JPH0231053B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a treatment for the skin disease commonly known as "dry skin" characterized by cracking, dandruff or peeling of the skin on the hands, feet and body, particularly for topical use to prevent or cure this condition in humans. It relates to compounds that have been discovered to be effective. Severe "dry skin" known as ichthyosis is a genetic disease. Ichthyosis refers to the scaly appearance of human skin. Ichthyosis, characterized by a "dry skin" appearance, is commonly found in young children. “It stuck”
Microscopic fish scales are prominent on the trunk and upper limbs. Large scales can be seen on the feet. A very small percentage of the population is affected by this genetic disease. Unlike ichthyosis, mild to normal "dry skin" is common in the population. This common "dry skin" condition is especially likely to occur during the fall and winter months, when relative humidity is relatively low. These are characterized by tears, redness, cracks or dandruff on the skin of the hands, feet, face, neck and feet. A common treatment for dry skin conditions is the topical application of oils or oil combinations and hydrating emollients. Also salicylic acid, urea, glycerol, propylene glycol, sorbitol or vitamin A
Ointments containing are used. However, conventional treatments are generally not successful and often do not reduce symptoms or promote healing. Since the mechanism that causes dry skin is not understood, treatments usually limit temporary relief or healing of dandruff or scales. Applicants have now discovered that the acid, amide or ammonium salts of alpha- or beta-hydroxyacids or alpha-keto acids and their esters can be used to satisfactorily prevent or treat "dry skin" conditions. Specifically, Applicants include in the pharmaceutically acceptable excipients (A) citric acid, glycolic acid, glucuronic acid, galacteuronic acid, glucuronolactone, gluconolactone, alpha-hydroxybutyric acid;
α-Hydroxyisobutyric acid, lactic acid, malic acid, mandelic acid, mucinic acid, pyruvic acid, methylpyruvate, ethylpyruvate, β-phenyl lactic acid, β
- at least one reactant selected from the group consisting of phenylpyruvic acid, sugar acid, tartaric acid, tartronic acid, and β-hydroxybutyric acid; and (B) ammonium hydroxide; the alkyl or alkanol substituent has 1 to 1 carbon atom; or It has been discovered that dry skin conditions in humans can be treated by topical administration of a therapeutically effective amount of a composition comprising a reaction product with a base selected from the group consisting of diaminoalkanes having from 2 to 10 carbon atoms. It is. A preferred embodiment of the invention includes (A) citric acid, glycolic acid, glucuronic acid, galacturonoic acid, glucuronolactone, in a pharmaceutically acceptable excipient;
Gluconolactone, α-hydroxybutyric acid, α-
Hydroxyisobutyric acid, lactic acid, malic acid, mandelic acid, mucilage acid, pyruvic acid, methylpyruvate, ethylpyruvate, β-phenyl lactic acid, β-
at least one reactant selected from the group consisting of phenylpyruvic acid, sugar acid, tartaric acid, tartronic acid, and β-hydroxybutyric acid; and (B) ammonium hydroxide, methylamine, ethylamine, monoethanolamine, monoisopropanolamine. , ethylenediamine, 1,2-diaminopropane, dimethylamine, diethylamine, diethanolamine, diisopropanolamine, N-methylethanolamine, N-ethylethanolamine, triethylamine, triethanolamine, N-methyldiethanolamine and triisopropylamine. A method is provided for treating dry skin conditions in humans by topical use of a composition comprising a reaction product with a base selected from: Topical solutions, creams or ointments containing 1 to 20%, preferably 2 to 10%, of the above reaction products are tested on humans with "dry skin" conditions, usually within about 1 to 2 weeks after application. It was confirmed that the affected area returned to its normal skin condition and that the treatment was effective. If two or more reaction products are used in the compositions of the invention, the total concentration of the products should not exceed 10% by weight of the composition. It has been discovered that topical use of the compositions of the present invention is generally effective in preventing the development of dry skin symptoms in individuals who occasionally experience redness or flaky skin. The invention therefore provides cosmetic compositions containing at least one of the above reaction products, which, when used topically, will necessarily prevent the development of dry skin conditions. The present invention further provides pharmaceutical compositions containing at least one of the reaction products described above which, when used topically, substantially treat dry skin conditions. The present invention further provides a method of treating dry skin with a composition of the above reaction product in a pharmaceutically acceptable excipient. Generally, the PH of the compositions of the invention should be between 3.5 and 7.5. In a preferred embodiment of the invention, the pharmaceutically acceptable excipient is at least one selected from the group consisting of water at a concentration of up to 99%, ethanol at a concentration of up to 70% and propylene glycol at a concentration of up to 30%. It is of seeds. The present invention also provides a safe and effective treatment that promotes healing of dry skin conditions within about 1 to 2 weeks with normal topical use of the pharmaceutical composition. Furthermore, the present invention provides a cosmetic product in the form of a liniment, cream or ointment which, when used topically at least daily on skin areas prone to redness, dandruff or scaly lesions, prevents the development of dry skin or restores a healthy skin condition. and methods for formulating pharmaceutical compositions. Preparation of Therapeutic Compositions Conventionally, alpha- or beta-hydroxyacids or alpha-keto acids have been prepared into compositions containing 5 to 10% by weight of the compound in creams or ointments for the treatment of severe dry skin conditions, such as ichthyosis. The PH of this composition was about 2 or less. In the treatment of common dry skin conditions according to the present invention, it has been found that the low PH composition described above causes certain skin irritation conditions (redness and burning sensation) on sensitive skin. Therefore, it has been desired to develop a composition that is therapeutically effective and non-irritating. The present invention provides pharmaceutically acceptable excipients including (A) citric acid, glycolic acid, glucuronic acid, galactouronic acid, glucuronolactone, gluconolactone,
α-hydroxybutyric acid, α-hydroxyisobutyric acid, lactic acid, malic acid, mandelic acid, mucic acid, pyruvic acid, methylpyruvate, ethylpyruvate, β-phenyl lactic acid, β-phenylpyruvate, sugar acid , tartaric acid, tartronic acid and β-hydroxybutyric acid.
Reactant and (B) ammonium hydroxide; an organic primary, secondary or tertiary alkylamine, alkanolamine, dialkylamine, dialkanolamine, alkylalkanol in which the alkyl or alkanol substituent has 1 to 8 carbon atoms; amine, trialkylamine, trialkanolamine, dialkylalkanolamine or alkyldialkanolamine; or a reaction product with a base selected from the group consisting of diaminoalkanes having 2 to 10 carbon atoms. The present invention provides a pharmaceutical composition for treating dry skin conditions. The reaction products of the present invention can be prepared in a solvent by citric acid, glycolic acid, glucuronic acid, galacteuronic acid, glucuronolactone, gluconolactone, α-hydroxybutyric acid, α-hydroxyisobutyric acid, lactic acid, malic acid, malderic acid, Mucilage acid, pyruvic acid, methylpyruvate, ethylpyruvate, β-
At least one reactant selected from the group consisting of phenyl lactic acid, β-phenylpyruvic acid, sugar acid, tartaric acid, tartronic acid and β-hydroxybutyric acid is combined with ammonium hydroxide; the alkyl or alkanol substituent has 1 to 1 carbon atom. organic first with 8
or from 2 to 10 carbon atoms; It is produced by reacting with a base selected from the group consisting of diaminoalkanes with The solvent used in the reaction is one or more selected from the group consisting of water, alcohol, ether and acetone, with water being preferred. The solvent concentration used in the reaction is about 5% to about 30%. This reaction can be carried out at temperatures of about 0 to about 75°C. Preferably, the reaction is carried out at room temperature. In preferred embodiments, the reaction product comprises about 1 to about 20% by volume of the total composition. In a more preferred embodiment, the reaction product is about 2 to about 10% by volume of the total composition. Compositions of the invention may include two or more different reaction products. Prophylactic and therapeutic compositions can be prepared in the form of liniments, creams or ointments. In this case, a liniment, cream or ointment can be easily produced by incorporating ingredients suitable for cosmetic use into the composition. The following examples illustrate the formulation of compositions according to the invention. While the Examples illustrate selected formulations useful in the present invention, they are intended to be illustrative and not limiting in any way. Therefore, any of the acids, esters, and amines mentioned above can be substituted in the following formulations according to the description of this invention. Example 1 5 g of glycolic acid was dissolved in 10 ml of water, and 3 ml of ethanolamine was added to partially neutralize the acidity of the solution. Eighty-two grams of a water-soluble liniment consisting of mineral oil, cottonseed oil, isopropyl palmitate, and water with a surfactant such as sorbitan sesquioleate were mixed with the above solution. The ingredient ratio of the above liniment is 15:15:5:
The ratio was 60:5 parts by weight. The resulting liniment was stored in a plastic squeeze bottle fitted with a nozzle. Example 2 5 ml of US Pharmacopoeia grade lactic acid was dissolved in 10 ml of water, and 5 ml of triethanolamine was added to partially neutralize the acidity of the solution. The above solution was mixed with 80 g of a water-resistant liniment prepared by adding a surfactant such as sorbitan sesquioleate to mineral oil, cottonseed oil, and water. The above liniment ingredients were in a proportion of 30:15:50:5 parts by weight, respectively. Example 3 A: Polyoxyethylene (20) sorbitan monooleate (hereinafter referred to as Tween 80) 5 g Cetyl alcohol 20 g B: Water 45 ml Propylene glycol 10 ml Glycolic acid 10 g Ethanolamine 7 ml Heat A and B above to 75°C, respectively. Then, B was gently added to A while stirring. The mixture was stirred until it solidified. PH of the water-removed cream thus obtained
was 4.7. Example 4 A: Tween 80 5g Cetyl alcohol 22g B: Water 55ml Propylene glycol 10ml Lactic acid 5ml Ethanolamine 2ml After heating A and B to 75°C, B was gently added while stirring A. The mixture was stirred until it solidified. The pH of the cream that is removed with water is
It was 4.5. Example 5 A: Tween 80 5g Cetyl alcohol 15g Stearyl alcohol 5g B: Water 60ml Propylene glycol 5ml Citric acid 2g Lactic acid 2ml Glycolic acid 2g Ethanolamine 3ml A and B were heated to 75°C, and while stirring A, B was added. I added quietly. Stirring was continued until the mixture solidified. The pH of the water-removal cream containing 3 active ingredients was 4.4. Example 6 7 g of glycolic acid was dissolved in 10 ml of ice water, and 5 ml of ethanolamine was added to partially neutralize the acidity of the solution.
The solution was mixed with 78 g of a water-resistant liniment made by adding petrolatum, mineral oil, spermaceti, and water with a surfactant such as sorbitan sesquioleate.
The ingredients of the above liniments are 10:10:6:68:6 respectively.
It was by weight. Example 7 Dissolve 5 ml of US Pharmacopoeia grade lactic acid in 10 ml of ice water, add 4 ml of triethanolamine to partially neutralize the acidity of the solution, and prepare a mixture of petrolatum, mineral oil, isopropyl myristate, spermaceti, and water with sorbitan sesquioleate. 81 g of a water-resistant liniment made from a surfactant was mixed with the above solution. The components of the liniment were 10:10:10:6:58:6 parts by weight, respectively. Test Results (A) Severe Dry Skin Patients with severe dry skin conditions such as ichthyosis were first moistened with a shower, and then a thin layer of the composition formulated according to Examples 4, 7, or 9 was applied to the left side of the body. Coated. The right side of the body was covered with vegetable oil or other over-the-counter medicine such as Vaseline. Topical treatments were continued twice a day for several weeks. After approximately one week of treatment, the left side of the body of all test patients became smoother and less rough than the right side. After 10 days of treatment, the rough skin on the left side of my body was virtually cleared. 2 to 3 from the beginning
Within a week, all the cracks, dandruff, and scales on the left side of his body disappeared, and his skin looked almost the same as normal skin. There was little or no improvement on the right side of the body treated with vegetable oil or petrolatum alone. Therefore, after three weeks, the patient was given the composition of the invention on the right side of his body.
Within 2 to 3 weeks, the skin on the right side of the body returned to its normal state. Once the skin was restored to its normal state, it remained improved even if the patient changed for several weeks to several months without the need to apply ointments. However, it was necessary to continue using the ointment to prevent obvious recurrence of the disease. (B) Normally Dry Skin People with mild to moderate dry skin conditions as evidenced by dry skin, cracking, or dandruff apply the liniments, creams, or ointments of the present invention formulated according to Examples 1 to 8 on their affected skin. I let it happen. 1 day 2
Local treatment continued for 2-3 weeks. Local treatment 3-
After 4 days, the dry skin of all 23 people tested disappeared. Within one week, the rough, cracked skin of 21 people tested improved. The skin generally became normal and smooth after two weeks of topical treatment. Unlike severe dry skin disease, normal dry skin conditions, once restored to normal, remain well until the cause of dry skin, such as low humidity, cold weather, detergents, soaps, drugs, etc., recurs. There is. It has been discovered that continuous twice daily topical treatment of the compositions of the present invention prevents the development of new dry skin lesions. Example 8 The active ingredients of the pharmaceutical composition for treating dry skin symptoms of the present invention are the reactant (A) (hereinafter referred to as "hydroxy acid") and the base (B) (hereinafter referred to as "hydroxy acid"). It is preferred to react less than 1 mole of ammonium hydroxide or organic amine per mole of hydroxy acid. The optimum molar ratio of hydroxy acid to ammonium hydroxide or organic amine is in the range 1:0.15 to 1:0.5. That is, 15-50% of the hydroxy acid used is reacted with ammonium hydroxide or an organic amine to form a salt, leaving the remaining hydroxy acid (50% or more) in the free acid form. In fact, Part 3 below
As shown in the table, the therapeutic composition of the present invention consists of both a hydroxy acid and its ammonium or organic amine salt. Although hydroxy acids (component A) are themselves effective in treating dry skin, unreacted hydroxy acids tend to irritate the skin due to their very low PH. Metal salts of hydroxy acids are not effective in treating dry skin (although they may be effective in reducing or eliminating the irritation caused by low pH). Hydroxy acids partially neutralized (partially reacted) with ammonium hydroxide or organic amines are effective in treating dry skin without irritating the skin. Such a therapeutic composition has a molar ratio of hydroxy acid and hydroxy acid ammonium salt or organic amine salt in the above range, and
The maximum therapeutic effect is achieved when the pH is in the range of 3.5 to 4.5, while avoiding skin irritation or stinging. The above facts are clear from the data in Tables 2 and 3 below. Table 1 below shows the relationship between the hydroxy acid concentration of unneutralized (free form) hydroxy acid compositions and the PH of the composition. It is advisable to prepare a stock solution of the reaction product before preparing the final composition. Some examples of the preparation of these stock solutions are shown below. Glycolic acid stock solution Dissolve 70 g of glycolic acid in 30 ml of water and slowly add 15 ml of ammonium hydroxide concentrate to this solution. During this period, the reaction mixture is externally cooled in an ice-water bath. The obtained stock solution is an aqueous solution with a pH of 3.7, and the molar ratio of glycolic acid/glycolic acid ammonium salt in the solution is 77/23.
1.4ml contains 1g of glycolic acid (based on total glycolic acid used). Gluconolactone stock solution Dissolve 100 g of gluconolactone in 175 ml of water and gradually add 6.5 ml of ammonium hydroxide concentrate to this solution. The obtained stock solution is an aqueous solution with a pH of 3.7, and the molar ratio of gluconic acid/gluconate ammonium salt in the solution is 83/17.
2.4ml contains 1g of gluconolactone (based on total gluconolactone used). Gluconolactone derived from organic amines
A stock solution can be made as follows. Dissolve 100g of gluconolactone in 200ml of water.
30 g of triethanolamine are slowly added to this solution. The obtained stock solution is an aqueous solution with a pH of 4.1, the molar ratio of gluconic acid/gluconic acid triethanolamine salt in the solution is 64/36, and gluconolactone (all the gluconic acid used) is contained in 2.8 ml of the solution. Contains 1g (based on nolactone). Malic acid stock solution Dissolve 100 g of DL malic acid in 200 ml of water and gradually add 25 ml of ammonium hydroxide concentrate to this solution. During this period, the reaction mixture is externally cooled in an ice-water bath. Since malic acid contains two carboxylic acids in one molecule, two moles of ammonium hydroxide are required for complete neutralization. The stock solution obtained as above is an aqueous solution with a pH of 3.8.
2.8 ml of solution contains 1 g of malic acid, 76% of which is in the unneutralized form. Malic acid stock solutions derived from organic amines can be prepared as follows. malic acid
Dissolve 100g in 200ml of water and add triethanolamine.
Gradually add 40 g to this solution. The stock solution obtained is an aqueous solution with a pH of 3.5 and contains 1 g of malic acid in 3 ml of solution, 82% of which is in the unneutralized form. Lactic Acid Stock Solution Dissolve 120 g of lactic acid [USP: 85%] in 90 ml of water and gradually add 15 ml of ammonium hydroxide concentrate to this solution. During this period, the reaction mixture is externally cooled in an ice-water bath. The obtained stock solution has a pH of
4.1, the molar ratio of lactic acid/lactate ammonium salt in the solution is 81/19, and 2 ml of solution
Contains 1g of lactic acid (based on total lactic acid used).

【table】

【table】

【table】

[Table] Comparative Example 1 The therapeutic effects of completely neutralized salts and partially neutralized salts of hydroxy acids on dry skin disease were investigated with an inorganic alkali. In the case of commercially available neutralized salts such as sodium gluconate, sodium citrate, and sodium tartrate, the salt was dissolved in two parts water and the solution was mixed with a USP water-releasing ointment. . Sodium lactate is available as a 60% aqueous solution and was mixed with a hydrophilic ointment. An example formulation of a therapeutic composition using equimolar amounts of a neutralized salt from a hydroxy acid and an inorganic alkali is as follows. 10 g (0.13 mol) of glycolic acid (crystalline) and 5.2 g (0.13 mol) of sodium hydroxide were dissolved in 25 ml of cold water and the resulting solution was mixed with a hydrophilic ointment to produce 100 g of a composition. Examples of formulations of therapeutic compositions using partially neutralized salts are as follows. Glycolic acid (crystalline) 10g
(0.13 mol) and 2.6 g (0.065 mol) of sodium hydroxide were dissolved in 25 ml of cold water and the resulting solution was mixed with a hydrophilic ointment to make 100 g of a composition. This composition had a pH of 3.9. Humans with normal or mild xerosis, as evidenced by dry flakes or cracks in the skin, were subjects for this study. These subjects were each given five doses of a composition containing a hydroxy acid, its inorganic alkali salt, or its neutralized product.
Topical application was instructed on a test skin area of cm diameter. Topical application was done 2-3 times a day without bandaging and continued for 2-3 weeks. Application is discontinued when resolution of xerosis in the treated area is judged to be clinically complete or when the treated area becomes irritated as indicated by clinical signs of redness or erythema. did. The above tests were conducted on various hydroxy acids and their alkali salts. The results are shown in Table 4 below. As is clear from these results, the composition containing 10% hydroxy acid showed excellent therapeutic effects on all the substances tested, but the composition containing alkaline salt (neutralized salt) of hydroxy acid showed excellent therapeutic effect on the topical treatment of dry skin disease. Treatment was ineffective. When a composition containing 10% hydroxy acid was applied, skin irritation occurred in many subjects (although some subjects did not experience skin irritation). Most subjects did not experience skin irritation (although hypersensitive subjects did experience skin irritation) when applying the hydroxy acid alkali salt-containing composition. When a hydroxy acid is partially neutralized with an alkali,
Although the resulting composition was marginally effective for the topical treatment of dry skin, the presence of non-neutralizing (free) alkali in the composition caused skin irritation in some subjects.

【table】

[Table] Example 9 Glycolic acid, lactic acid, malic acid, citric acid, tartaric acid, and mandelic acid were used as hydroxy acids, and no base was added to these hydroxy acids (comparative experiment), NaOH or
carried out with the addition of KOH (comparative experiment) and with the addition of ammonium hydroxide, monoamines (ethanolamine, triethanolamine) or diamines (diaminoethane, diaminopropane, diaminobutane, diaminodecane) according to the invention as bases. Tests similar to Example 8 and Comparative Example 1 were conducted. The results obtained are shown in Table 5.

【table】

[Table] The present invention may be carried out in other specific ways without departing from its spirit or essential characteristics.
Therefore, the present embodiments are intended to be illustrative in all respects and are not intended to be limiting, and the scope of the present invention is indicated in the claims rather than in the above specification, and changes within the meaning and scope of the present invention are to be considered as equivalent. are all considered to be included within the scope of this claim.

Claims (1)

[Scope of Claims] 1 (A) Citric acid, glycolic acid, glucuronic acid, galacteuronic acid, glucuronolactone,
Gluconolactone, α-hydroxybutyric acid, α
- Hydroxyisobutyric acid, lactic acid, malic acid, mandelic acid, mucilage acid, pyruvic acid, methylpyruvate, ethylpyruvate, β-phenyl lactic acid, β-phenylpyruvate, sugar acid, tartaric acid, tartronic acid and at least one reactant selected from the group consisting of β-hydroxybutyric acid and (B) ammonium hydroxide;
secondary, secondary or tertiary alkylamine, alkanolamine, dialkylamine, dialkanolamine, alkylalkanolamine, trialkylamine, trialkanolamine,
characterized in that the reaction product with a base selected from the group consisting of dialkyl alkanolamines or alkyl dialkanolamines; or diaminoalkanes having 2 to 10 carbon atoms is contained in a pharmaceutically acceptable excipient. A pharmaceutical composition for the treatment of dry skin conditions in humans. 2 The reaction products are (A) citric acid, glycolic acid, glucuronic acid, galactuduronic acid, glucuronolactone, gluconolactone, α-hydroxybutyric acid, α-hydroxyisobutyric acid, lactic acid, malic acid, mandelic acid, mucilage acid , pyruvate, methylpyruvate, ethylpyruvate, β-phenyl lactic acid, β
- at least one reactant selected from the group consisting of phenylpyruvic acid, sugar acid, tartaric acid, tartronic acid and β-hydroxybutyric acid; and (B) ammonium hydroxide, methylamine, ethylamine, monoethanolamine, monoisopropanol. Amine, ethylenediamine, 1,2-
Diaminopropane, dimethylamine, diethylamine, diethanolamine, diisopropanolamine, N-methylethanolamine, N
The composition according to claim 1, wherein the composition is a reaction product with a base selected from the group consisting of ethylethanolamine, triethylamine, triethanolamine, N-methidiethanolamine and triisopropylamine. 3. Claim 1, wherein the excipient is at least one selected from the group consisting of water at a concentration of up to 99%, ethanol at a concentration of up to 70%, and propylene glycol at a concentration of up to 30%. Or the composition according to item 2. 4. The composition according to any one of claims 1 to 3, wherein the composition has a pH of 3.5 to 7.5. 5. The composition of any one of claims 1 to 4, wherein the reaction product is present in a concentration of 1 to about 20% by volume of the total composition. 6. A composition according to any one of claims 1 to 4, wherein the reaction product is present in a concentration of 2 to about 10% by volume of the total composition. 7. Claims 1-6 wherein the composition comprises a reaction product consisting of 5 to 7 parts glycolic acid and 3 to about 5 parts monoethanolamine in 10 parts water per 100 parts excipient. The composition according to any one of the above. 8 Composition: mineral oil, cottonseed oil, isopropyl palmitate, water and surfactant: 15:15:5:60:
Claims 1, 2, 4, 4 or 6 comprising the reaction product of 5 parts glycolic acid and 3 parts ethanolamine in 100 parts excipients present in a ratio of 5 parts Compositions as described. 9 The composition contains 20 parts of cetyl alcohol, 5 parts of polyoxyethylene (20) sorbitan monooleate,
A composition according to any one of claims 1, 2, 4, 5 or 6 comprising the reaction product of 10 parts of glycolic acid and 7 parts of ethanolamine in 45 parts of water and 10 parts of propylene glycol. thing. 10 The composition consists of 7 parts of glycolic acid in 10 parts of water in 100 parts of excipients in which petrolatum, mineral oil, spermaceti, water and surfactants are present in the ratio of 10:10:6:68:6.
7. A composition according to any one of claims 1, 2, 4, 5 or 6, comprising the reaction product of 5 parts of ethanolamine and 5 parts of ethanolamine.