MXPA00005595A - Topical zinc compositions and methods of use - Google Patents

Abstract

Compositions including zinc compounds and select amino acids in a carrier base, and methods of skin treatment with such compositions, are described. The compositions are useful for healing skin and minimizing the irritation incurred from contact with the zinc compound without loss of zinc availability during absorption into the integument.

Description

"COMPOSITIONS OF TOPICAL ZINC AND METHODS OF USE" FIELD OF THE INVENTION The present invention relates to zinc-containing compositions and methods for the topical use of these compositions for treating subcutaneous wounds, irritations, lesions, abrasions or the like. More particularly, the invention relates to zinc containing compositions containing an amino acid to minimize external irritation of zinc when applied to the skin without decreasing the amount of free zinc available for absorption.

BACKGROUND OF THE INVENTION The value of zinc in tissue growth and repair is well documented. Zinc is essential for the function of at least 70 enzymes and is involved in a variety of metabolic processes. Zinc is a limiting factor in the formation of RNA and DNA. Zinc is also a limiting factor in zinc-dependent enzymes such as RNA and DNA polymerases, deoxythymidine kinase, and reverse transcriptase, which are responsible for the regulation of RNA and DNA metabolism. In the decreased availability of zinc it slows down protein synthesis, thereby slowing cell reproduction and inhibiting tissue repair. Approximately half of the body's total zinc content of 2-3 grams (based on an adult 70-kilogram average) is found in ossified tissues and therefore, is not readily available for metabolic processes. Even when the skin boasts a higher zinc concentration than most tissues (10 micrograms per gram of tissue), it is rapidly depleted during the regeneration process. The deoxyrimidine kinase activity in the rapidly regenerating connective tissue has been experimentally shown to decrease as soon as six days after the animals are subjected to a zinc-deficient diet, demonstrating that an external supply of zinc is essential. to be used in tissue repair. In fact, zinc supplementation has been shown to markedly improve wound healing in zinc-deficient people, while topical zinc improves wound healing in zinc-deficient and normal people. Zinc salts are known to inhibit viral bacterial growth. Zinc sulfate ophthalmic preparations to treat herpetic keratitis have been recommended since 1943. Oral preparations of zinc citrate used to treat gingivitis and periodontitis have been shown to reduce the formation of platelets and inhibit bacterial growth. Oral preparations of several zinc salts have been shown to reduce the symptoms and duration of the common flu caused by rhinoviruses, but they are unpleasant in taste and cause mouth irritation and nausea. Until the development of a zinc salt formulation with an agreeable and less irritating flavor amino acid, patients often refused to continue treatment with oral preparations containing zinc salts. Successful topical treatment of infections and skin lesions with zinc salts is well documented. Topical zinc pyrithione is an effective anti-fungal agent effective in treating Malassezia fúrfur, the agent that causes various skin disorders including pityriasis versicolor. Zinc pyrithione has also been used to treat psoriasis and dandruff by inhibiting the overproliferation of cells characterized by these conditions. The application of a zinc chloride solution before and after exposure to ultraviolet light in mice free of hair reduced the number of cells burned by the sun in the epidermis and was reported in 1976 as a successful topical treatment of carcinoma of the skin. basic cell in a human patient. The erythrocyte-zinc lotion is sebosuppressive and potentially beneficial for the acne patient. The herpes of the lips occurs in 50 percent of the population, while genital herpes is now one of the most common venereal diseases. Zinc salts irreversibly inhibit the reproduction of herpes virus and are effective in treating herpes infection. The zinc ions irreversibly inhibit the glycoprotein functions of the herpes simplex virus (HSV) accumulating in the sulfhydryl groups of glycoprotein B in the viral membrane, blocking the synthesis of DNA. In the closely related rhinovirus, there is a theory that free zinc ions also sequester in the membrane, inhibiting viral binding with ICAM receptor sites in mucous membranes. Other closely related viruses can be similarly affected by zinc ions. U.S. Patent No. 5,545,673 discloses in vitro the evidence that HIV infectivity was reduced or completely eliminated when the concentrated viral materials were incubated with 1 percent to 1.5 percent zinc acetate for 2 hours. HSV has significant hemology for the varicella-zoster virus. Herpes zoster rashes are thought to be more frequent in older people not due to improper immune function, but due to slowed mobilization of the immune system. It is evident that rapid treatment with a zinc salt would be extremely beneficial and would significantly decrease the viral load and painful lesions independently of the activation of the immune system. Zinc salt solutions applied to herpetic lesions decrease viral load and markedly improve healing regimes, releasing herpes symptoms as healing occurs. The long-term topical application of zinc salt solutions appears to greatly reduce or eliminate reappearances of genital herpetic lesions as well as prevent the multiform of postherpetic erythema. It has been assumed that the provision of a high concentration (compared to the body's natural and fluid tissue levels of the ionic zinc) from the virucidal agent to the site of infection can prevent the retrograde propagation of the virus along the involved nodes. Zinc oxide has been shown in numerous studies to accelerate the healing of both chronic and acute wounds. This effect may be due in part to the stimulation of the epidermal basic cells, which are seen in the mice, and partly due to increased insulin-like growth factor-1 and mRNA (messenger RNA), which can be seen in the tissue of granulation of full thickness wounds in domestic pigs. Zinc paste dressings containing inorganic zinc compounds, e.g., zinc sulfate and zinc oxide, have long seen a normal treatment of venous stasis ulcers. Zinc chloride paste has been shown to be effective in debridement and granulation tissue formation in chronic leg ulcers. Zinc oxide has been shown to activate cleansing and re-epithelialization of leg ulcers and reduce infections and deterioration of ulcers. Unfortunately, topical application of some zinc solutions can cause painful and irritating side effects if not used in very low concentrations. Zinc sulphate solutions of 0.2 percent to 1 percent can cause serious irritation, unpleasant dryness, and can stimulate the emetic reflex when applied circumbucally. Reports of dermal irritation in animal skin abrasion models that examine wound healing show the following: 1 percent aqueous zinc chloride is seriously irritating; 20 percent aqueous zinc acetate is slightly less irritating; 20 percent zinc oxide in suspension, 1 percent aqueous zinc sulfate, and 20 percent zinc pyrithione in suspension, are not too irritating. Less irritating zinc salts such as zinc oxide (which is only slightly soluble in water), were only marginally effective in stimulating epidermal healing compared to more irritant and more water soluble zinc salts. In addition, it is interesting to note that in other studies zinc solutions, particularly zinc sulfate, do not maintain constant local concentration levels when applied to the skin as zinc oxide does. The zinc in these studies is not slowly solubilized to provide a constant level of absorption, since it is in free solution. This indicates that a zinc preparation that provides a higher concentration of zinc solubilized in a formulation with minimal irritation allowing controlled absorption would be of great clinical value. Compositions for treating various skin irritations are also known including zinc and other material or materials. These are described, for example, in the following North American patents: U.S. Patent No. 4,937,234, discloses a pharmaceutically acceptable composition that provides minerals (s) (eg, Zn) in a bioavailable form by the inclusion of certain amino acids (see column 2). , lines 56-59), with the molar amount of an acidic mineral salt (eg, zinc gluconate) to an amino acid (eg, lysine) that is about 0.05M: 1.0M to about 1.0M: 0.05M and neutralized up to a pH of ß to 8. Zinc oxide is mentioned only as not being insoluble in water. In Example 13, the zinc oxide is solubilized in water by the addition of ascorbic acid. Several skin irritations can heal. - U.S. Patent Number 4,711,780 describes a composition for treating surface epithelium to promote epithelial regeneration. The composition includes a mixture of a zinc salt, vitamin C, and a sulfur amino acid. Zinc oxide is not disclosed. The composition is said to be useful for treating a wide variety of conditions, including skin conditions, such as burns, cuts, fever blisters, poison ivy, chigger bites, diaper rash, genital herpes blisters, and sunburn. Depending on the treatment site, the composition will take different forms as appropriate, such as a water, oil or gel vehicle; a spraying, or a bandage of powder or with medicine. U.S. Patent No. 5,582,817 describes a composition for treating various skin diseases, see column 6, lines 48-58. The composition includes a zinc salt, a zinc complex, or a salt of a zinc complex. The complex or salt may be based on a compound of zinc and an amino acid. Zinc oxide is mentioned and used only as a "relatively insoluble metal salt". The co-use of a solubilization agent is not disclosed. The composition is said to have unexpected action to induce metallothionic and suppress the production of sunburn cells by ultraviolet rays. U.S. Patent No. 5,708,023 discloses a composition for application to a surface (such as skin) including an irritant-inactivating agent and a substance that prevents the irritant-inactivating agent from binding to the surface. The pharmaceutically acceptable cationic substances can also be used to block the binding sites, e.g., the relatively soluble zinc cations and zinc salts (e.g., zinc gluconate, zinc acetate and zinc sulfate). Examples of other pharmaceutically acceptable cationic substances disclosed are the quaternary ammonium compounds which are further defined as including amino acids. This additional characterization, however, of the quaternary ammonium compounds is an error. While the quaternary ammonium compounds have four (4) groups (none of which is hydrogen) bound to (1) nitrogen atom, which then possesses a positive (+) charge of 1, all 21 naturally occurring and biologically important amino acids has the structure R-CH (NH2) -COOH. Clearly the amino acids do not satisfy the cationic substance described. Examples of suitable irritant materials for treatment include HIV and the hepatitis virus. U.S. Patent No. 5,260,066 discloses a cryogel bandage (a hydrogel containing PVA) containing a therapeutic agent such as inorganic and organic zinc salts as antimicrobials, and amino acids such as glycine. Zinc oxide is not disclosed. Many existing topical formulations are inadequate because they produce such local irritation that they are not easily tolerated. Others also frequently lack sufficient effective concentration of zinc ion due to the low solubility of zinc oxide in the absence of suitable solubilizing agents. In addition, existing formulations have unpleasant flavors, making the circumbucal application impractical. It would be highly desirable that there be a topical zinc formulation and a method of use that is aimed at deficiencies in existing treatments.

OBJECTS AND BRIEF DESCRIPTION OF THE INVENTION A principal object of the present invention is to provide a topical zinc composition for the administration and healing of skin wounds, irritations, abrasions and the like, including herpes-like lesions. Another object of the invention is to provide a topical zinc composition that provides a high effective concentration of available zinc and minimizes skin irritation. Another object of the invention is to provide a topical zinc composition containing a selected amino acid. Another object of the invention is to provide a method for treating the skin with a topical zinc composition containing a selected amino acid. The composition of the present invention includes (1) a pharmaceutically acceptable zinc compound, preferably zinc oxide or a divalent zinc complex, (2) a selected amino acid, preferably glycine, and (3) a base of the pharmaceutically acceptable carrier, such as a solid or semi-solid carrier base. The zinc compound is present in the base of the protator along with a large excess of the amino acid (from 2 to 20 molar equivalents with respect to zinc) to provide a composition with high availability of zinc ion and minimal skin irritation when applied topically to the skin. A composition of the invention is used by applying the composition to an affected area of the surface of the skin, and spreading the composition in order to contact and coat the area. The application to an affected area can be repeated periodically as necessary until sufficient healing is achieved. The composition can also be applied to an occlusive or non-occlusive dressing. When the bandage is placed on the skin, the composition is placed in contact with the skin to heal the affected area.

DETAILED DESCRIPTION OF CURRENTLY PREFERRED MODALITIES OF THE INVENTION In accordance with the present invention, it has been found that compositions containing a zinc compound; an appropriate carrier base, for example a cream, balsam, lotion, ointment which carries water or the like; and certain amino acids, where the molecular ratio of amino acid to zinc is within the range of 2: 1 to 20: 1, causes minimal irritation while providing free zinc ions sufficient for local absorption in the intergument and zinc availability for inhibition viral and scarring. The composition contains from about 1 milligram to about 20 milligrams of zinc per gram of the composition. The zinc compounds they have used in combination with certain amino acids can be in any of the commonly used forms such as sulfate, chloride, acetate, gluconate, ascorbate, citrate, aspartate, picolinate, orotate and transferrin salts, as well as zinc oxide. and divalent zinc complexes with an amino acid. It has been found that zinc oxide solubilized with glycine is particularly preferred. The amino acids useful for the purpose of this invention are glycine, L-lysine, and D, L-lysine. Useful appropriate complexes are formed by reacting the zinc oxide with monocarboxylic acids of the aforementioned amino acids, and have the composition Zn (Amino Acid) 2 • These complexes are soluble in water, particularly in the presence of an excess of amino acid, they release essentially all the zinc, like the Zn ^ + ion towards an aqueous solution, are minimally irritating because the amino acid modifies the irritant effect of zinc, and have very good flavors, with taste being an important consideration since the invention can be applied circumbucally . However, amino acids such as aspartic and glutamic acids are not useful for forming the aforementioned complexes. These amino acids are dicarboxylic. Preferred divalent zinc complexes with the monocarboxylic amino acid are a zinc glycine complex having a formula Zn (C2H N02) 2"nH2" where n has a value of 1.1, or 2, combined with 0.3 to 5.4 parts by weight of anhydrous glycine; and a zinc D, L-lysine complex having a formula Zn (05 ^ 3 ^ 02) 2 '4H20 combined with 0.35 to 3.5 parts by weight of the anhydrous glycine. Suitable carrier base compounds may contain components that are selected from a wide range of pharmaceutically acceptable materials known in the art of preparing topical solid or semi-solid formulations, such as creams, moisturizers, lotions, emollients, balms and the like . This base formulation may include, but is not limited to purified water, sunflower oil, stearic acid, cocoa butter, monoglyceryl stearate, stearic triglyceride, stearyl alcohol, zabila barbadensis gel, jojoba oil, a-acetate tocopheryl (Vitamin E), carrot extract, jasmine extract, chamomile extract, calendula or marigold extract, red clover flower extract, methyl paraben, propyl paraben, caramel, retinyl palmitate and fragrance oil. It is important that no component of this base formulation possess the potential for intense ionic zinc chelation, since the presence of this compound will inactivate the zinc ions that provide the desired physiological benefit of availability for the use of enzyme to improve the proliferation of the tissue and healing as well as antiviral activity. The chemical principles that regulate the chelation of metal ions by organic compounds are well known in such a way that a person skilled in the art can determine, by visual inspection of a written chemical structure, whether a given chemical compound has the potential or not. for intense chelation of ionic zinc (taking into account the pH changes that can be caused by the base). It is well known, for example, that these varied structures such as those represented by citric acid, tartaric acid, 8-hydroxyquinoline, ortho-phenanthroline, and ethylenediaminetetraacetic acid (EDTA), are structurally and electronically configured to form chelated complexes very critical, that is, highly stable with the zinc ion. Therefore, any of the structures that are chemical analogues of the strong chelation compounds mentioned above, or any of the other compounds, should be avoided in formulating the base of the carrier. The compositions of the invention are also suitable for application to the skin by means of a bandage or an occlusive or non-occlusive bandage. The compositions of the invention can be brought to advantage in a conventional manner. When the bandage is placed on the skin through an area to be treated, the composition is brought into contact with the skin and acts on the skin in the same manner as described above in relation to the compositions applied. directly. In this manner, the zinc-containing compositions prepared according to the present invention include pharmaceutically acceptable zinc oxide and a selected amino acid. The compositions possess a very pleasant taste, modify the irritant effect of zinc and release ionic zinc towards a semi-aqueous solution and / or a suspension at concentrations that are calculated to be within the order of one thousand times the normal blood level of zinc. The gradient of the very high concentration between the available ionic zinc and the blood and zinc concentrations of the tissue fluid coupled with the effect of the components of the creams, balsams, ointments, etc. (with respect to facilitating the penetration of zinc ions through the epithelial layer) provides the intense anti-viral healing and wound healing properties of zinc that will be available when needed in order to effectively treat the skin . The following examples illustrate the compositions of the invention and the methods for preparing the topical application formulations.

EXAMPLE 1 Moisturizing Cream Containing Zinc with Vitamin E and Cocoa Butter A base of moisturizer cream containing the following ingredients was prepared: purified water, sunflower oil, stearic acid, cocoa butter, monoglyceryl stearate, stearic triglyceride, stearyl alcohol, zabila barbadensis gel, jojoba oil, -tocopheryl (Vitamin E), carrot extract, jasmine extract, chamomile extract, calendula extract, red clover flower extract, methyl paraben, propyl paraben, caramel, retinyl palmitate and fragrance oil. The basic ingredients were used in conventional amounts in view of the object to provide a moisturizing cream. A mixture of 0.440 gram of zinc oxide and 4.05 grams of anhydrous glycine was dissolved in 6.8 grams of purified water by heating in a Pyrex beaker at a temperature of 71.1 ° C in a 750-watt microwave oven. The hot crystalline solution was added to 115 grams of the cream base and mixed vigorously to form a smooth opaque cream containing 0.279 percent Zn ^ X The product had consistencyacceptable flavor and astringency without causing irritant effects during application. In an efficacy test against the Herpes Simplex Virus (HSV) Type 1, a labial sore (lower oral lip) developing in a person known to have HSV that has reappeared within 2 hours of onset of typical prodromal symptoms ( that is, sensitivity, erythema, mild edema, itching) by manually applying approximately 50 milligrams of the cream to the developing lesion. The relief of symptoms occurred within a few minutes. The application of the cream was repeated every 3 to 4 hours for 16 hours. The treatment was truncated because the symptoms were eradicated during that time. A small painless open lesion was subsequently developed at 24 hours with rapid resolution.

EXAMPLE 2 Zinc Containing Zabila Vera Ointment A base of aloe ointment of 35.5 grams (including water, glyceryl stearate, PEG-100 stearate, glycerin, aloe vera gel, aluminum magnesium silicate, PEG-150 distearate, stearyl alcohol, quaternium 15, oil of fragrance, diazolidinyl urea, and methyl paraben) was combined with 0.187 gram of zinc oxide and 1.73 grams of glycine dissolved in 2.9 grams of purified water at 71.1 ° C in a small Pyrex container. The stirred mass was heated to a temperature of 39 ° C to 40 ° C, at which point the mixture could be mixed uniformly to form a smooth translucent ointment by means of a rubber spatula. The zinc content of the product was 0.37 percent. The product had acceptable flavor, consistency and astringency without causing irritant effects during application.

EXAMPLE 3 Vitamin E Ointment with Zinc A 45.4 gram Vitamin E Ointment base including petrolatum, isopropyl myristate, α-tocopheryl acetate (Vitamin E acetate), candelilla wax, cetyl alcohol, retinyl palmitate (palmitate Vitamin A), lecithin, and natural fragrance was combined with 0. 180 grams of zinc oxide and 1.67 grams of glycine (dissolved in 2.8 grams of purified water at 71.1 ° C) in a small Pyrex vessel and mixed with vigorous stirring with a rubber spatula. The product was a smooth, pale, yellow and slightly translucent ointment.

The zinc content of the product was 0.29 percent.

The product had acceptable consistency, taste and astringency without causing irritant effects during application.

EXAMPLE 4 Zabila Vera Balsam and Vitamin E with Zinc 60 grams of an extract base of zabila vera and tocopherol (Vitamin E) including white gel lilly, paraffin, beeswax, panthenol, SHEA butter, squalene, olive oil, copaiba oil, kukui nut oil, babassu oil , octyl methoxycinnamate (sunscreen), sunflower oil, soybean oil and flavoring was combined with 0.243 gram of zinc oxide and 2. 24 grams of glycine (dissolved in 3.76 grams of purified water at 71.1 ° C) in a small Pyrex container, and mixed together by vigorous stirring with a rubber spatula. The product was a pale, smooth, slightly translucent balm. The zinc content of the product was 0.29 percent. The product had acceptable consistency, taste and astringency without causing irritant effects during application. As will be apparent to a person skilled in the art, various modifications may be made within the scope of the foregoing description. These modifications being within the capability of a person in the art form a part of the present invention and are encompassed by the appended claims.

Claims (20)

CLAIMS:

1. A solid or semi-solid composition for topical skin application comprising: a pharmaceutically acceptable carrier base; at least one zinc compound; and at least one amino acid; wherein at least one amino acid is present in an amount corresponding to from about 2 to 20 molar equivalents relative to the zinc in the composition, the composition contains from about 1 milligram to about 20 milligrams of zinc per gram of the composition, and the zinc is released from the composition towards the skin to which the composition is applied.

The composition of claim 1, wherein at least one amino acid is a monocarboxylic amino acid capable of forming a complex with at least one zinc compound.

The composition of claim 1 or 2, wherein at least one amino acid is glycine, L-lysine, D, L-lysine or a combination thereof.

4. The composition of claim 1, wherein at least one amino acid is glycine.

5. The composition of claim 1, wherein at least one zinc compound is zinc oxide, Zinc Zinc (Amino Acid), or a combination thereof, and wherein the amino acid is glycine, L-lysine, D, L -line, or a combination thereof.

The composition of claim 1, wherein at least one zinc compound is zinc oxide and at least one amino acid is glycine.

The composition of claim 2, wherein at least one zinc compound is a divalent zinc complex with the monocarboxylic amino acid.

The composition of claim 7, wherein the complex is a zinc glycine complex having a formula Zn (C2H4 O2) 2 'nH2 ^ in which n has a value of 1.1 / 2 or 2, which is combined with 0.3 to 5.4 parts by weight of the anhydrous glycine.

The composition of claim 7, wherein the complex is a zinc D, L-lysine complex having a formula Zn (C6H13N2O2) 2 * 4H2 ° combined with 0.35 to 3.5 parts by weight of the anhydrous glycine.

The composition of claim 1, wherein the base of the carrier is a cream, balsam, gel, ointment, emollient or lotion.

The composition of claim 1, wherein the composition is present in a skin bandage.

12. A method for treating the skin comprising- (a) applying a composition containing a zinc compound to an area of the skin; (b) dispersing or propagating the composition in a manner that causes the composition to cover said area; and (c) repeat (a) and (b) as necessary; wherein the composition comprises a base of a pharmaceutically acceptable carrier, at least one zinc compound, and at least one amino acid, wherein at least one amino acid is present in an amount corresponding to from about 2 to 20 molar equivalents in relation to zinc, the composition contains from about 1 milligram to 20 milligrams of zinc per gram of the composition, and zinc is released from the composition into the skin area.

13. A method for treating the skin comprising- (a) applying a composition containing a zinc compound to a skin bandage; and (b) applying the skin bandage to an area of the skin so that the composition remains in contact with the area; wherein the composition comprises a base of a pharmaceutically acceptable carrier, at least one zinc compound, and at least one amino acid, and wherein at least one amino acid is present in an amount corresponding to from about 2 to 20 equivalents molars relative to zinc, the composition contains from about 1 milligram to about 20 milligrams of zinc per gram of the composition, and zinc is released from the composition towards the skin area.

The method of claim 12 or 13, wherein at least one amino acid is a monocarboxylic amino acid capable of forming a complex with at least one zinc compound.

15. The method of claim 12 or 13, wherein at least one amino acid is glycine, L-lysine, D, L-lysine or a combination thereof.

16. The method of claim 12 or 13, wherein at least one amino acid is a glycine.

The method of claim 12 or 13, wherein at least one zinc compound that is zinc oxide, (zinc oxide) Zinc2, or a combination thereof.

18. The method of claim 12 or 13, wherein at least one zinc compound is zinc oxide and at least one amino acid is glycine.

The method of claim 14, wherein at least one zinc compound is a divalent zinc complex with at least one amino acid.

20. The method of claim 12 or 13, wherein the base of the carrier is a cream, balsam, gel, ointment, emollient or lotion.