JPH0471053B2 - - Google Patents

Description

[Detailed description of the invention]

"Object of the Invention" Industrial Application Field The present invention relates to a skin external preparation for treating acne. Conventional technology Acne is a skin disease that mainly occurs during adolescence and is called acne vulgaris.It is clinically defined as "chronic inflammatory changes that occur in the pores, mainly in the pilosebaceous system." There is. The etiology of acne is currently not clear, and although it is a skin disease in which various factors are intricately intertwined, it is generally believed that excessive sebum secretion, hair follicle keratinization, and bacteria within the hair follicle play important roles. ing. Therefore, creams and ointments containing sebum secretion inhibitors and antibacterial substances are commonly used as external medicines for acne treatment. However, existing anti-acne drugs containing various drugs have various drawbacks. For example, female hormones, which are sebum secretion inhibitors, suppress the growth of the epidermis and reduce the secretion of sebaceous glands, but the side effects caused by hormonal drugs are not desirable for adolescent men and women. Also, hexachlorophene,
Antibacterial agents such as trichlorocarbanilide and benzalkonium chloride have shown extremely high antibacterial activity in vitro against Propioni-bacterium acnes, a bacteria that lives on the skin. However, when used in creams, ointments, etc. to treat acne, in most cases they do not have the expected therapeutic effect. Problems to be Solved by the Invention The present inventors have conducted intensive research to obtain a drug that does not exhibit hormone-like side effects, is gentle on the skin, and has an excellent acne treatment effect.As a result, the general formula [In the formula, the dotted line indicates that it may be a double bond] A compound represented by or its ester or ether (hereinafter simply referred to as "compound []")
A composition containing a keratolytic agent, a gelling agent, and/or an alcohol produces an unexpectedly excellent effect due to the combination of the compound [] and the keratolytic agent, and also overcomes the formulation drawbacks of the compound []. The present invention was completed based on the discovery that the present invention can improve the low solubility of keratolytic agents, alleviate the irritation of keratolytic agents, and furthermore achieve early treatment of acne by increasing the absorption effect. "Structure of the Invention" Means for Solving the Problems The compound used in the present invention [] has an excellent anti-androgen effect [Japanese Patent Publication No. 16856/1983,
JP-A-57-53499, JP-A-58-57227. ], especially oxendrone (16β-ethyl-
17β-hydroxy-4-estren-3-one)
is commercially available as a treatment for benign prostatic hyperplasia (trade name "Prostetin", Takeda Pharmaceutical Company Limited). Esters and ethers contained in the compound []
It means a compound in which the hydroxyl moiety at position 17 is esterified or etherified. Examples of the ester at position 17 include esters with a C _1-18 alkanoyl group and a C _2-18 alkenoyl group, and these groups may be substituted. Specific examples of the C _1-18 alkanoyl group include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, bivaloyl, caproyl, enantoyl, capryloyl, lauroyl, myristoyl, palmitoyl, stearoyl, and the like. Specific examples of the _C2-18 alkenoyl group include crotonoyl, oleoyl, linoleoyl, and linolenoyl. Substituents for these alkanoyl groups and alkenoyl groups include halogen atoms (e.g. fluorine, chlorine, etc.),
Hydroxy group, mercapto group, oxo group, thioquine group, C _1-6 alkoxy group (e.g. methoxy, ethoxy, etc.), C _1-6 alkylthio group (e.g. methylthio, ethylthio, etc.), C _1-18 alkanoyloxy group (C _{1-18 -18} alkanoyl (e.g. as described above), _C2-18 alkenoyloxy group ( _C2-18 alkenoyl as e.g. as described above), _C6-12 aryl group (e.g. phenyl, naphthyl, etc.),
Examples include _C6-12 aryloxy groups. More specific examples of substituted alkanoyl groups include chloroacetyl, phenylacetyl, phenoxyacetyl, benzoyl, caproyloxyacetyl, enantoyloxyacetyl, (2-ethylbutyryloxy)acetyl, and the like. Ethers at position 17 include ethers with C _1-6 alkyl groups such as methyl, ethyl, propyl, butyl, and pentyl, and C _1-6 alkoxy groups such as methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl.
In addition to ethers with C _1-6 alkyl groups, ethers with groups such as tetrahydropyranyl, tetrahydrofuryl, and tetrahydrothienyl can be mentioned. These esters and ethers are produced by known methods or methods known per se. The compounding amount of the compound [] in the composition of the present invention is 0.001 to 2 W/V%. If it is less than 0.001 W/V%, the effects of the present invention cannot be exhibited. Although the larger the amount, the greater the acne treatment effect, 2W/V% or less is actually sufficient. Keratolytic agents (preparations that have the effect of suppressing hyperkeratinization of sebaceous gland ducts) that are preferably incorporated into general acne treatment compositions include sulfur, selenium disulfide, benzoyl peroxide, salicylic acid, and vitamin A. Although there are acids, urea and resorcinol are particularly suitable in consideration of the synergistic effect with oxendrone or its derivatives, and the amount thereof in the external skin preparation is preferably 0.05 to 5 W/V%. Specifically, the gelling agent used in the present invention is carboxyvinyl polymer (CVP, e.g.
Goodrich Carbopol 940, Goodrich 941, Wako Pure Chemical Hivis Wako 103, 104, 105, etc.), carboxymethyl cellulose (CMC), carboxymethyl cellulose sodium (CMC-
Among them, CVP is preferable. In addition to its gelling effect, these gelling agents may also act as thickeners and stabilizers. The amount of gelling agent in the composition of the present invention is
It is 0.001-20W/V%. The preferred amount of CVP mentioned as a preferred gelling agent is 0.01 to 5W/
V%. The alcohols used in the present invention include monohydric alcohols and polyhydric alcohols, and alcohols selected from these may be used alone or in combination. Examples of monohydric alcohols include aliphatic alcohols such as ethanol, n-propanol, i-propanol, n-butanol, i-butanol, sec-butanol, tert-butanol, n-pentanol, n-hexanol, lauryl alcohol, and cetyl alcohol. C _1-18 alcohol,
Examples include alicyclic _C3-17 alcohols such as cyclopropanol and cyclobutanol, and phenyl- _1-6 alkanols such as benzyl alcohol and phenethyl alcohol. Among these, ethanol and benzyl alcohol are frequently used, and these alcohols serve to compensate for the low solubility of the compound and increase the absorption and permeability of the composition of the present invention. Examples of polyhydric alcohols include aliphatic C _2-6 polyhydric alcohols (with 2 to 6 hydroxyl groups) such as ethylene glycol, propylene glycol, trimethylene glycol, 1,3-butanediol, glycerin, and sorbitol.
In addition, examples include diethylene glycol, polyethyl glycol (average molecular weight 200-2000), dipropylene glycol, polypropylene glycol (average molecular weight 200-2000). These polyhydric alcohols act as solvents like monohydric alcohols, and may also act as humectants. The blending amount of alcohol in the composition of the present invention is 5 to 70 W/V%. The skin external preparation of the present invention contains commonly used auxiliary ingredients such as sebum secretion inhibitors, antibacterial agents, surfactants, thickeners, humectants, astringents, PH regulators, fragrances, pigments, and water. They can be blended as appropriate within a range that does not impair the effects of the invention. Examples of sebum secretion suppressants include female hormones such as estradiol.
Antibacterial agents include hexachlorophene, trichlorocarbanilide, benzalkonium chloride, phenol, cetylpyridinium chloride, undecylenic acid, bithionol, and the like. Examples of the surfactant include nonionic surfactants, anionic surfactants, and amphoteric surfactants, with nonionic surfactants and anionic surfactants being preferred. Examples of nonionic surfactants include polyoxyethylene aliphatic alcohol ether (EO polymerization degree 5-50, aliphatic alcohol has 12-18 carbon atoms, such as Brij 35, Brij 78, Brij 98, etc.), polyoxyethylene fatty acid ester (EO polymerization degree is 8-50, fatty acid has 12-18 carbon atoms, e.g.
Myrij45, Myrij52, Myrij53, etc.), sorbitan fatty acid ester (EO polymerization degree 0-40, fatty acid has carbon number
12 to 18, such as Tween20, Tween 40, Tween 60, Tween
80, Span20, 40, 60, 80, etc.), polyoxyethylene hydrogenated castor oil (EO polymerization degree 5-60,
For example, Nitsukor HCO-50, Nitsukor HCO-60, Nitsukor HCO-100, etc.). Examples of anionic surfactants include sodium soap (12 to 18 carbon atoms);
Examples include potassium soap (carbon number 12-18). Examples of humectants include hyaluronic acid, chondroitin sulfate, pyrrolidone carboxylic acid, and salts thereof. Examples of astringents include tannins. The usage amount of these auxiliary ingredients is usually 0.01~
10 W/V%, preferably 0.1 to 3 W/V%. The composition of the present invention comprises the above-mentioned compound []
It can be produced by mixing an appropriate amount of auxiliary ingredients in addition to the active ingredients of a keratolytic gelling agent and/or an alcohol by a method known per se. Further, the PH range of the present composition is usually in the range of 4 to 8, preferably in the range of 6 to 8.
The pH may be adjusted using a regulator. The external skin preparation of the present invention may be in any form as long as it can be applied to the skin, such as a cream, ointment, or lotion. A formulation example as a gel ointment is described in Examples. Effects The skin external preparation of the present invention may be applied to the affected area in an amount of about 0.1 mg to 0.5 g at a time, usually once to several times a day, depending on the symptoms. With this application method, mild acne usually disappears in a few days, and even severe acne disappears in 2 to 3 weeks. Furthermore, no side effects are observed even when this treatment method is applied. Example Prescription Example 1 Oxendrone 0.2g to benzyl alcohol 5.0g
15.0 g of polyethylene glycol (PEG-600) is added and dissolved, and then a solution of 1.0 g of urea dissolved in 10.0 g of purified water is added. Next, 0.8g of carboxyvinyl polymer (Carbopol 940) and 0.1g of hyaluronic acid.
A solution prepared by dissolving 20.0 g of purified water was added thereto and mixed with stirring, followed by further addition of 27.7 g of purified water and neutralization with 0.2 g of triethanolamine to obtain a gel-like external preparation. Oxendrone 0.2-2.0 in the same manner as Prescription Example 1
A gel ointment was obtained containing %. Their blending amounts are shown in the table as Formulation Examples 1 to 8 along with Formulation Example 1.

[Table] Clinical Examples The effects of the present invention will be explained in more detail by giving clinical examples. (Drug used) The gel ointment type skin external preparation obtained in Formulation 1 above was used. (Targets used and observation period) A total of 15 men and women aged 15 to 30. (How to use) After thoroughly washing the face with cosmetic soap, the above-mentioned gel ointment type skin external preparation was applied 1 to 3 times a day only on the skin eruption. (Observation items and observation date) Observations were made for the three symptoms of comedones, papules, and impetigo, and the severity of each finding was graded as high (4) and moderate, respectively.
The evaluation was divided into five levels: (3), mild (2), slight (1), and none (0). In addition, the severity of acne vulgaris before treatment can be classified as severe, moderate, or severe by combining the severity of these three symptoms.
The symptoms were divided into three stages: mild. Follow-up observations were conducted before treatment, 1 week after treatment (), 2 weeks after treatment (), 3 weeks after treatment (), and 4 weeks after treatment (). (Overall improvement degree) The degree of improvement in symptoms was divided into five levels: markedly relieved (), considerably relieved (), somewhat relieved (+), unchanged (±), and worsened (-) depending on the drug used compared to before use. (Usefulness) Based on the overall improvement level, it was judged as extremely useful (), quite useful (), somewhat useful (+), and ineffective (±).

【table】

[Table] As is clear from the above results, there were a total of 3 males and 12 females.
The clinical test results for 15 people were ± (unchanged) for 1 person (5
%), 1 (5%) said + (somewhat relieved), 4 (30%) said it was quite useful, and 9 (60%) said it was extremely useful. A significant effect has been demonstrated.

Claims (1)

[Claims] 1. General formula [In the formula, the dotted line indicates that it may be a double bond] 0.001 to 2 w/v% of the compound and/or its ester, ether, 0.05 to 2 w/v% of urea and/or resorcinol
0.1w/v% 0.001-20w/v% gelling agent and/or 5
A skin external preparation characterized by containing ~70w/v% alcohol.