embodiment 52 comprising no more than 10% by weight of panthenol.

Embodiment 54. The storage stable topical composition of embodiment 52 comprising about 5% by weight of panthenol.

Aspect 55. according to aspect 12 or aspect 51,

about 5% by weight of ascorbic acid;

about 5% by weight of urease; and

about 0.1% to 2% by weight of ferulic acid;

A storage stable topical composition comprising a solvent, which is 1,3-propanediol, which dissolves the above components.

Embodiment 56. The storage stable topical composition of any one of embodiments 51-54, wherein the one or more optional additional ingredients comprises madecassoside (eg, madecassoside asiaticoside).

Embodiment 57. The storage stable topical composition of embodiment 42 comprising up to about 1% by weight of madecassoside.

Aspect 58. An emulsion composition comprising:

a composition according to any one of aspects 1 to 57;

oil component; and

An emulsion composition comprising an optional emulsifier.

Embodiment 59. The emulsion composition of Embodiment 58, wherein the oil component is silicone-based.

Aspect 60. The emulsion composition of aspect 58 or aspect 59 comprising an emulsifier.

Embodiment 61. The emulsion composition of embodiment 58 or embodiment 59, wherein the emulsifier is selected from polysorbate, laureth-4, potassium cetyl sulfate, and silicone and silicone-elastomer based emulsifiers and emulsion blends.

Embodiment 62. A ready-to-use topical preparation of ascorbic acid in a multi-use container prefilled with the storage stable topical composition according to any one of embodiments 1-57, wherein the multi-use container contains a single dose of the storage stable topical composition. A topical preparation comprising a means for dispensing.

Embodiment 63. The topical formulation of embodiment 62, wherein the storage stable topical composition exhibits degradation of less than 10 mol% ascorbic acid after storage for 6 weeks at 40°C ± 2°C in the container.

Embodiment 64. The topical formulation of embodiment 62, wherein the storage stable topical composition exhibits degradation of less than 10 mol% ascorbic acid after storage for 6 months at 25°C ± 2°C in the container.

Embodiment 65. The topical formulation of any one of embodiments 58-60, wherein the storage stable topical composition is sealed within a container.

Embodiment 66. The topical formulation of any one of embodiments 58-61, wherein the container is disposed within a package.

Embodiment 67. A process for stabilizing ascorbic acid for storage comprising:

1% to 20% by weight of a urease selected from urea, hydroxyethyl urea, and combinations thereof;

10% to 94% by weight of a non-aqueous skin compatible solvent comprising a C(3-6) polyol, ethoxydiglycol, dimethyl ether, or a combination thereof;

0.1 to 5% or less of cinnamic acid or a derivative thereof; and

optionally one or more additional agents

By combining with 5% to 28% by weight of ascorbic acid,

A process for stabilizing ascorbic acid comprising dissolving ascorbic acid to produce a storage stable, non-aqueous, single phase clear liquid composition of ascorbic acid.

Embodiment 68. The method of embodiment 67, wherein one or more additional agents are combined;

A stabilization process for ascorbic acid comprising 0.5% to 2% of Pine maritime pine bark extract.

Embodiment 69. The method of embodiment 67, wherein one or more additional agents are combined;

Process for stabilizing ascorbic acid, comprising from 3% to 10% by weight of azelaic acid.

Aspect 70. Aspect 67,

combining 0.5% to 2% by weight of acetyl zingerone and 1.5% to 5% by weight of an emulsifier to form a second liquid composition; and

A process for stabilizing ascorbic acid, further comprising combining the second liquid composition with the liquid composition of ascorbic acid to form an emulsion.

Aspect 71. The method of aspect 67,

combining 0.5% to 2% by weight of a lipid component and 1.5% to 5% by weight of an emulsifier to create a second liquid composition; and

A process for stabilizing ascorbic acid, further comprising combining the second liquid composition with the liquid composition of ascorbic acid to form an emulsion.

Embodiment 72. The process of embodiment 71, wherein the lipid component is selected from cholesterol, ceramides, free fatty acids, and combinations thereof.

Embodiment 73. The method of embodiment 67, wherein one or more additional agents are combined;

A process for stabilizing ascorbic acid, comprising from 0.5% to about 2% by weight of a hydroxy acid.

Embodiment 74. The method of embodiment 73, wherein the hydroxy acid is selected from glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, gluconolactone, lactobionic acid, maltobionic acid, and combinations thereof , the stabilization process of ascorbic acid.

Aspect 75. A product produced by the process according to any one of Aspects 67-74.

Embodiment 76. The product of embodiment 75, which is used for wound healing.

Embodiment 77. The product of embodiment 75, which is a serum.

High Potency Vitamin C Chemical Peel Solution

Aspect 1. A storage stable topical composition comprising:

5% to 28% by weight of ascorbic acid;

5% to 20% by weight of urease;

2% to 30% by weight of a chemical exfoliant; and

less than 10% by weight of one or more optional additional components in total;

a non-aqueous skin compatible solvent comprising a polyol, C(2-6) alkanediol, glycol ether, dimethyl ether, ethanol, isopropyl alcohol, or a combination thereof, which dissolves the above components; wherein ascorbic acid dissolves at a concentration [AA] greater than its maximum concentration [X] in the solvent alone, and urea dissolves at a concentration that is at least ([AA]-[X])*1.25.

Embodiment 2. The storage stable topical composition of Embodiment 1, wherein the composition exhibits degradation of less than 5 mol% ascorbic acid after storage for 6 weeks at 40°C ± 2°C in a sealed container.

Embodiment 3. The storage stable topical composition of Embodiment 1, wherein the composition exhibits degradation of less than 2 mol% ascorbic acid after storage for 6 months at 40°C ± 2°C in a multipurpose container.

Embodiment 4. The storage stable topical composition of Embodiment 1, wherein the composition exhibits degradation of less than 5 mol% ascorbic acid after storage for 12 months at 40°C ± 2°C in a multipurpose container.

Embodiment 5. The storage stable topical composition of Embodiment 1, wherein the urease is urea.

Embodiment 6. The storage stable topical composition of Embodiment 1, wherein the urease is hydroxyethyl urea.

Embodiment 7. The storage stable topical composition of Embodiment 1, wherein the urease is a mixture of urea and hydroxyethyl urea.

Aspect 8. A storage stable topical composition according to any one of Aspects 1-7, comprising 5-20% urease.

Aspect 9. A storage stable topical composition according to any one of Aspects 1-7, comprising 5-15% urease.

Aspect 10. A storage stable topical composition according to any one of Aspects 5-7, comprising 5-10% urease.

Aspect 11. A storage stable topical composition according to any one of Aspects 1-10 comprising 5-25% ascorbic acid.

Aspect 12. The storage stable topical composition of any one of Aspects 1-10 comprising 5-25% ascorbic acid.

Aspect 13. A storage stable topical composition according to aspects 1 to 10 comprising 20 to 25% ascorbic acid.

Aspect 14. The method of any one of Aspects 1-13, wherein the solvent is 1,3 propanediol, 1,2 propanediol, 1,3 butanediol, 1,5 pentanediol, 1,2 hexanediol, 1,6 hexane A storage stable topical composition selected from diols, glycerol, diglycerol, ethoxydiglycol, ethanol, isopropyl alcohol, and dimethyl isosorbide.

Embodiment 15. The storage stable topical composition of embodiment 14, wherein the solvent is 1,3 propanediol.

Embodiment 16. The storage stable topical composition of embodiment 14, wherein the solvent is a mixture of 1,3 propanediol and 1,2 hexanediol.

Embodiment 17. The storage stable topical composition of any one of Embodiments 1-16, wherein the chemical exfoliant is an alpha hydroxy acid or benzoic acid.

Embodiment 18. The method of any one of Embodiments 1-17, wherein the chemical exfoliant is glycolic acid, lactic acid, mandelic acid, salicylic acid, capryloyl salicylic acid, salicyloyl phytosphingosine, phenol, gluconolactone, lactobionic acid , maltobionic acid, and combinations thereof.

Embodiment 19. The storage stable topical composition of Embodiment 17 or Embodiment 18, wherein the chemical exfoliant is salicylic acid.

Aspect 20. The storage stable topical composition of aspect 19 comprising 2 to 20% by weight of salicylic acid.

Aspect 21. The storage stable topical composition of aspect 20 comprising 2% salicylic acid by weight.

Aspect 22. The storage stable topical composition of aspect 20 comprising 5 to 15 weight percent salicylic acid.

Aspect 23. The storage stable topical composition of aspect 22 comprising 10% salicylic acid by weight.

Embodiment 24. The method of any one of Embodiments 1-23, wherein the one or more optional additional ingredients are selected from tocopherols, tocotrienols (e.g., alpha, beta, delta, and gamma tocopherols or alpha, beta, delta, and gamma tocotrienols), Azelaic acid, cinnamic acid or cinnamic acid derivatives, panthenol, Pine maritime pine bark extract, emulsifier, hyaluronic acid complex, madecassoside, madecassoside asiaticoside, acetyl gingerone, bakuchiol, diglycerin, bis ethylhexylhydride A storage stable topical composition selected from oxydimethoxybenzylmalonate, and dimethyl isosorbide.

Aspect 25. according to any one of aspects 1 to 24,

25% by weight of ascorbic acid;

20% by weight of urease; and

2% by weight of salicylic acid;

A storage stable topical composition comprising 53% by weight of 1,3 propanediol dissolving the above ingredients.

Aspect 26. according to any one of aspects 1 to 24,

20% by weight of ascorbic acid;

17% by weight of urease;

10% by weight of salicylic acid; and

A storage stable topical composition comprising 53% by weight of 1,3 propanediol.

Embodiment 27. The storage stable topical composition of any one of Embodiments 1-24, wherein the ratio of ascorbic acid to urease is from 1.0 to 2.2.

Embodiment 28. The storage stable topical composition of any one of Embodiments 1-24, wherein the ratio of ascorbic acid to urease is from 1.10 to 1.25.

Embodiment 29. The storage stable topical composition of Embodiment 24, wherein the one or more optional additional ingredients comprises acetyl zingerone.

Embodiment 30. The storage stable topical composition of embodiment 29 comprising less than or equal to 2% by weight of acetyl zingerone.

Embodiment 31. The storage stable topical composition of embodiment 30 comprising about 0.5% by weight of acetyl zingerone.

Embodiment 32. The storage stable topical composition of embodiment 24, wherein the one or more optional additional ingredients comprises cinnamic acid or a cinnamic acid derivative.

Embodiment 33. The storage stable topical composition of embodiment 32, wherein the cinnamic acid derivative is selected from ferulic acid, caffeic acid, coumaric acid, cinapic acid, and derivatives thereof.

Embodiment 34. The storage stable topical composition of embodiment 33 comprising from 0.1 to 2% by weight of ferulic acid.

Aspect 35. The storage stable topical composition of aspect 33 comprising 1% by weight or less of ferulic acid.

Embodiment 36. The storage stable topical composition of embodiment 33 comprising about 0.5% by weight ferulic acid.

Aspect 37. A storage stable topical composition according to any one of aspects 1 to 36 comprising 40 to 60% by weight of a solvent comprising propanediol.

Aspect 38. A storage stable topical composition according to any one of aspects 1 to 37 comprising 53% by weight of a solvent comprising propanediol.

Aspect 39. A storage stable topical composition according to any one of aspects 1 to 37 comprising 43% by weight of a solvent comprising propanediol.

Embodiment 40. The storage stable topical composition of any one of Embodiments 1-37 comprising 43% by weight of a solvent comprising propanediol and 10% dimethyl isosorbide.

Embodiment 41. The storage stable topical composition of embodiment 24, wherein the one or more optional additional ingredients comprises 0.5% by weight of diglycerin and Pine maritime pine bark extract.

Embodiment 42. The storage stable topical composition of any one of Embodiments 1-23, wherein the one or more optional additional ingredients comprises azelaic acid.

Embodiment 43. The storage stable topical composition of embodiment 42 comprising from 3% to 10% azelaic acid by weight.

Embodiment 44. The storage stable topical composition of embodiment 42 comprising about 7.5% by weight azelaic acid.

Embodiment 45. The storage stable topical composition of any one of embodiments 1-23, wherein the one or more optional additional ingredients comprises madecassoside.

Aspect 46. An emulsion composition comprising:

a composition according to any one of aspects 1 to 45;

oil component; and

An emulsion composition comprising an optional emulsifier.

Embodiment 47. The emulsion composition of Embodiment 46, wherein the oil component is silicone-based.

Aspect 48. The emulsion composition according to aspect 46 or aspect 47, comprising an emulsifier.

Embodiment 49. The emulsion composition of Embodiment 48, wherein the emulsifier is selected from polysorbate, laureth-4, potassium cetyl sulfate, and silicone and silicone-elastomer based emulsifiers and emulsion blends.

Embodiment 50. A ready-to-use topical preparation of the storage stable topical composition in a multi-use container pre-filled with the storage stable topical composition according to any one of embodiments 1-45, wherein the multi-use container contains a single administration of the storage stable topical composition. A topical preparation comprising means for dispensing the amount.

Embodiment 51. The topical formulation of embodiment 50, wherein the storage stable topical composition exhibits degradation of less than 5 mol % ascorbic acid after storage for 6 weeks at 40°C ± 2°C in the container.

Embodiment 52. The topical formulation of embodiment 50, wherein the storage stable topical composition exhibits degradation of less than 5 mol % ascorbic acid after storage for 6 months at 40°C ± 2°C in the container.

Embodiment 53. The topical formulation of any one of embodiments 50-52, wherein the storage stable topical composition is sealed within a container.

Embodiment 54. The topical formulation of any one of embodiments 50-53, wherein the container is disposed within a package.

Embodiment 55. A process for preparing a stable topical composition comprising:

5% to 28% by weight of ascorbic acid;

5% to 20% by weight of urease;

2% to 30% by weight of a chemical exfoliant; and

less than 10% by weight of one or more optional additional ingredients in total

combining with a non-aqueous skin compatible solvent comprising a polyol, C(2-6) alkanediol, glycol ether, dimethyl ether, ethanol, isopropyl alcohol, or combinations thereof;

A process for preparing a stable topical composition wherein ascorbic acid is dissolved at a concentration [AA] that is greater than its maximum concentration [X] in solvent alone and urea is dissolved at a concentration that is at least about ([AA]-[X])*1.25 .

Aspect 56. A product produced by the process according to aspect 55.

Embodiment 57. The product of embodiment 56, which is a chemical exfoliation formulation.

High Potency Vitamin C and Sugar Alcohol Topical Formulation

Aspect 1. A storage stable topical liquid composition comprising:

(a) 5% to 28% by weight of ascorbic acid;

(b) 5% to 20% by weight of a sugar alcohol agent; and

less than 10% by weight of one or more optional additional components in total;

A storage stable topical liquid composition comprising a non-aqueous skin compatible solvent comprising a polyol, C(1-6) alkanediol, glycol ether, dimethyl ether, or a combination thereof, which dissolves the above ingredients.

Embodiment 2. The storage stable topical liquid composition of Embodiment 1, wherein the composition exhibits degradation of less than 3 mol% ascorbic acid after storage for 8 weeks at 40°C ± 2°C in a sealed container.

Embodiment 3. The storage stable topical liquid composition of Embodiment 1, wherein the composition exhibits degradation of less than 3 mol% ascorbic acid after storage for 8 months at 40°C ± 2°C in a multipurpose container.

Embodiment 4. The storage stable topical liquid composition of Embodiment 1, wherein the composition exhibits degradation of less than 5 mol% ascorbic acid after storage for 16 months at 40°C ± 2°C in a multipurpose container.

Aspect 5. The storage stable topical liquid composition according to any one of Aspects 1 to 4, wherein the sugar alcohol agent is selected from xylitol and xylitol derivatives.

Embodiment 6. The storage-stable topical use according to any one of Embodiments 1 to 5, wherein the sugar alcohol agent is selected from xylityl glucoside, anhydroxylitol, sorbitol, lactitol, maltitol, erythritol, mannitol, and combinations thereof. liquid composition.

Aspect 7. The storage stable topical liquid composition according to any one of Aspects 1 to 4, wherein the sugar alcohol agent is a C5 to C6 sugar alcohol.

Embodiment 8. The storage stable topical liquid composition according to Embodiment 7, wherein the sugar alcohol agent is xylitol.

Aspect 9. The storage stable topical liquid composition of aspect 8 comprising 7 to 20% by weight of xylitol.

Aspect 10. The storage stable topical liquid composition of Aspect 9 comprising 7 to 15% by weight of xylitol.

Aspect 11. A storage stable topical liquid composition according to aspect 10 comprising 10 to 15% by weight of xylitol.

Aspect 12. The storage stable topical liquid composition of aspect 10 comprising 7 to 10% by weight of xylitol.

Aspect 13. A storage stable topical liquid composition according to any one of Aspects 8-12 comprising 10 to 20% by weight of ascorbic acid.

Aspect 14. The storage stable topical liquid composition of any one of Aspects 8-12, comprising 15 to 20% by weight of ascorbic acid.

Aspect 15. The storage stable topical liquid composition of any one of Aspects 8-12 comprising 15% by weight of ascorbic acid.

Aspect 16. The method of any one of Aspects 1-15, wherein the solvent is 1,3 propanediol, 1,2 propanediol, 1,3 butanediol, 1,5 pentanediol, 1,2 hexanediol, 1,6 hexane A storage stable topical liquid composition selected from diols, glycerol, diglycerol, ethoxydiglycol, and dimethyl isosorbide.

Aspect 17. The storage stable topical liquid composition of any one of Aspects 1-16, wherein the solvent is 1,3 propanediol.

Aspect 18. The storage stable topical liquid composition of any one of Aspects 1-16, wherein the solvent is a mixture of 1,3 propanediol and 1,2 hexanediol.

Aspect 19. A storage stable topical liquid composition according to any one of Aspects 1-18, comprising one or more additional ingredients.

Aspect 20. The storage stable topical liquid composition of aspect 19, wherein the one or more optional additional ingredients comprises a chemical exfoliant (eg, 0.1-2% of the composition).

Embodiment 21. The storage stable topical liquid composition of embodiment 20, wherein the chemical exfoliant is salicylic acid.

Aspect 22. The storage stable topical liquid composition of any one of Aspects 19-21, wherein the one or more additional ingredients comprises a moisturizer (eg, 1-5% of the composition).

Embodiment 23. The storage stable topical liquid composition of embodiment 22, wherein the humectant is urease or glycerin.

Embodiment 24. The method of embodiment 19, wherein the one or more additional ingredients are selected from tocopherols, tocotrienols (e.g., alpha, beta, delta, and gamma tocopherols or alpha, beta, delta, and gamma tocotrienols), azelaic acid, hydroxy acids (e.g., alpha, beta, delta, and gamma tocotrienols). For example, salicylic acid), urease, panthenol, Pine maritime pine bark extract, ferulic acid, glycerin, emulsifier, hyaluronic acid complex, madecassoside, madecassoside asiaticoside, acetyl gingerone, bakuchiol, and bis ethylhexyl A storage stable topical liquid composition selected from hydroxydimethoxybenzylmalonates.

Embodiment 25. The storage stable, topical liquid composition of embodiment 19, wherein the one or more optional additional ingredients are selected from one or more of salicylic acid, ferulic acid, Pine maritime pine bark extract, urease, and glycerin.

Aspect 26. The storage stable topical liquid composition of any one of aspects 19-25 comprising 0.5% salicylic acid.

Aspect 27. The storage stable topical liquid composition of any one of aspects 19-25 comprising 0.5% ferulic acid.

Aspect 28. The storage stable topical liquid composition of aspect 27 comprising 0.5% salicylic acid and 0.5% ferulic acid.

Aspect 29. The storage stable topical liquid composition of any one of aspects 19-25 comprising 1.5% ferulic acid.

Embodiment 30. The storage stable topical liquid composition of any one of embodiments 19-30 comprising 0.5% Pine maritime pine bark extract.

Aspect 31. The storage stable topical liquid composition of any one of aspects 19-30, wherein the at least one additional ingredient comprises urease.

Embodiment 32. The storage stable topical liquid composition of embodiment 31, wherein the urease is selected from urea, hydroxyethyl urea, or a combination of urea and hydroxyethyl urea.

Aspect 33. The storage stable topical liquid composition of aspect 32 comprising 2.5% urea.

Embodiment 34. The storage stable topical liquid composition of embodiment 33 comprising 2.5% urea, 0.5% salicylic acid, and 0.5% ferulic acid.

Embodiment 35. The storage stable topical liquid composition of any one of Embodiments 1-34, wherein the ascorbic acid is dissolved at a concentration greater than its maximum concentration in the solvent alone.

Aspect 36. according to any one of aspects 1 to 19,

15% to 20% by weight of ascorbic acid;

7% to 10% by weight of xylitol; and

less than 10% by weight total of one or more optional additional components selected from urea, salicylic acid, and ferulic acid;

A storage stable topical liquid composition comprising 1,3 propanediol or 1,2 propanediol dissolving the above components.

Aspect 37. The storage stable topical liquid composition of aspect 36 comprising about 15% by weight of ascorbic acid.

Aspect 38. The storage stable topical liquid composition of aspect 36 or aspect 37 comprising 7.5% by weight of xylitol.

Aspect 39. The storage stable topical liquid composition of any one of Aspects 36-38 comprising 2.5% by weight of urea.

Aspect 40. The storage stable topical liquid composition of any one of Aspects 36-39 comprising 0.5% by weight of salicylic acid.

Aspect 41. The storage stable topical liquid composition of any one of Aspects 36-40 comprising 0.5% by weight of ferulic acid.

Aspect 42. The storage stable topical liquid composition of Aspect 1, which is of Table 8.

Aspect 43. The storage stable topical liquid composition of Aspect 1, which is of Table 9.

Embodiment 44. The storage stable topical liquid composition of any one of embodiments 1-43, wherein the xylitol containing composition reduces or eliminates pathogenic staphylococcal mutations while maintaining staphylococcal integrity when applied to the skin.

Embodiment 45. A ready-to-use topical formulation in a multi-use container prefilled with the storage stable topical composition according to any one of embodiments 1-43, wherein the multi-use container is configured to dispense a single dose of the storage stable topical composition. A topical preparation comprising a means for

Embodiment 46. The topical formulation of embodiment 45, wherein the storage stable topical composition exhibits degradation of less than 3 mol % ascorbic acid after storage for 4 weeks at 40°C ± 2°C in the container.

Embodiment 47. The topical formulation of embodiment 45, wherein the storage stable topical composition exhibits degradation of less than 3 mol % ascorbic acid after storage for 8 months at 40°C ± 2°C in the container.

Embodiment 48. The topical formulation of embodiment 45, wherein the storage stable topical composition exhibits degradation of less than 5 mol% ascorbic acid after storage for 16 months at 40°C ± 2°C in the container.

Embodiment 49. The topical formulation of any one of embodiments 45-48, wherein the storage stable topical composition is sealed from the atmosphere in a container.

Embodiment 50. The topical formulation of any one of embodiments 45-49, wherein the container is disposed within a package.

Non-aqueous urea emulsion composition

Embodiment 1. A storage stable topical emulsion composition comprising the following (a) and (b):

(a) an internal phase which is a homogeneous solution,

1% to 30% by weight of urease;

an internal phase comprising at least 10% by weight of a non-aqueous skin compatible solvent selected from polyols, C(1-6) alkanediols, glycol ethers, dimethyl ethers, and combinations thereof, which dissolve the components; and

(b) an external phase comprising at least 10% by weight of a silicone agent, by weight of the composition, selected from cyclic, linear, and branched silicones, silicone crosspolymers, and combinations thereof;

wherein the internal phase is immiscible with the external phase and is contained within the external phase.

Embodiment 2. The storage stable topical emulsion composition of Embodiment 1, wherein the external phase is a silicone solution in an oil phase.

Embodiment 3. The method of Embodiment 1 or Embodiment 2, wherein the silicone agent is dimethicone, PEG-10/15 crosspolymer, dimethicone/polyethylene glycol (PEG)-10/15 crosspolymer, lauryl PEG-9 polydimethylsiloxyethyl A storage stable topical emulsion composition selected from dimethicone, and combinations thereof.

Aspect 4. The storage stable topical emulsion composition according to any one of Aspects 1 to 3, comprising 5 to 20% by weight of a silicone agent.

Embodiment 5. The storage stability (e.g., non-aqueous) of any one of Embodiments 1-4 after storage at 25 °C ± 2 °C or 40 °C ± 2 °C for 6 weeks in a sealed container. A storage stable topical emulsion composition, which exhibits degradation of less than 10 mol% of urease in a skin compatible solvent.

Embodiment 6. The method of any one of Embodiments 1-4, wherein storage stability (eg, non-aqueous skin A storage stable topical emulsion composition, which exhibits degradation of less than 10 mol% of urease in a compatible solvent.

Embodiment 7. The method of any one of Embodiments 1-4, wherein storage stability (e.g., non-aqueous skin A storage stable topical emulsion composition, which exhibits degradation of less than 10 mol% of urease in a compatible solvent.

Embodiment 8. The storage stable topical emulsion composition according to any one of Embodiments 1 to 7, wherein the urease is urea.

Embodiment 9. The storage stable topical emulsion composition of any one of Embodiments 1-7, wherein the urease is hydroxyethyl urea.

Aspect 10. The storage stable topical emulsion composition of any one of Aspects 1-7, wherein the urease is a mixture of urea and hydroxyethyl urea.

Aspect 11. The method of any one of Aspects 1-10, wherein the non-aqueous solvent is 1,3 propanediol, 1,2 propanediol, 1,3 butanediol, 1,5 pentanediol, 1,2 hexanediol, 1 ,6 A storage stable topical emulsion composition selected from hexanediol, glycerol, diglycerol, ethoxydiglycol, dimethyl isosorbide, and combinations thereof.

Embodiment 12. The storage stable topical emulsion composition of Embodiment 11, wherein the solvent is 1,3 propanediol.

Aspect 13. A storage stable topical emulsion composition according to any one of aspects 1 to 12, which exhibits a rate of urea degradation that is less than the rate of urea degradation of a homogeneous inner phase solution in the absence of an outer phase emulsion.

Aspect 14. A storage stable topical emulsion composition according to any one of Aspects 1-13, comprising from 20% to 80% by weight of an external phase of silicone.

Aspect 15. A storage stable topical emulsion composition according to any one of aspects 1 to 14, comprising from 5% to 20% by weight of urease.

Embodiment 16. The storage stable topical emulsion composition according to any one of Embodiments 1 to 15, wherein the weight percent ratio of the inner phase to the outer phase in the composition is 19 or less.

Aspect 17. The storage stable topical emulsion composition according to any one of Aspects 1 to 16, further comprising up to 10% by weight total of one or more optional additional ingredients dissolved in the first phase and/or the outer phase.

Embodiment 18. The method of embodiment 17, wherein the one or more optional additional ingredients are tocopherols, tocotrienols (e.g., alpha, beta, delta, and gamma tocopherols or alpha, beta, delta, and gamma tocotrienols), ferulic acid, ascorbic acid, azela Acids, hydroxy acids (eg, salicylic acid), panthenol, Pine marigold bark extract, hyaluronic acid complex, cholesterol esters, cholesterol, ceramides, linoleic acid, linolenic acid, madecassoside, acetyl gingerone, bakuchiol, bis- A storage stable topical emulsion composition selected from ethylhexyl hydroxydimethoxy benzylmalonate, zinc oxide, and titanium dioxide.

Aspect 19. The storage stable topical emulsion composition of any one of Aspects 1-18 comprising from about 5% to about 20% by weight of urea.

Aspect 20. The storage stable topical emulsion composition of any one of Aspects 1-19, comprising about 5% by weight of urea.

Aspect 21. The storage stable topical emulsion composition of aspect 19 comprising about 10% by weight of urea.

Aspect 22. The storage stable topical emulsion composition of any one of Aspects 17-21, wherein the optional additional ingredient comprises ascorbic acid.

Embodiment 23. A storage stable topical emulsion composition according to embodiment 22, comprising up to 20% ascorbic acid by weight dissolved in the inner or outer phase.

Embodiment 24. The storage stable topical emulsion composition of embodiment 23 comprising about 5% to 10% by weight of ascorbic acid dissolved in the inner or outer phase.

Aspect 25. The storage stable topical emulsion composition of any one of Aspects 17-24, wherein the optional additional ingredient comprises ferulic acid.

Aspect 26. The storage stable topical emulsion composition of aspect 25 comprising 0.1% to 2% by weight of ferulic acid.

Aspect 27. The storage stable topical emulsion composition of any one of aspects 17-26, wherein the optional additional ingredient comprises vitamin E.

Embodiment 28. The storage stable topical emulsion composition of Embodiment 27, wherein the vitamin E is selected from alpha, beta, delta, and gamma tocopherols and alpha, beta, delta, and gamma tocotrienols, and combinations thereof.

Aspect 29. A storage stable topical emulsion composition according to aspect 27 comprising up to 2% by weight of vitamin E.

Aspect 30. The storage stable topical emulsion composition of any one of Aspects 17-29, wherein the optional additional ingredient comprises about bis-ethylhexyl hydroxydimethoxy benzylmalonate.

Aspect 31. A storage stable topical emulsion composition according to aspect 30 comprising no more than 2% by weight of bis-ethylhexyl hydroxydimethoxy benzylmalonate.

Aspect 32. The storage stable topical emulsion composition of any one of Aspects 17-31, wherein the optional additional ingredient comprises retinol.

Aspect 33. A storage stable topical emulsion composition according to aspect 32, comprising less than or equal to 1% by weight of retinol.

Aspect 34. The storage stable topical emulsion composition of any one of aspects 17-33, wherein the optional additional ingredient comprises azelaic acid.

Embodiment 35. The storage stable topical emulsion composition of embodiment 34 comprising from 2% to 10% by weight of azelaic acid.

Embodiment 36. The storage stable topical emulsion composition of embodiment 34 comprising 5% by weight azelaic acid.

Embodiment 37. The storage stable topical emulsion composition of any one of embodiments 17-36, wherein the optional additional ingredient comprises bakuchiol.

Embodiment 38. The storage stable topical emulsion composition of embodiment 37 comprising no more than 2% bakuchiol by weight.

Embodiment 39. The storage stable topical emulsion composition of any one of embodiments 17-38, wherein the optional additional ingredient comprises a C10 to C30 cholesterol/lanosterol ester.

Embodiment 40. The storage stable topical emulsion composition of embodiment 39 comprising no more than 5% by weight of a C10 to C30 cholesterol/lanosterol ester.

Embodiment 41. The storage stable topical emulsion composition of any one of embodiments 17-40, wherein the optional additional ingredient comprises madecassoside asiaticoside.

Embodiment 42. A storage stable topical emulsion composition according to embodiment 41 comprising less than or equal to 1% by weight of madecassoside asiaticoside.

Embodiment 43. The storage stable topical emulsion composition of embodiment 41, wherein the optional additional ingredient comprises glycyrrhetinic acid.

Embodiment 44. The storage stable topical emulsion composition of embodiment 43 comprising less than or equal to 1% by weight of glycyrrhetinic acid.

Embodiment 45. The storage stable topical emulsion composition of any one of Embodiments 17-43, wherein the optional additional ingredient comprises Pine maritime pine bark extract.

Embodiment 46. The storage stable topical emulsion composition of embodiment 45 comprising from 0.5% to 2% by weight of Pine maritime pine bark extract.

Aspect 47. The storage stable topical emulsion composition of any one of Aspects 17-46, wherein the optional additional ingredient comprises a ceramide.

Embodiment 48. The storage stable topical emulsion composition of Embodiment 47, wherein the ceramide is selected from ceramide EOP, ceramide AP, ceramide NG, ceramide NP, ceramide NS, ceramide EOS, ceramide S, ceramide AS, and combinations thereof.

Embodiment 49. The storage stable topical emulsion composition of embodiment 47 comprising 2% by weight or less of ceramide.

Embodiment 50. The storage stable topical emulsion composition of any one of embodiments 17-47, wherein the optional additional ingredient comprises cholesterol.

Embodiment 51. The storage stable topical emulsion composition of embodiment 50 comprising less than 2% cholesterol by weight.

Embodiment 52. The storage stable topical emulsion composition of embodiment 52, wherein the optional additional ingredient comprises a free fatty acid.

Embodiment 53. The storage stable topical emulsion composition of embodiment 52, wherein the free fatty acid is selected from linoleic acid, linolenic acid, stearic acid, palmitic acid, oleic acid, alpha-linoleic acid, oleic acid, and combinations thereof.

Embodiment 54. The storage stable topical emulsion composition of embodiment 53 comprising less than 1% by weight of free fatty acids.

Embodiment 55. The storage stable topical emulsion composition of any one of embodiments 1-54, wherein the droplets of the inner phase are contained within the outer phase.

Embodiment 56. A ready-to-use topical formulation in a multi-use container pre-filled with the storage stable topical composition according to any one of embodiments 1-55, wherein the multi-use container is used for dispensing a single dose of the storage stable topical composition. A topical preparation comprising means.

Embodiment 57. The topical formulation of embodiment 56, wherein the multi-use container is a sustained release container that provides a constant delivery of urea over a period of time.

Embodiment 58. The topical formulation of embodiment 57, wherein the sustained release container does not release all of the urea at one time.

Embodiment 59. The topical composition of embodiment 56, wherein the storage stable topical composition exhibits degradation of less than 10 mol% urea after storage for 6 weeks at 25°C ± 2°C or 40°C ± 2°C in the container. preparations.

Embodiment 60. The topical composition of embodiment 56, wherein the storage stable topical composition exhibits degradation of less than 10 mol% urea after storage for 6 months at 25°C ± 2°C or 40°C ± 2°C in the container. preparations.

Embodiment 61. The topical formulation of any one of embodiments 56-60, wherein the storage stable topical composition is sealed within a container.

Embodiment 62. The topical formulation of any one of embodiments 56-62, wherein the container is disposed within a package.

Embodiment 63. A method of preparing a storage stable emulsion composition for topical application, comprising:

1% to 30% by weight of a urease selected from urea, hydroxyethyl urea, and combinations thereof;

10% to 80% by weight or more of a non-aqueous skin compatible solvent selected from polyols, C(1-6) alkanediols, glycol ethers, dimethyl ethers, and combinations thereof;

optionally by combining one or more additional agents,

urease and one or more additional agents are dissolved in a non-aqueous solvent to create an internal phase that is a homogeneous solution; and

suspending in the inner phase an outer phase comprising at least 10% by weight of a silicone compound dissolved in an oil phase solution;

A method for preparing a storage stable emulsion composition comprising the step of producing a storage stable emulsion composition.

Embodiment 64. The method of preparing the storage stable emulsion composition of Embodiment 61, wherein the silicone compound is selected from cyclic, linear, and branched silicones, silicone crosspolymers, and combinations thereof.

Embodiment 65. The method of preparing a storage stable emulsion composition of Embodiment 61 or Embodiment 62, wherein the at least one additional agent comprises ascorbic acid.

Embodiment 66. The method of preparing the storage stable emulsion composition of Embodiment 61, wherein the internal phase comprises up to 20% by weight ascorbic acid.

Embodiment 67. The method of preparing the storage stable emulsion composition of embodiment 64, wherein the internal phase comprises from about 5% to about 10% ascorbic acid by weight.

Aspect 68. The method of any one of Aspects 61-65, wherein the one or more additional agents comprises ferulic acid.

Embodiment 69. The method of preparing the storage stable emulsion composition of embodiment 66 comprising no more than 2% by weight of ferulic acid.

Embodiment 70. The method of embodiment 61, wherein the one or more additional agents are

0.5% to about 2% ferulic acid; and

A process for preparing a storage stable emulsion composition comprising 0.5% to 2% of Pine maritime pine bark extract.

Embodiment 71. The method of preparing the storage stable emulsion composition of embodiment 61, wherein the at least one additional agent comprises from about 3% to about 10% by weight of azelaic acid.

Embodiment 72. The method of preparing a storage stable emulsion composition according to any one of embodiments 61 to 69, wherein the external phase further comprises a lipid component.

Embodiment 73. The method of preparing the storage stable emulsion composition of embodiment 70, wherein the lipid component is selected from cholesterol, ceramides, free fatty acids, and combinations thereof.

Embodiment 74. The method of any one of Embodiments 61-71, wherein the external phase prevents or reduces precipitation of urea out of the emulsion composition.

Embodiment 75. The method of any one of Embodiments 61-72, wherein prior to dissolution in a non-aqueous solvent, the urease is a crystalline form of urease having a particle size of at least about 100 μm.

Embodiment 76. The method of preparing a storage stable emulsion composition of Embodiment 70, wherein suspending the internal phase in the external phase prevents or reduces recrystallization of urea from the internal phase.

Embodiment 77. The method of preparing a storage stable emulsion composition according to embodiment 74, wherein the suspending step comprises suspending droplets of the inner phase into the outer phase.

Aspect 78. A product produced by the process according to any one of Aspects 61-77.

Embodiment 79. The product of embodiment 78, which is a serum.

Non-Aqueous Azelaic Acid Topical Formulation

Aspect 1. A storage stable topical composition comprising:

(a) 1% to 20% by weight of azelaic acid; and

(b) from 1% to 20% by weight of urease;

A storage stable topical composition comprising a non-aqueous skin compatible solvent comprising a polyol, C(3-6) alkanediol, glycol ether, dimethyl ether, or a combination thereof, which dissolves the above ingredients.

Aspect 2. The storage stable topical composition of aspect 1, wherein the composition is substantially free of water.

Aspect 3. The storage stable topical composition of aspect 1 comprising less than 1% by weight of water.

Aspect 4. The storage stable topical composition of Aspect 1, which is anhydrous.

Aspect 5. The storage stable topical composition of any one of Aspects 1-5, wherein the composition is substantially free of volatile alcohols.

Aspect 6. The storage stable topical composition of any one of Aspects 1-5, wherein the composition is substantially free of monohydric alcohol.

Embodiment 7. The storage stable topical composition of Embodiment 6, wherein the monohydric alcohol is selected from one or more of ethyl alcohol, methyl alcohol, isopropyl alcohol, butyl alcohol, amyl alcohol, and cetyl alcohol.

Embodiment 8. The storage stable topical composition of any one of Embodiments 1-7, wherein the urease is urea.

Embodiment 9. The storage stable topical composition of any one of Embodiments 1-8, wherein the urease is hydroxyethyl urea.

Embodiment 10. The storage stable topical composition of any one of Embodiments 1-9, wherein the urease is a mixture of urea and hydroxyethyl urea.

Aspect 11. The storage stable topical composition of any one of Aspects 1-10, wherein the solvent is 1,3 propanediol.

Aspect 12. The storage stable topical composition of any one of Aspects 1-11, wherein the solvent is a mixture of 1,3 propanediol and 1,2 hexanediol.

Embodiment 13. The method of any one of Embodiments 1-12, wherein storage stability (e.g., decomposition of less than 10 mol% urease and azelaic acid) after storage at 40°C ± 2°C for 6 weeks in a sealed container. ), a storage stable topical composition.

Embodiment 14. The method of any one of Embodiments 1 to 13, wherein storage stability (e.g., degradation of less than 10 mol% urease and azelaic acid) after storage at 25°C ± 2°C for 6 months in a multipurpose container. shown), a storage stable topical composition.

Embodiment 15. The method of any one of Embodiments 1-14, wherein storage stability (e.g., degradation of less than 10 mol% urease and azelaic acid) after storage at 25°C ± 2°C for 12 months in a multipurpose container. shown), a storage stable topical composition.

Aspect 16. The storage stable topical composition of any one of Aspects 1-15, comprising from 30% to 95% by weight of a non-aqueous solvent.

Aspect 17. The method of any one of Aspects 1-16, wherein the non-aqueous solvent is 1,3 propanediol, 1,2 propanediol, 1,3 butanediol, 1,5 pentanediol, 1,2 hexanediol, 1 ,6 A storage stable topical composition selected from hexanediol, glycerol, diglycerol, ethoxydiglycol, dimethyl isosorbide, and combinations thereof.

Embodiment 18. The storage stable topical composition of Embodiment 17, wherein the solvent is 1,3 propanediol.

Embodiment 19. The storage stable topical composition of any one of Embodiments 1-18, wherein the composition exhibits a rate of azelaic acid degradation that is less than the degradation rate of azelaic acid in the absence of urease.

Aspect 20. The storage stable topical composition of any one of Aspects 1-19, comprising from 5% to 20% by weight of azelaic acid.

Aspect 21. The storage stable topical composition of any one of Aspects 1-20, comprising from 10% to 20% by weight of azelaic acid.

Aspect 22. The storage stable topical composition of any one of Aspects 1-21, comprising from 10% to 15% (eg, from 10% to 12%) azelaic acid by weight.

Aspect 23. The storage stable topical composition of aspect 20 comprising from 5% to 12% azelaic acid by weight.

Aspect 24. The storage stable topical composition of aspect 20 comprising from 5% to 10% azelaic acid by weight.

Aspect 25. The storage stable topical composition of any one of Aspects 1-19 comprising about 5% by weight of azelaic acid.

Aspect 26. The storage stable topical composition of any one of Aspects 1-20 comprising about 10% by weight of azelaic acid.

Aspect 27. The storage stable topical composition of any one of Aspects 1-26, comprising from 1% to 10% by weight of urease.

Aspect 28. The storage stable topical composition of any one of Aspects 1-27 comprising from 3% to 10% by weight of urease.

Aspect 29. The storage stable topical composition of any one of Aspects 1-28, comprising from 5% to 10% by weight of urease.

Embodiment 30. The storage stable topical composition of any one of Embodiments 1-29, wherein the ratio of azelaic acid to urease is from 2.0 to 2.5.

Aspect 31. The storage stable topical composition of any one of Aspects 1-30, further comprising one or more optional additional ingredients up to a total of 10% by weight or less.

Embodiment 32. The method of embodiment 31, wherein the one or more optional additional ingredients are tocopherols, tocotrienols (e.g., alpha, beta, delta, and gamma tocopherols or alpha, beta, delta, and gamma tocotrienols), ferulic acid, ascorbic acid, azela Acids, hydroxy acids (e.g., salicylic acid), panthenol, Pine marigold bark extract, hyaluronic acid complex, cholesterol esters, cholesterol, ceramides, linoleic acid, linolenic acid, madecassoside, madecassoside asiaticoside, acetyl ginger A storage stable topical composition selected from rhone, bakuchiol, bis-ethylhexyl hydroxydimethoxy benzylmalonate, zinc oxide, and titanium dioxide.

Embodiment 33. The method of embodiment 32, wherein the at least one additional ingredient is at least one antioxidant selected from Vitis vinifera (grape) seed extract, Camellia sinensis leaf extract, Quercus robusta tree extract, and Pine maritime pine bark extract. A storage stable topical composition comprising a.

Embodiment 34. The storage stable topical composition of Embodiment 33, wherein the one or more additional ingredients comprises Vitis vinifera (grape) seed extract, Camellia sinensis leaf extract, Quercus lobur tree extract, and Pine maritime pine bark extract. composition for.

Embodiment 35. The storage stable topical composition of any one of embodiments 31-34, wherein the one or more additional ingredients comprises ascorbic acid.

Embodiment 36. The storage stable topical composition of embodiment 35 comprising no more than 10% by weight of ascorbic acid.

Embodiment 37. The storage stable topical composition of embodiment 36 comprising from 5% to 10% by weight of ascorbic acid.

Aspect 38. The storage stable topical composition of any one of Aspects 31-37, wherein the optional additional ingredient further comprises ferulic acid.

Aspect 39. The storage stable topical composition of aspect 38 comprising 2% by weight or less of ferulic acid.

Embodiment 40. The storage stable topical composition of any one of embodiments 31-39, wherein the one or more optional additional ingredients comprises vitamin E.

Embodiment 41. The storage stable topical composition of embodiment 40, wherein the vitamin E is selected from alpha, beta, delta, and gamma tocopherols and alpha, beta, delta, and gamma tocotrienols, and combinations thereof.

Embodiment 42. The storage stable topical composition of embodiment 40 comprising less than or equal to 2% by weight of vitamin E.

Embodiment 43. The storage stable topical composition of any one of Embodiments 31-42, wherein the one or more optional additional ingredients comprises bis-ethylhexyl hydroxydimethoxy benzylmalonate.

Aspect 44. The storage stable topical composition of aspect 43 comprising up to 2% by weight of bis-ethylhexyl hydroxydimethoxy benzylmalonate.

Aspect 45. The storage stable topical composition of any one of aspects 31-44, wherein the at least one optional additional ingredient is retinol.

Embodiment 46. The storage stable topical composition of embodiment 45 comprising less than or equal to 1% by weight retinol.

Embodiment 47. The storage stable topical composition of any one of embodiments 31-46, wherein the one or more optional additional ingredients comprises bakuchiol.

Embodiment 48. The storage stable topical composition of embodiment 47 comprising less than or equal to 1% bakuchiol by weight.

Embodiment 49. The storage stable topical composition of any one of embodiments 31-48, wherein the one or more optional additional ingredients comprises a C10 to C30 cholesterol/lanosterol ester.

Embodiment 50. The storage stable topical composition of embodiment 49 comprising no more than 5% by weight of a C10 to C30 cholesterol/lanosterol ester.

Embodiment 51. The storage stable topical composition of any one of embodiments 31-50, wherein the one or more optional additional ingredients comprises madecassoside.

Embodiment 52. The storage stable topical composition of embodiment 51 comprising less than or equal to 1% by weight of madecassoside.

Embodiment 53. The storage stable topical composition of any one of embodiments 31-52, wherein the one or more optional additional ingredients comprises glycyrrhetinic acid.

Embodiment 54. The storage stable topical composition of embodiment 53 comprising less than or equal to 1% by weight of glycyrrhetinic acid.

Embodiment 55. The storage stable topical composition of any one of embodiments 31-54, wherein the one or more optional additional ingredients comprises Pine maritime pine bark extract.

Embodiment 56. The storage stable topical composition of embodiment 55 comprising up to 2% by weight of Pine maritime pine bark extract.

Embodiment 57. The storage stable topical composition of any one of embodiments 31-56, wherein the one or more optional additional ingredients comprises a ceramide.

Embodiment 58. The storage stable topical composition of embodiment 57, wherein the ceramide is selected from ceramide EOP, ceramide AP, ceramide NG, ceramide NP, ceramide NS, ceramide EOS, ceramide S, ceramide AS, and combinations thereof.

Embodiment 59. The storage stable topical composition of embodiment 57 or embodiment 58 comprising no more than 2% by weight of ceramide.

Embodiment 60. The storage stable topical composition of any one of embodiments 31-59, wherein the one or more optional additional ingredients comprises cholesterol.

Embodiment 61. The storage stable topical composition of embodiment 60 comprising less than 2% cholesterol by weight.

Embodiment 62. The storage stable topical composition of any one of embodiments 31-61, wherein the one or more optional additional ingredients comprises a free fatty acid.

Embodiment 63. The storage stable topical composition of embodiment 62, wherein the free fatty acid is selected from linoleic acid, linolenic acid, stearic acid, palmitic acid, oleic acid, alpha-linoleic acid, oleic acid, and combinations thereof.

Embodiment 64. The storage stable topical composition of embodiment 62 or embodiment 63 comprising less than 1% by weight of free fatty acids.

Aspect 65. according to any one of aspects 30 to 64,

10% to 15% by weight of azelaic acid; and

5% to 10% by weight of urease;

A storage stable topical composition comprising a solvent comprising one or more C(3-6) alkanediols which dissolves the above components.

Embodiment 66. The storage stable topical composition of embodiment 65 comprising 12% by weight azelaic acid.

Embodiment 67. The storage stable topical composition of embodiment 65 comprising 10% by weight azelaic acid.

Embodiment 68. The storage stable topical composition of embodiment 65 or embodiment 67 comprising 5% by weight of urea.

Embodiment 69. The storage stable topical composition of any one of embodiments 65-68, wherein the solvent consists of 1,3-propanediol.

Embodiment 70. The method of any one of embodiments 65-68, wherein the solvent is a mixture of 1,3-propanediol and 1,2-hexanediol (e.g., at least 10:1, such as at least 15:1 or at least 20 :1 ratio), a storage stable topical composition.

Embodiment 71. The storage stable topical composition of embodiment 65, which is of Table 1 or Table 2.

Embodiment 72. The storage stable topical composition of any one of Embodiments 1 to 71 contained in an emulsion further comprising an external phase comprising at least 10% by weight of a silicone agent.

Embodiment 73. A ready-to-use topical formulation in a multi-use container prefilled with the storage stable topical composition according to any one of embodiments 1-72, wherein the multi-use container is configured to dispense a single dose of the storage stable topical composition. A topical preparation comprising means.

Embodiment 74. The topical formulation of embodiment 73, wherein the storage stable topical composition exhibits degradation of less than 10 mol% urea after storage for 6 weeks at 40°C ± 2°C in the container.

Embodiment 75. The topical formulation of embodiment 73, wherein the storage stable topical composition exhibits degradation of less than 10 mol% azelaic acid after storage for 6 months at 25°C ± 2°C in the container.

Embodiment 76. The topical formulation of any one of embodiments 73-75, wherein the storage stable topical composition is sealed within a container.

Embodiment 77. The topical formulation of any one of embodiments 73-76, wherein the container is disposed within a package.

Embodiment 78. A process for preparing a storage stable topical composition comprising:

1% to 20% by weight of azelaic acid;

1% to 20% by weight of a urease selected from urea, hydroxyethyl urea, and combinations thereof;

30% to 95% by weight of a non-aqueous skin compatible solvent selected from polyols, C(2-6) alkanediols, glycol ethers, dimethyl ethers, and combinations thereof;

optionally by combining one or more additional agents,

A process for preparing a storage stable topical composition comprising the step of dissolving urease and azelaic acid in a non-aqueous solvent to produce a storage stable, homogeneous solution.

Embodiment 79. The process of preparing a storage stable topical composition according to embodiment 78, further comprising suspending an emulsifier comprising 10% by weight of a silicone compound in said homogeneous solution to form a storage stable emulsion composition.

Embodiment 80. The process of preparing a storage stable topical composition of Embodiment 79, wherein the silicone compound is selected from cyclic, linear, and branched silicones, silicone crosspolymers, and combinations thereof.

Embodiment 81. The process of preparing a storage stable topical composition of embodiment 78, wherein the at least one additional agent comprises ascorbic acid.

Embodiment 82. The process of preparing the storage stable topical composition of embodiment 78, wherein the homogeneous solution comprises 20% by weight or less ascorbic acid.

Embodiment 83. The process of preparing the storage stable topical composition of embodiment 82, wherein the homogeneous solution comprises from about 5% to about 10% ascorbic acid by weight.

Embodiment 84. A process for preparing a storage stable topical composition according to any one of embodiments 78-83, wherein the one or more additional agents comprises ferulic acid.

Embodiment 85. The process of preparing the storage stable topical composition of embodiment 84, wherein the homogeneous solution comprises 2% by weight or less of ferulic acid.

Embodiment 86. The method of embodiment 78, wherein the one or more additional agents are

0.5% to about 2% by weight of ferulic acid; and

A process for the preparation of a storage stable topical composition comprising 0.5% to 2% by weight of Pine maritime pine bark extract.

Embodiment 87. The process of preparing a storage stable topical composition according to embodiment 79, wherein the emulsion composition further comprises a lipid component.

Embodiment 88. The process of preparing a storage stable topical composition according to embodiment 87, wherein the lipid component is selected from cholesterol, ceramides, free fatty acids, and combinations thereof.

Embodiment 89. The process of preparing a storage stable topical composition according to embodiment 79, wherein the emulsion composition prevents or reduces precipitation of urea out of the emulsion composition.

Embodiment 90. The process of preparing a storage stable topical composition according to embodiment 79, wherein the droplets of the homogeneous solution are contained within an outer phase of an emulsified solution.

Aspect 91. A product produced by the process according to any one of Aspects 78-90.

As will be apparent to those skilled in the art upon reading this disclosure, each individual embodiment described and illustrated herein can be readily separated from, or similar to, the features of any other several embodiments without departing from the scope or spirit of the present teachings. It has distinct components and properties that can be combined. Any recited method may be performed in the order listed or in any other order logically possible.

The invention is further defined by reference to the following examples. These examples are representative and should not be construed as limiting the scope of the present invention.

Example

Examples 1-5 relate to several formulations of the present disclosure, including a stabilized vitamin C topical formulation of the present disclosure, wherein the formulations include, for example, at least

5% to 28% by weight of ascorbic acid;

5% to 20% by weight of urease;

Optionally from 0.1% to 5% by weight of cinnamic acid or a derivative thereof; and

contains less than 10% by weight of one or more optional additional ingredients in total;

contains a non-aqueous skin compatible solvent comprising a polyol, C(2-6) alkanediol, glycol ether, dimethyl ether, or a combination thereof, which dissolves the above components; Ascorbic acid dissolves at a concentration (AA) that is greater than its maximum concentration (X) in solvent alone, and urea dissolves at a concentration that is at least (AA-X)*1.25.

Example 6 relates to a vitamin C chemical exfoliation solution formulation of the present disclosure, wherein the formulation comprises, for example, at least

5% to 28% by weight of ascorbic acid;

5% to 20% by weight of urease;

2% to 30% by weight of a chemical exfoliant; and

contains less than 10% by weight of one or more optional additional ingredients in total;

contains a non-aqueous skin compatible solvent comprising a polyol, C(2-6) alkanediol, glycol ether, dimethyl ether, ethanol, isopropyl alcohol, or a combination thereof, which dissolves the above ingredients; Ascorbic acid dissolves at a concentration [AA] that is greater than its maximum concentration [X] in solvent alone, and urea dissolves at a concentration that is at least ([AA]-[X])*1.25.

Examples 7-9 relate to vitamin C and sugar alcohol formulations of the present disclosure, wherein the formulations include, for example, at least

(a) 5% to 28% by weight of ascorbic acid;

(b) 5% to 20% by weight of a sugar alcohol agent; and

contains less than 10% by weight of one or more optional additional ingredients in total;

Contains a non-aqueous skin compatible solvent, including a polyol, C(1-6) alkanediol, glycol ether, dimethyl ether, or a combination thereof, which dissolves the above ingredients.

Examples 10-11 relate to anhydrous urea emulsion formulations of the present disclosure containing, for example, at least components (a) and (b): (a) at least 10% by weight of a polyol, C(1-6 ) 1% to 30% by weight of urease dissolved in a non-aqueous skin compatible solvent selected from alkanediols, glycol ethers, dimethyl ethers, or combinations thereof; and (b) an outer phase comprising at least 10% by weight of a silicone agent, by weight of the composition, selected from cyclic, linear, and branched silicones, silicone crosspolymers, and combinations thereof, wherein the inner phase is immiscible with the outer phase and the outer phase is Contained within -.

Examples 12-13 relate to non-aqueous azelaic acid formulations of the present disclosure.

Example 1: Evaluation of Ingredients in Stabilized Vitamin C Topical Formulations

A series of experiments were conducted to evaluate and optimize the components of the subject formulation. AA refers to L-ascorbic acid. U refers to urea. % values are weight percent.

Summary of experiment

Ascorbic Acid to Urea

- The maximum amount of AA solubilized in 1,3-propanediol before recrystallization was about 12%. This solubility limit was also observed for propylene glycol (1,2 propanediol).

- First: fully solubilize AA/U with 20% AA and 15% U in 1.3 propanediol.

- Reduced to 10% U content, still no recrystallization.

- reduced to a U content of 5% and recrystallization occurred.

- A U content of 8% was tested and recrystallization occurred.

- Thus, a U content of 10% appears to be close to the minimum amount of U required to solubilize 20% AA.

- U in combination with an AA content of 15%:

- 5% of U prevented recrystallization.

- 3.75% of U prevented recrystallization.

- 2.5% of U caused recrystallization.

- Maximum saturation level experiment

- 30% AA and 20% U in 1.3 propanediol resulted in recrystallization.

- 28% of AA, 20% of U fully solubilized AA without recrystallization.

- A limitation of this composition is the solubility of U in 1.3 propanediol - saturation of about 27.8% is reached before recrystallization of U is discernible.

- Using these numbers is how the following equation was obtained to determine the amount of U and thus the ratio of AA to U in high concentration ascorbic acid formulations:

- (AA-X)*1.25 = U %, where X = % maximum solubility of AA in the selected solvent. In this case, as mentioned above, X = 12%.

The above equation is appropriate for compositions containing ascorbic acid at a lower limit of 5%, since it includes other polyols such as dimethyl isosorbide (DMI) that provide very low or virtually no solubility of AA. to be. Thus, when a mixture of propanediol and DMI is used as the solvent, for example, the value of X may be 5% (the maximum solubility of AA) depending on the ratio of propanediol and DMI used.

menstruum

1,3 propanediol, 1,2 propanediol, butylene glycol, pentylene glycol, and hexanediol were identified as preferred solvents. 1,3 propanediol (trade name: Zemea) differs in nature from the various polyols described and is more preferred. Below is a review of the various polyols, why 1,3 propanediol is special and preferred:

1,3-Propanediol, sometimes referred to in the art as propanediol, has gentleness to the skin (even when applied unmixed or at 100% concentration), relatively low viscosity (and therefore "light on the skin"). It is unique in that it possesses a combination of environmental friendliness (not petroleum derived), natural derivatives (corn or sugarcane), low odor, and suitable ability to solubilize ascorbic acid.

1,2-propanediol, otherwise referred to in the art as propylene glycol, has a low viscosity and moderate ability to solubilize ascorbic acid, but is well known to cause skin irritation and sensitization. In addition, it is derived from petroleum and has an unpleasant odor reminiscent of acetone.

1,3-propanediol, otherwise referred to in the art as butylene glycol, is of low viscosity, possesses adequate ability to solubilize ascorbic acid, and is relatively mild to the skin. However, like propylene glycol, it is derived from petroleum (not environmentally friendly) and has an unpleasant odor reminiscent of acetone.

Also applicable to dipropylene glycol.

1,5-pentanediol, otherwise referred to in the art as pentylene glycol, possesses moderate ability to solubilize ascorbic acid, low odor, and certain versions are not derived from petroleum, but from sugar cane or corn. However, when applied to the skin, it imparts a less desirable "heavier" texture on the skin. In addition, its recommended use level is capped at a limit of 5% as the main solvent.

1,2-hexanediol possesses adequate ability to solubilize ascorbic acid. However, when applied to the skin, it gives a less desirable "heavier" texture on the skin, has an unpleasant odor reminiscent of acetone, and is derived from petroleum. In addition, its recommended usage level is capped at a limit usage of 10% as a major solvent.

Glycerin and diglycerin have adequate ability to solubilize ascorbic acid, are relatively mild to the skin, have a low odor, and are not derived from petroleum. However, they are of a very viscous nature and are overly tacky as well as imparting an undesirable “heavy” texture on the skin.

Dimethyl isosorbide is relatively mild to the skin, is not derived from petroleum, and imparts a desirable "light" texture when applied to the skin. However, it has a very limited ability to solubilize ascorbic acid and has a distinct, albeit slightly, chemical odor reminiscent of chlorine.

urease

Urea is preferred over hydroxyethyl urea. There are a number of reasons for this:

Urea possesses desirable wettability, barrier repair, and very mild keratolytic properties when used in sufficiently low concentrations (10-15% or less) in leave-on applications, and in combination with dry and/or harsh It is very effective in improving the feel and appearance of the skin.

Urea is naturally present in the human body as well as especially in the skin, where it serves as a natural moisturizing factor (NMF).

Hydroxyethyl urea has similar wetting properties to urea, but does not possess the same level of barrier repair and mild keratolytic properties.

Hydroxyethyl urea may also contain trace amounts of diethanolamine, which is listed as a potential carcinogen by California's Proposition 65 and requires warnings for products sold to consumers. For these reasons, at least one manufacturer of hydroxyethyl urea has stated that it will discontinue manufacturing of this component (AkzoNobel).

Optional Additional Ingredients

Additional ingredients were selected for their compatibility (eg, miscibility) with 1,3 propanediol, 1,2 propanediol, and 1,3 butanediol. Additional remarks and observations are made below for each optional additional ingredient that can be adapted for use in the compositions of the present disclosure.

Panthenol (pro-vitamin B5)

It is a humectant that exhibits soothing and moisturizing properties for the skin. Both the enantiomers, D-panthenol and L-panthenol, are powerful humectants. However, only D-panthenol is converted to pantothenic acid in the skin, conferring additional benefits to the skin (eg wound healing).

Studies indicate that panthenol can relieve irritation to the skin by other ingredients. Studies also indicate the ability of panthenol to repair barriers (stimulate physiological lipid synthesis).

DL-panthenol is a racemic mixture of two enantiomers; It is in powdered/crystalline form. D-panthenol is a viscous liquid. DL-panthenol is freely soluble (up to 50%) in 1,3 propanediol, 1,2 propanediol, and 1,3 propanediol. D-panthenol is also freely soluble in 1,3 propanediol, 1,2 propanediol, and 1,3 propanediol, and there is no risk of recrystallization at any concentration (since it is already a liquid at room temperature).

Inhibition of transepidermal water loss is evident at concentrations above 1%.

Panthenol is used as an optional additive in exemplary compositions of the present disclosure.

hyaluronic acid

Hyaluronic acid is a humectant that exhibits the ability to form a viscoelastic film on the skin that prevents transepidermal moisture inhibition.

It is usually incorporated in aqueous solutions in its salt form, sodium hyaluronate.

However, there are raw material formulations with very little water, in which case they are incorporated into the vehicle of glyceryl polymethacrylate, butylene glycol (1,3 butanediol), and natto gum (trade name Hydrafilm 3MW by The Innovation Company). do. This makes these ingredients compatible with the non-aqueous formulations of the present disclosure.

Documentation from The Innovation Company indicates usage of this material up to 9.1% by weight of the final formula.

The chemical composition is as follows:

75 to 85% glyceryl polymethacrylate

15 to 20% butylene glycol

0.5 to 2% natto gum

0.5 to 2% hyaluronic acid

Hyaluronic acid is optionally added to exemplary compositions of the present disclosure. In some cases, 0.5% to 2.0% by weight of hyaluronic acid is used.

Pine maritime pine bark extract

A component of the bark extract of Pine maritime pine species exhibits the ability to regenerate vitamin C.

There are also studies showing their general antioxidant, anti-inflammatory, and anti-acne properties.

Pycnogenol can be used as an alternative when Pine maritime pine bark extract is desired.

A material combination from Kinetik called Pantrofina Skin360 (PS360) is optionally used in the subject formulation.

Unlike Pycnogenol, PS360 is already in liquid form, making it very easy to incorporate it into the compositions of the present disclosure when diglycerin is used as a solvent.

In addition, Res Pharma Industriale provides in vitro and clinical data showing the effects of PS360 on free radical damage, inflammation, and acne at a concentration of 0.5% by weight.

The chemical composition is as follows:

90 to 95% diglycidine,

5-10% Pine maritime pine bark extract.

Pine maritime pine bark extract is optionally added to exemplary compositions of the present disclosure.

Madecassoside

Centella asiatica extract is usually used for its soothing properties.

Madecassoside is a highly glycosylated triterpene from Centella asiatica. It is marketed by ingredient supplier SEPPIC and shares in vitro and clinical data indicating its anti-inflammatory and other effects on skin.

Although this is a very expensive ingredient ($6.10 per gram), clinical data from SEPPIC indicates a desirable ability to reduce erythema (redness of the skin) at a concentration of 0.2%.

At a concentration of 0.2%, madecassoside is soluble in 1,3 propanediol, 1,2 propanediol, and 1,3 butanediol.

In some embodiments, the madecassoside is madecassoside asiaticoside.

azelaic acid

Azelaic acid (AzA) is widely studied for its ability to treat acne, rosacea, and melasma due to the fact that it has been studied and sold as a prescription drug. Although poorly understood, these effects are believed to be the result of AzA's antibacterial, anti-inflammatory, and keratolytic effects, as well as its inherent ability to induce apoptosis in abnormal melanocytes.

It is poorly soluble in most solvents. As a result, all products, both prescription drugs and cosmetics currently on the market, are sold as opaque emulsions, in which AzA is not solubilized, but instead finely milled into a powder and suspended in a viscous vehicle.

Because of the inability to solubilize AzA, a desirable ingredient to maximize the delivery of active ingredients into the skin, the team supporting the prescription drug product Finacea (now considered the gold standard) chose to adjust the pH, which is intuitive. This is because, counterintuitively, the salt form of AzA (formed in an aqueous environment with a pH higher than AzA's pKa, 4.15) was found to be slightly better at penetrating the skin.

The inventors have found that AzA can be solubilized in 1,3 propanediol at relatively high concentrations of up to 10%.

The solubility of AzA in 1,3 propanediol can be slightly increased in the presence of hydroxyethyl urea.

For example, 7.5% AzA can be solubilized with 10% AA, 5% U in 1.3 propanediol base.

Azelaic acid is optionally added to exemplary compositions of the present disclosure.

ferulic acid

Ferulic acid is an antioxidant that increases the photoprotective effect of AA on the skin. It may also stabilize AA somewhat in aqueous systems.

Ferulic acid is readily soluble in 1,3 propanediol, 1,2 propanediol, 1,3 butanediol, and dimethyl isosorbide.

In some cases, isosorbide can increase the effectiveness of ferulic acid by enhancing skin penetration.

Ferulic acid is optionally added to exemplary compositions of the present disclosure.

Acetyl Gingerone

Acetyl zingerone is a broad-spectrum antioxidant that can prevent lipid peroxidation. It has been engineered to be a more stable, more potent derivative of zingerone.

Sytheon provides in vitro and clinical data demonstrating its antioxidant, photoprotective, and antiaging properties.

Acetyl zingerone can be used as a substitute for tocopherol.

Acetyl gingerone is readily soluble in 1,3 propanediol, 1,2 propanediol, and 1,3 butanediol at desired concentrations (0.5 to 1%), eliminating the need for emulsifiers that would be required for tocopherols.

Acetyl zingerone is optionally added to exemplary compositions of the present disclosure.

glycyrrhizic acid

Like many other derivatives from licorice root (glycyrrhiza glabra, glycyrrhiza uralensis), glycyrrhizic acid exhibits anti-inflammatory, antioxidant, and skin lightening properties.

Unlike 18B-glycyrrhetinic acid, glycyrrhetic acid is soluble in 1,3-propanediol.

Other derivatives of licorice root may be used, such as dipotassium glycyrrhizate, monoammonium glycyrrhizate, and the like.

Glycyrrhizic acid is optionally added to exemplary compositions of the present disclosure.

Example 2: Exemplary Stabilized Vitamin C Topical Formulations

The exemplary formulations in Table 2 were prepared and evaluated.

Example 3: Exemplary Stabilized Vitamin C Topical Formulations

Ratio of ascorbic acid to urea

To determine the preferred ratio of ascorbic acid to urea in a composition of the present disclosure, ascorbic acid that can be solubilized by thermal exposure (below 80°C to prevent degradation of ascorbic acid) in a given solvent without precipitation upon cooling. First determine the maximum concentration for Experiments have shown that these concentrations are approximately 10-12% for 1,3 propanediol, propylene glycol (1,2, propanediol), and butylene glycol (1,3 butanediol), and significantly higher for dimethyl isosorbide. show low

Next, the concentration of ascorbic acid above the maximum concentration mentioned above is solubilized using urea as a co-solvent. Repetitive experiments of this nature using different concentrations and ratios of urea to ascorbic acid revealed the following relationship between these two materials (ascorbic acid and urea) useful for producing fully solubilized compositions that are storage stable:

(AA-X)*1.25 = U

AA = concentration of ascorbic acid

X = point of maximum solubilization of ascorbic acid in the selected solvent

U = concentration of urea

Compositions with ascorbic acid concentrations as low as 5% can be prepared if the polyol solvent used provides very low solubility, such as in dimethyl isosorbide (DMI). Thus, a mixture of propanediol and DMI can yield an X value (maximum solubility of AA) of 5% depending on the ratio of propanediol and DMI, for example.

Generally, 1,3 propanediol is preferred over 1,2 propanediol, butylene glycol, pentylene glycol, or hexanediol. 1,3 propanediol is preferred over various polyols described in the art. Below is a review of the various polyols, why 1,3 propanediol is special and preferred:

1,3-Propanediol, otherwise referred to in the art as propanediol, is hypoallergenic to the skin (even when applied unmixed or at 100% concentration), relatively low in viscosity (and therefore "light" on the skin). It is unique in that it possesses a combination of environmental friendliness (not petroleum derived), natural derivatives (corn or sugarcane), low odor, and suitable ability to solubilize ascorbic acid.

1,2-propanediol, otherwise referred to in the art as propylene glycol, has a low viscosity and moderate ability to solubilize ascorbic acid, but causes skin irritation and sensitization. In addition, it is derived from petroleum and has an unpleasant odor reminiscent of acetone.

1,3 Propanediol, otherwise referred to in the art as butylene glycol, is of low viscosity, possesses adequate ability to solubilize ascorbic acid, and is relatively mild to the skin. However, like propylene glycol, it is derived from petroleum (not environmentally friendly) and has an unpleasant odor reminiscent of acetone.

Note that these properties also apply to dipropylene glycol.

1,5 pentanediol, otherwise referred to in the art as pentylene glycol, has adequate ability to solubilize ascorbic acid, low odor, and certain versions are not derived from petroleum, but from sugar cane or corn. However, when applied to the skin, it imparts a less desirable "heavier" texture on the skin. In addition, its recommended use level is generally capped at a limit of 5% as the main solvent.

1,2 Hexanediol possesses adequate ability to solubilize ascorbic acid. However, when applied to the skin, it gives a less desirable "heavier" texture on the skin, has an unpleasant odor reminiscent of acetone, and is derived from petroleum. In addition, its recommended usage level is capped at a limit usage of 10% as a major solvent.

Glycerin and diglycerin have adequate ability to solubilize ascorbic acid, are relatively mild to the skin, have a low odor, and are not derived from petroleum. However, they are very viscous and impart an undesirable "heavy" texture on the skin as well as being overly tacky.

Dimethyl isosorbide is relatively mild to the skin, is not derived from petroleum, and imparts a desirable "light" texture when applied to the skin. However, it has a very limited ability to solubilize ascorbic acid and has a distinct, albeit slightly, chemical odor reminiscent of chlorine.

Urea is preferred over hydroxyethyl urea. There are a number of reasons for this, summarized below:

When used in low enough concentrations (10-15% or less) in leave-on applications, urea possesses desirable wettability, barrier repair, and very mild keratolytic properties, which in combination improve the feel and appearance of dry and/or rough skin. very effective in improving Urea is naturally present in the human body as well as especially in the skin, where it serves as a natural moisturizing factor (NMF).

Hydroxyethyl urea has wettability properties similar to urea, but does not possess barrier repair and mild keratolytic properties. Hydroxyethyl urea may also contain trace amounts of diethanolamine, a potential carcinogen.

Additional ingredients compatible with the ascorbic acid/solvent/urea combination of interest may be included.

The exemplary formulations of Table 3 were prepared and evaluated for having desirable properties including storage stability.

Other Variations: Dimethyl isosorbide, caprylyl glycol, or decylene glycol may be used as an alternative or additional solvent in the compositions of Table 2 or Table 3.

Example 4 Storage Stability of Stabilized Vitamin C Topical Formulations

stability method

Samples are stored in sealed containers, sealed from the atmosphere at 40 degrees Celsius for up to 12 weeks. The results from week 0 to week 8 are shown in Table 4. In general, 8 weeks of storage under these conditions is expected to equate to 16 months of storage at room temperature. The composition in the container is sampled at each time point and evaluated for the degree of degradation of vitamin C using HPLC analysis.

composition

An exemplary composition was prepared containing approximately 20% vitamin C (referenced formulation 6 in Table 3).

The storage stability of these compositions was improved with the addition of additional components of ferulic acid at a concentration of 0.5%, tocopherol and glycol ethers at a concentration of 1%, alkanediols, laureth-23, panthenol, triethanolamine, phenoxyethanol, and sodium hyaluronate. A control composition containing a clinically similar amount of vitamin C (15%) dissolved in water was compared. Results are shown in Table 4. Exemplary serum (approximately 15% vitamin C) compositions are out of specification (OOS) by 2 weeks of testing (or the equivalent of 4 months at room temperature), as opposed to control compositions that are out of specification (OOS) after 8 weeks of testing (or room temperature). Equivalent to 16 months at ) and still within the criterion.

Example 5: Comparative Study of Stabilized Vitamin C Topical Formulations

US Patent No. 6,020,367 (patent '367) attempted to demonstrate the feasibility of a "supersaturated solution" of vitamin C in a polyol. Although several compositions of the '367 patent have been prepared according to the present disclosure, many of the "supersaturated solutions" of vitamin C of the '367 patent do not remain substantially solubilized at room temperature over time. Rather, the solution initially produces a turbid appearance and then settles down, causing vitamin C crystals to develop. These compositions are non-uniform and are not suitable for use as final products.

glycerin solvent

A mixture of 25% ascorbic acid and 75% glycerin was prepared. Ascorbic acid was solubilized by heating at 95 °C, resulting in a clear solution. Upon cooling to room temperature, crystallization was evident within the first 24 hours of storage.

Butylene glycol solvent

According to the '367 patent, butylene glycol has a lower ability to solubilize ascorbic acid.

A mixture of 25% ascorbic acid and 75% butylene glycerin was prepared. Despite heating (under stirring) at a maximum temperature of 95°C, butylene glycol failed to solubilize the ascorbic acid content, resulting in a "turbid" appearance and precipitation upon cessation of stirring.

propylene glycol solvent

According to the '367 patent, propylene glycol has the lowest ability of these solvents to solubilize ascorbic acid. A mixture of 25% ascorbic acid and 75% propylene glycerin was prepared. Ascorbic acid was solubilized by heating at 95 °C, resulting in a clear solution. Upon cooling to room temperature, crystallization was evident within the first 24 hours of storage.

It is important to note that the fragile nature of ascorbic acid makes it sensitive to heat as well as to the presence of water and air. A risk exists for degradation of ascorbic acid when heated above 80°C, even in anhydrous vehicles such as polyols. The described solutions prepared according to the instructions of the '367 patent showed signs of decomposition when heated to the described range of 85 to 95 °C.

United States patent application US 2007/0077261 (Publication '261) discloses a composition comprising a wide range of ascorbic acid and urea, but has a "floor" (the minimum amount of urea required to solubilize a particular amount of ascorbic acid) and a "ceiling". "(The maximum amount of ascorbic acid that can be solubilized through this method) fails to identify both.

Example 3 of Publication '261 discloses a composition comprising 50% propylene glycol, 22% urea, and 28% ascorbic acid, heated to 75°C with stirring until clear, then cooled to room temperature. . This example has been reproduced. The solution began to precipitate within 24 hours, demonstrating a failure to understand and account for the required amount of urea to ascorbic acid.

Using the equation of the present disclosure set forth above, the correct concentration of urea to solubilize 28% of ascorbic acid in propylene glycol would be 20% (the appropriate "bottom"). In fact, a solution of 28% ascorbic acid and 20% urea in propylene glycol was prepared and remained fully solubilized after 30 days of storage at room temperature. Experiments also show that these concentrations of ascorbic acid (28%) and urea (20%) are also the maximum concentrations ("ceiling") at which urea itself dissolves in propylene glycol, butylene glycol, and propanediol before it begins to precipitate out of solution. ) shows that

Experiments have shown that concentrations of urea in the range of 5 to 40% cannot solubilize 40% of ascorbic acid in the polyol base:

40% ascorbic acid, 5% urea, 55% propylene glycol

40% ascorbic acid, 10% urea, 50% propylene glycol

40% ascorbic acid, 20% urea, 40% propylene glycol

40% ascorbic acid, 40% urea, 20% propylene glycol

All mixtures were heated to 85 °C. However, none were solubilized even after stirring at a maximum temperature of 85 °C. In addition, the urea content disclosed in some examples of Publication '261 is not only unnecessarily high (possibly due to a failure to identify the "floor") but also renders the composition not useful as a leave-on facial product, resulting in a burning sensation and irritation. cause skin irritation. When applied to the face, these compositions result in a strong burning and stinging sensation that is immediately evident. This is expected to be due to the keratolytic properties of urea. Also, the urea content disclosed in some examples of Publication '261 was precipitated in the formulation. In leave-on products for facial use, the maximum urea content is generally 10 to 15%. A higher than necessary urea concentration in a leave-on product can result in a burning sensation on the skin.

Alternatively, Formulation 5 of Table 3 and Formulation 2 of Table 2 of this disclosure are identified as rinse-off products.

Example 6: Exemplary Stabilized Vitamin C Chemical Peel Solution

Certain aspects of Examples 1-4 can be applied, for example, to the preparation of the chemical exfoliation solutions of the present disclosure described herein.

The exemplary formulations in Table 5 were prepared and evaluated for having desirable properties as chemical exfoliation solutions, including storage stability.

Example 6: Storage stability of vitamin C chemical exfoliation solution

stability method

Samples are stored in sealed containers at 40 degrees Celsius for up to 12 weeks. Preliminary results at 6 weeks are shown in Table 6. In general, six weeks of storage under these conditions is expected to equate to one year of storage at room temperature. The composition in the container is sampled weekly and evaluated for the degree of degradation of vitamin C using HPLC analysis.

composition

Exemplary compositions were prepared containing approximately 20% vitamin C (formulations 2 to 3 mentioned in Table 2) or approximately 25% vitamin C (formulation 1 mentioned in Table 5).

The storage stability of these compositions was compared to a control composition containing the same amount of vitamin C dissolved in water with no additional ingredients. Results are shown in Table 6. The exemplary mask (approximately 25% vitamin C) composition is still within specification after 6 weeks, in contrast to the control composition, which is out of specification (OOS) by 3 weeks of testing (or the equivalent of 6 months at room temperature).

Example 7: Evaluation of vitamin C and sugar alcohol formulations

A series of experiments were conducted to evaluate and optimize the components of the subject formulation. AA refers to L-ascorbic acid. S refers to a sugar alcohol agent. % values are weight percent.

Summary of experiment

Ascorbic acid (AA) and sugar alcohol (S) dissolved in non-aqueous solvent

The maximum amount of AA solubilized in 1,3-propanediol before recrystallization was about 12%. This solubility limit was also observed for propylene glycol (1,2 propanediol). The inventors have found that a mixture of ascorbic acid and a sugar alcohol such as xylitol can be dissolved in a non-aqueous solvent such as 1,3-propanediol to provide a stable solution. The use of a combination of ascorbic acid and xylitol also provides stable solutions with high concentrations of AA, eg higher concentrations than can be obtained in the solvent alone.

menstruum

1,3 propanediol, 1,2 propanediol, butylene glycol, pentylene glycol, and hexanediol were identified as preferred solvents. 1,3 propanediol (trade name: Zemea) differs in nature from the various polyols described and is more preferred. Below is a review of the various polyols, why 1,3 propanediol is special and preferred:

- 1,3-propanediol, sometimes referred to in the art as propanediol, is hypoallergenic to the skin (even when applied unmixed or at 100% concentration), relatively low viscosity (and therefore "light" to the skin) It is unique in that it possesses a combination of environmental friendliness (not petroleum derived), natural derivatives (corn or sugarcane), low odor, and suitable ability to solubilize ascorbic acid.

- 1,2-propanediol, otherwise referred to in the art as propylene glycol, has a low viscosity and moderate ability to solubilize ascorbic acid, but is well known to cause skin irritation and sensitization. In addition, it is derived from petroleum and has an unpleasant odor reminiscent of acetone.

- 1,3-propanediol, otherwise referred to in the art as butylene glycol, is of low viscosity, possesses adequate ability to solubilize ascorbic acid, and is relatively mild to the skin. However, like propylene glycol, it is derived from petroleum (not environmentally friendly) and has an unpleasant odor reminiscent of acetone.

- Also applicable to dipropylene glycol.

- 1,5-pentanediol, otherwise referred to in the art as pentylene glycol, possesses moderate ability to solubilize ascorbic acid, low odor, and certain versions are not derived from petroleum, but from sugar cane or corn. However, when applied to the skin, it imparts a less desirable "heavier" texture on the skin. In addition, its recommended use level is capped at a limit of 5% as the main solvent.

- 1,2-Hexanediol possesses adequate ability to solubilize ascorbic acid. However, when applied to the skin, it gives a less desirable "heavier" texture on the skin, has an unpleasant odor reminiscent of acetone, and is derived from petroleum. In addition, its recommended usage level is capped at a limit usage of 10% as a major solvent.

- Glycerin and diglycerin have adequate ability to solubilize ascorbic acid, are relatively mild to the skin, have a low odor, and are not derived from petroleum. However, they are of a very viscous nature and are overly tacky as well as imparting an undesirable “heavy” texture on the skin.

- Dimethyl isosorbide is relatively mild to the skin, is not derived from petroleum, and imparts a desirable "light" texture when applied to the skin. However, it has a very limited ability to solubilize ascorbic acid and has a distinct, albeit slightly, chemical odor reminiscent of chlorine.

Optional Additional Ingredients

Additional ingredients were selected for their compatibility (eg, miscibility) with 1,3 propanediol, 1,2 propanediol, and 1,3 butanediol. Further remarks and observations for each optional additional ingredient are given below.

Panthenol (pro-vitamin B5)

It is a humectant that exhibits soothing and moisturizing properties for the skin. Both the enantiomers, D-panthenol and L-panthenol, are powerful humectants. However, only D-panthenol is converted to pantothenic acid in the skin, conferring additional benefits to the skin (eg wound healing).

Studies indicate that it can alleviate irritation to the skin by other ingredients.

Studies also indicate barrier repair capacity (stimulation of physiological lipid synthesis).

DL-panthenol is a racemic mixture of two enantiomers; It is in powdered/crystalline form.

D-panthenol is a viscous liquid.

DL-panthenol is freely soluble (up to 50%) in 1,3 propanediol, 1,2 propanediol, and 1,3 propanediol.

D-panthenol is also freely soluble in 1,3 propanediol, 1,2 propanediol, and 1,3 propanediol, and there is no risk of recrystallization at any concentration (since it is already a liquid at room temperature).

Inhibition of transepidermal water loss is evident at concentrations above 1%.

hyaluronic acid

Hyaluronic acid is a humectant that exhibits the ability to form a viscoelastic film on the skin that prevents transepidermal moisture inhibition.

It is usually incorporated in aqueous solutions in its salt form, sodium hyaluronate.

However, there are raw material formulations with very little water, in which case they are incorporated into the vehicle of glyceryl polymethacrylate, butylene glycol (1,3 butanediol), and natto gum (trade name Hydrafilm 3MW by The Innovation Company). do. This makes these ingredients compatible with the non-aqueous formulations of the present disclosure.

Documentation from The Innovation Company indicates usage of this material up to 9.1% by weight of the final formula.

The chemical composition is as follows:

75 to 85% glyceryl polymethacrylate

15 to 20% butylene glycol

0.5 to 2% natto gum

0.5 to 2% hyaluronic acid

Pine maritime pine bark extract

A component of the bark extract of Pine maritime pine species exhibits the ability to regenerate vitamin C.

There are also studies showing their general antioxidant, anti-inflammatory, and anti-acne properties.

Pycnogenol can be used as an alternative when Pine maritime pine bark extract is desired.

A material formulation from Kinetik called Pantrofina Skin360 (PS360) is used in the subject formulation.

Unlike Pycnogenol, PS360 is already in liquid form, making it very easy to incorporate diglycerin when using it as a solvent.

In addition, Res Pharma Industriale provides in vitro and clinical data showing the effects of PS360 on free radical damage, inflammation, and acne at a concentration of 0.5% by weight.

The chemical composition is as follows:

- 90 to 95% diglycidine

- 5 to 10% Pine maritime pine bark extract

Madecassoside

Centella asiatica extract is usually used for its soothing properties.

Madecassoside is a highly glycosylated triterpene from Centella asiatica. It is marketed by ingredient supplier SEPPIC and shares in vitro and clinical data indicating its anti-inflammatory and other effects on skin.

Although this is a very expensive ingredient ($6.10 per gram), clinical data from SEPPIC indicates a desirable ability to reduce erythema (redness of the skin) at a concentration of 0.2%.

At a concentration of 0.2%, madecassoside is soluble in 1,3 propanediol, 1,2 propanediol, and 1,3 butanediol.

In some embodiments, the madecassoside is madecassoside asiaticoside.

azelaic acid

Azelaic acid (AzA) is widely studied for its ability to treat acne, rosacea, and melasma due to the fact that it has been studied and sold as a prescription drug. Although poorly understood, these effects are believed to be the result of AzA's antibacterial, anti-inflammatory, and keratolytic effects, as well as its inherent ability to induce apoptosis in abnormal melanocytes.

It is poorly soluble in most solvents. As a result, all products, both prescription drugs and cosmetics currently on the market, are sold as opaque emulsions, in which AzA is not solubilized, but instead finely milled into a powder and suspended in a viscous vehicle.

Because of the inability to solubilize AzA, a desirable ingredient to maximize the delivery of active ingredients into the skin, the team supporting the prescription drug product Finacea (now considered the gold standard) chose to adjust the pH, which is intuitive. In contrast, the salt form of AzA (formed in an aqueous environment with a pH higher than AzA's pKa, 4.15) was found to be slightly better at penetrating the skin.

The inventors have found that AzA can be solubilized in 1,3 propanediol at relatively high concentrations of up to 10%.

The solubility of AzA in 1,3 propanediol can be slightly increased in the presence of hydroxyethyl urea.

For example, 7.5% AzA can be solubilized with 10% AA, 5% U in 1.3 propanediol base.

Acetyl Gingerone

Acetyl zingerone is a broad-spectrum antioxidant that can prevent lipid peroxidation. It has been engineered to be a more stable, more potent derivative of zingerone.

Sytheon provides in vitro and clinical data demonstrating its antioxidant, photoprotective, and antiaging properties.

Acetyl zingerone can be used as a substitute for tocopherol.

Acetyl gingerone is readily soluble in 1,3 propanediol, 1,2 propanediol, and 1,3 butanediol at desired concentrations (0.5 to 1%), eliminating the need for emulsifiers that would be required for tocopherols.

glycyrrhizic acid

Like many other derivatives from licorice root (Glycyrrhiza glabra, Glycyrrhiza uralensis), glycyrrhizic acid exhibits anti-inflammatory, antioxidant, and skin lightening properties.

Unlike 18B-glycyrrhetinic acid, glycyrrhetic acid is soluble in 1,3-propanediol.

Other derivatives of licorice root may be used, such as dipotassium glycyrrhizate, monoammonium glycyrrhizate, and the like.

Example 8: Exemplary Vitamin C and Sugar Alcohol Formulations

The exemplary formulations of Tables 7-9 were prepared and evaluated.

Processes for preparing the compositions listed in Tables 7 to 9 are described below.

1. The process for preparing the composition includes dispersing xylitol and, when present, urea in Zemea (propanediol). The solution is then heated and mixed until it dissolves and the solution becomes clear.

2. The process includes dispersing salicylic acid and ferulic acid. The solution is then dissolved and mixed until the solution is clear.

4. Next, the process includes dispersing ascorbic acid and mixing until it dissolves and the solution becomes clear.

Example 9: Storage stability of vitamin C and sugar alcohol formulations

stability method

Samples are stored in sealed containers, sealed from the atmosphere at 40 degrees Celsius for up to 16 weeks. Results from weeks 0 to 12 are shown in Table 10. In general, 8 weeks of storage under these conditions is expected to equate to 16 months of storage at room temperature. The composition in the container is sampled at each time point and evaluated for the degree of degradation of vitamin C using HPLC analysis.

composition

Exemplary compositions were prepared containing various percentages of ascorbic acid shown in Tables 7-9.

The storage stability of these compositions was improved with the addition of additional components of ferulic acid at a concentration of 0.5%, tocopherol and glycol ethers at a concentration of 1%, alkanediols, laureth-23, panthenol, triethanolamine, phenoxyethanol, and sodium hyaluronate. A control composition containing the same amount of vitamin C dissolved in water was compared. The results are shown in Table 10. Exemplary serum (approximately 15% vitamin C) compositions were out of specification (OOS) by 2 weeks of testing (or equivalent to 4 months at room temperature) as opposed to control compositions that were tested at 8 weeks (or equivalent to 4 months at room temperature). equivalent) and still within the criterion.

The exemplary formulations of Tables 7-9 with approximately 15% vitamin C were prepared and evaluated for having desirable properties including storage stability.

Although exemplary embodiments of the present invention have been described as being specific, it will be appreciated that various other modifications will become apparent to those skilled in the art and can be readily made thereby without departing from the spirit and scope of the present invention. Accordingly, the scope of the claims appended hereto is not intended to be limited to the examples and descriptions presented above, but rather the claims are intended to cover all characteristics that would be treated as equivalent by those skilled in the art of formulating topically applied personal care and dermatological products. It should be construed as including all characteristics of the patent novelty of the present invention, including.

Example 10: Storage stability of non-aqueous (eg, anhydrous) urea emulsion formulations

The exemplary formulations of Tables 11-16 were prepared and evaluated for having desirable properties including storage stability.

Generating an anhydrous urea emulsion using any of the ingredients in Tables 11-16 involves combining the inner phase ingredients with propanediol under agitation and then adding the mixture of inner phase ingredients to the outer phase under agitation until an emulsion is formed. include that

Example 11: Storage stability

composition

Approximately 10% urea (e.g., formulation 1 mentioned in Table 11 or Table 12, formulation 2 or 4 in Table 12, formulation with 10% urea in Tables 13-16) or approximately 5% urea ( Exemplary compositions were prepared containing, for example, Formulation 2 or Formulation 4 mentioned in Table 11, or Formulation 5 mentioned in Table 12, 5% urea formulations in Tables 13-16).

Stability can be measured by the amount of ammonia released and/or the smell of ammonia, which is an indicator of urea degradation. Solubility can be measured by the grittiness of the emulsion as a result of precipitation of urea that is not sufficiently solubilized. Thus, absence of ammonia released and/or ammonia odor is an indicator of storage stability; The absence of grittiness is a result of strong solubility. In addition, none of the compositions listed in Tables 11 to 16 released an ammonia odor even when stored at room temperature for one year or longer, indicating that the compositions are storage stable.

Example 12: Non-Aqueous Azelaic Acid Formulation

Evaluation of Ingredients

Exemplary non-aqueous liquid compositions of the present disclosure have proven stable against urea degradation and stable against precipitation of components. The inventors have discovered that compositions comprising a combination of azelaic acid and urea provide this stability, and also have desirable physical properties (eg, as described herein) when applied topically to the skin.

To determine the preferred ratio of azelaic acid to urea in a particular composition of the present disclosure, the maximum concentration of azelaic acid that can be solubilized by thermal exposure in a given solvent without precipitation upon cooling is first determined. Experiments have shown that these concentrations are approximately 10-12% for 1,3 propanediol, propylene glycol (1,2, propanediol), and butylene glycol (1,3 butanediol), and significantly higher for dimethyl isosorbide. show low

Compositions with azelaic acid concentrations as low as 1 to 5% by weight can be prepared if the polyol solvent used provides very low solubility, such as in dimethyl isosorbide (DMI). Thus, a mixture of propanediol and DMI can yield a weight percent value (eg, maximum solubility of AzA) of 10 to 12 weight percent depending on the ratio of propanediol and DMI, for example.

The ratio of azelaic acid to urea in the liquid composition is such that the weight percent of azelaic acid is one or more C(2-6) alkanediols, such as 1,3-propanediol, or 1,3-propanediol and 1,2-hexane. When 10% to 12% dissolved in a solvent component composed of a mixture of diols, it may be 2.0 to 2.5 (eg 2.0). See, for example, the compositions in Tables 1 and 2.

Generally, 1,3 propanediol is preferred over 1,2 propanediol, butylene glycol, pentylene glycol, or hexanediol. 1,3 propanediol is preferred over various polyols described in the art. Below is a review of the various polyols, why 1,3 propanediol is special and preferred:

1,3 Propanediol, otherwise referred to in the art as propanediol, is hypoallergenic to the skin (even when unmixed or applied at 100% concentration), relatively low viscosity (and thus perceived as "light" to the skin) ), environmental friendliness (not petroleum derived), natural derivatives (corn or sugar cane), low odor, and suitable ability to solubilize azelaic acid.

1,2 Propanediol, otherwise referred to in the art as propylene glycol, is of low viscosity and possesses adequate ability to solubilize azelaic acid, causing skin irritation and sensitization. In addition, it is derived from petroleum and has an unpleasant odor reminiscent of acetone.

1,3 Propanediol, otherwise referred to in the art as butylene glycol, is of low viscosity, possesses adequate ability to solubilize azelaic acid, and is relatively mild to the skin. However, like propylene glycol, it is derived from petroleum (not environmentally friendly) and has an unpleasant odor reminiscent of acetone.

Note that these properties also apply to dipropylene glycol.

1,5 pentanediol, otherwise referred to in the art as pentylene glycol, has adequate ability to solubilize azelaic acid, low odor, and certain versions are not derived from petroleum, but from sugar cane or corn. However, when applied to the skin, it imparts a less desirable "heavier" texture on the skin. In addition, its recommended use level is generally capped at a limit of 5% as the main solvent.

1,2 Hexanediol possesses adequate ability to solubilize azelaic acid. However, when applied to the skin, it gives a less desirable "heavier" texture on the skin, has an unpleasant odor reminiscent of acetone, and is derived from petroleum. In addition, its recommended usage level is capped at a limit usage of 10% as a major solvent.

Glycerin and diglycerin have a low ability to solubilize azelaic acid, are relatively mild to the skin, have a low odor, and are not derived from petroleum. They are very viscous and impart an undesirable "heavy" texture on the skin as well as being overly tacky.

Dimethyl isosorbide is relatively mild to the skin, is not derived from petroleum, and imparts a desirable "light" texture when applied to the skin. However, it has a very limited ability to solubilize azelaic acid and has a distinct, albeit slightly, chemical smell reminiscent of chlorine.

Urea is preferred over hydroxyethyl urea. There are a number of reasons for this, summarized below:

When used in low enough concentrations (10-15% or less) in leave-on applications, urea possesses desirable wettability, barrier repair, and very mild keratolytic properties, which in combination improve the feel and appearance of dry and/or rough skin. very effective in improving Urea is naturally present in the human body as well as especially in the skin, where it serves as a natural moisturizing factor (NMF).

Hydroxyethyl urea has wettability properties similar to urea, but does not possess barrier repair and mild keratolytic properties. Hydroxyethyl urea may also contain trace amounts of diethanolamine, a potential carcinogen.

Additional ingredients compatible with the azelaic acid/solvent/urea combination of interest may be included.

The exemplary formulations in Table 17 were prepared and evaluated for having desirable properties.

Other Variations: Dimethyl isosorbide, caprylyl glycol, or decylene glycol may be used as alternative or additional solvents in the compositions of Table 17.

Additional exemplary formulations in Table 18 were prepared and evaluated as having desirable properties.

Other Variations: Dimethyl isosorbide, caprylyl glycol, or decylene glycol may be used as an alternative or additional solvent in the compositions of Table 18.

Example 13: Storage stability

stability method

Exemplary compositions are evaluated for storage stability, eg, chemical stability and/or physical stability (eg, absence of precipitation or recrystallization from a liquid composition) of an ingredient (eg, urea or azelaic acid). For example, the composition is stored in a container over time, sampled at various time points, and evaluated for the level of degradation of urea. Any degradation of urea to ammonia can be assessed by a variety of methods. Urea degradation can be assessed by pH change over time and/or detection of ammonia via odor or other qualitative test.

Exemplary compositions are evaluated for stability in comparison to control compositions containing ethanol or isopropyl alcohol. The exemplary compositions are evaluated for stability in comparison to a control composition containing greater than 2% by weight of water.

Claims (50)

A storage stable topical composition comprising:
a. 5% to 28% by weight of ascorbic acid;
b. 5% to 20% by weight of urea agent;
c. 0.1% to 5% by weight of cinnamic acid or a derivative thereof; and
d. less than 10% by weight of one or more optional additional components in total;
e. a non-aqueous skin compatible solvent comprising a polyol, C _(1-6) alkanediol, glycol ether, dimethyl ether, or a combination thereof, which dissolves the above components; wherein the ascorbic acid dissolves at a concentration (AA) that is greater than its maximum concentration (X) in the solvent alone and the urea dissolves at a concentration that is at least (AA-X)*1.25. The storage stable topical composition of claim 1 , which exhibits degradation of less than 10 mol% of ascorbic acid after storage for 6 weeks at 40°C ± 2°C in a sealed or multi-use container. According to claim 1 or 2,
about 15% by weight ascorbic acid;
About 8% by weight of urease;
about 1% by weight of ferulic acid; and
A storage stable topical composition comprising a solvent comprising 1,3-propanediol. According to claim 1 or 2,
about 20% by weight of ascorbic acid;
about 10% by weight of urease;
about 0.5% by weight ferulic acid; and
A storage stable topical composition comprising a solvent that is 1,3-propanediol. According to claim 1 or 2,
about 15% by weight ascorbic acid;
About 8% by weight of urease;
about 0.5% by weight ferulic acid; and
A storage stable topical composition comprising a solvent that is 1,3-propanediol. According to claim 1 or 2,
about 10% by weight of ascorbic acid;
About 3% by weight of urease;
about 0.5% to about 2% by weight of ferulic acid; and
A storage stable topical composition comprising a solvent that is 1,3-propanediol. According to claim 1 or 2,
about 5% by weight of ascorbic acid;
about 5% by weight of urease; and
about 0.1% to 2% by weight of ferulic acid;
A storage stable topical composition comprising a solvent that is 1,3-propanediol. As an emulsion composition,
a composition according to any one of claims 1 to 7;
oil component; and
An emulsion composition comprising an optional emulsifier. The emulsion composition according to claim 8, wherein the oil component is silicone-based. 10. The emulsion composition according to claim 8 or 9, wherein the emulsifier is selected from polysorbate, laureth-4, potassium cetyl sulfate, and silicone and silicone-elastomer based emulsifiers and emulsion blends. A storage stable topical composition comprising:
a. 5% to 28% by weight of ascorbic acid;
b. 5% to 20% by weight of urease;
c. 2% to 30% by weight of a chemical exfoliant; and
d. less than 10% by weight of one or more optional additional components in total;
e. a non-aqueous skin compatible solvent comprising a polyol, C _(2-6) alkanediol, glycol ether, dimethyl ether, ethanol, isopropyl alcohol, or a combination thereof, which dissolves the above components; The storage stable topical composition wherein the ascorbic acid is dissolved at a concentration [AA] that is greater than its maximum concentration [X] in the solvent alone, and the urea is dissolved at a concentration that is at least ([AA]-[X])*1.25 . 12. The storage stable topical composition of claim 11, which exhibits degradation of less than 5 mol % ascorbic acid after storage for 6 weeks at 40°C ± 2°C in a sealed or multi-use container. 13. A storage stable topical composition according to claim 11 or 12 comprising 2% salicylic acid by weight. 13. The storage stable topical composition of claim 11 or 12 comprising 5 to 15% by weight of salicylic acid. 13. A storage stable topical composition according to claim 11 or 12 comprising 10% salicylic acid by weight. 16. The method of any one of claims 11-15, wherein the one or more optional additional ingredients are tocopherols, tocotrienols (e.g., alpha, beta, delta, and gamma tocopherols or alpha, beta, delta, and gamma tocotrienols), azela Acid, cinnamic acid or derivatives of cinnamic acid, panthenol, pinus pinaster bark extract, emulsifier, hyaluronic acid complex, madecassoside, madecassoside asiaticoside, acetyl gingerone, bakuchiol, diglycerin , bis ethylhexylhydroxydimethoxybenzylmalonate, and dimethyl isosorbide. According to any one of claims 11 to 16,
25% by weight of ascorbic acid;
20% by weight of urease; and
2% by weight of salicylic acid;
A storage stable topical composition comprising 53% by weight of 1,3 propanediol dissolving the above ingredients. According to any one of claims 11 to 16,
20% by weight of ascorbic acid;
17% by weight of urease; and
10% by weight of salicylic acid;
A storage stable topical composition comprising 53% by weight of 1,3 propanediol. 17. The storage stable topical composition according to any one of claims 11 to 16, wherein the ratio of ascorbic acid to urease is from 1.0 to 2.2 or from 1.10 to 1.25. As an emulsion composition,
a composition according to any one of claims 11 to 19;
oil component; and
An emulsion composition comprising an optional emulsifier. As a storage stable topical liquid composition,
a. 5% to 28% by weight of ascorbic acid;
b. 5% to 20% by weight of a sugar alcohol agent; and
c. less than 10% by weight of one or more optional additional components in total;
d. A storage stable topical liquid composition comprising a non-aqueous skin compatible solvent comprising a polyol, C _(1-6) alkanediol, glycol ether, dimethyl ether, or a combination thereof, which dissolves the above components. 22. The storage stable topical liquid composition of claim 21, which exhibits degradation of less than 3 mol% ascorbic acid after storage for 8 weeks at 40°C ± 2°C in a sealed or multi-use container. The storage stable topical liquid composition according to claim 21 or 22, wherein the sugar alcohol is selected from xylitylglucoside, anhydroxylitol, sorbitol, lactitol, maltitol, erythritol, mannitol, and combinations thereof. 23. The storage stable topical liquid composition according to claim 21 or 22, wherein the sugar alcohol is a C5 to C6 sugar alcohol, preferably xylitol. 25. The storage stable topical liquid according to any one of claims 21 to 24 comprising 10 to 20% by weight of ascorbic acid or 15 to 20% by weight of ascorbic acid, and preferably 15% by weight of ascorbic acid. composition. 26. The method of any one of claims 21 to 25, wherein the solvent is 1,3 propanediol, 1,2 propanediol, 1,3 butanediol, 1,5 pentanediol, 1,2 hexanediol, 1,6 hexanediol A storage stable topical liquid composition selected from glycerol, diglycerol, ethoxydiglycol, and dimethyl isosorbide. 27. The storage stable topical liquid composition according to any one of claims 21 to 26, wherein the solvent is 1,3 propanediol or a mixture of 1,3 propanediol and 1,2 hexanediol. 28. A storage stable topical liquid composition according to any one of claims 21 to 27 comprising one or more additional ingredients. The method of any one of claims 21 to 28,
a. 15% to 20% by weight of ascorbic acid;
b. 7% to 10% by weight of xylitol; and
c. less than 10% by weight total of one or more optional additional components selected from urea, salicylic acid, and ferulic acid;
d. A storage stable topical liquid composition comprising 1,3 propanediol or 1,2 propanediol dissolving the above components. 30. The storage stable topical composition of any one of claims 21-29, wherein the composition containing xylitol reduces or eliminates pathogenic staphylococcal mutations while maintaining the integrity of staphylococcus epidermidis when applied to the skin. A storage stable topical emulsion composition comprising the following a and b:
a. As an internal phase that is a homogeneous solution,
1% to 30% by weight of urease;
an internal phase comprising at least 10% by weight of a non-aqueous skin compatible solvent selected from polyols, C _(1-6) alkanediols, glycol ethers, dimethyl ethers, and combinations thereof, which dissolve the components; and
b. an external phase comprising at least 10% by weight of a silicone agent, by weight of the composition, selected from cyclic, linear, and branched silicones, silicone crosspolymers, and combinations thereof;
wherein the internal phase is immiscible with the external phase and is contained within the external phase. 32. The storage stable topical emulsion composition of claim 31, wherein the external phase is a solution of silicone in an oil phase. 33. The method of claim 31 or 32, wherein the silicone agent is dimethicone, PEG-10/15 crosspolymer, dimethicone/polyethylene glycol (PEG)-10/15 crosspolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone. A storage stable topical emulsion composition selected from ticone, and combinations thereof. 34. The method of any one of claims 31 to 33, i) storage stability (eg, non-aqueous skin) at 25 °C ± 2 °C or 40 °C ± 2 °C for 6 weeks in a sealed container. shows a degradation of less than 10 mol% of urease in a compatible solvent); ii) a storage stable topical emulsion composition that exhibits a rate of urea degradation that is less than that of a homogeneous internal phase solution in the absence of an external phase emulsion. 35. The storage stable topical emulsion composition according to any one of claims 31 to 34 comprising an external phase of 20% to 80% by weight of silicone. 36. The storage stable topical emulsion composition according to any one of claims 31 to 35 comprising 5% to 20% by weight of urease. 37. The storage stable topical emulsion composition according to any one of claims 31 to 36, wherein the weight percent ratio of the inner phase to the outer phase in the composition is 19 or less. 38. The method according to any one of claims 31 to 37, further comprising up to 10% by weight total dissolved in the first phase and/or outer phase of one or more optional additional components, wherein the one or more optional additional components are tocopherols, Tocotrienols (e.g., alpha, beta, delta, and gamma tocopherols or alpha, beta, delta, and gamma tocotrienols), ferulic acid, ascorbic acid, azelaic acid, hydroxy acids (e.g., salicylic acid), panthenol, pine Genus Sea Pine Bark Extract, Hyaluronic Acid Complex, Cholesterol Esters, Cholesterol, Ceramides, Linoleic Acid, Linolenic Acid, Madecassoside, Acetyl Gingerone, Bakuchiol, Bis-Ethylhexyl Hydroxydimethoxy Benzylmalonate, Zinc Oxide, and Dioxide A storage stable topical emulsion composition selected from titanium. 39. Storage stable topical use according to any one of claims 31 to 38 comprising from about 5% to about 20% urea, preferably about 5% urea, or about 10% urea by weight. emulsion composition. 40. The storage stable topical emulsion composition according to any one of claims 31 to 39, wherein the droplets of the inner phase are contained within the outer phase. As a storage stable topical composition,
a. 1% to 20% by weight of azelaic acid; and
b. 1% to 20% by weight of urease;
A storage stable topical composition comprising a non-aqueous skin compatible solvent comprising a polyol, C _(3-6) alkanediol, glycol ether, dimethyl ether, or a combination thereof, which dissolves the above components. 42. The storage stable topical composition of claim 41 which is substantially free of water, preferably anhydrous. 43. A substantially volatile alcohol, preferably a monohydric alcohol, more preferably selected from one or more of ethyl alcohol, methyl alcohol, isopropyl alcohol, butyl alcohol, amyl alcohol, and cetyl alcohol according to claim 41 or 42. A storage stable topical composition free from monohydric alcohol. 44. The method according to any one of claims 41 to 43, wherein storage stability (e.g., less than 10 mol% of urease and azelaic acid) after storage for 6 weeks at 40°C ± 2°C in a sealed or multipurpose container. a storage stable topical composition that exhibits degradation). 45. The method according to any one of claims 41 to 44, from 5% to 20% by weight of azelaic acid, preferably from 10% to 20% by weight of azelaic acid, more preferably from 10% to 15% by weight of azelaic acid. A storage stable topical composition comprising (eg, 10% to 12% by weight) azelaic acid. 46. The storage stable topical composition of any one of claims 41 to 45, comprising from 5% to 10% by weight of urease, wherein the weight percent ratio of azelaic acid to urease is from 2.0 to 2.5. 47. The method of any one of claims 41-46, tocopherols, tocotrienols (e.g., alpha, beta, delta, and gamma tocopherols or alpha, beta, delta, and gamma tocotrienols), ferulic acid, ascorbic acid, azela Acids, hydroxy acids (eg, salicylic acid), panthenol, Pine marigold bark extract, hyaluronic acid complex, cholesterol esters, cholesterol, ceramides, linoleic acid, linolenic acid, madecassoside, acetyl gingerone, bakuchiol, bis- A storage stable topical composition further comprising at least one optional additional component selected from ethylhexyl hydroxydimethoxy benzylmalonate, zinc oxide, and titanium dioxide, totaling up to 10% by weight. The method of any one of claims 41 to 47,
a. 10% to 15% by weight of azelaic acid; and
b. 5% to 10% by weight of urease;
A storage stable topical composition comprising a solvent comprising one or more C _(3-6) alkanediols which dissolves the above components. 49. The storage stable topical composition of claim 48 comprising 10% or 12% azelaic acid and 5% urea by weight. 50. The method of any one of claims 41-49, wherein the solvent is 1,3-propanediol or a mixture of 1,3-propanediol and 1,2-hexanediol (e.g., at least 10:1, such as at least in a ratio of 15:1 or at least 20:1).