CN1070369C - Alteration of hair growth - Google Patents

Abstract

Topical application of an antiandrogen (with a dermatologically acceptable carrier) alters the rate and character of androgen-stimulated hair growth in intact, sexually mature men. In the experiments proposed in this invention, a steroid-containing Compositions of 5-alpha-reductase inhibitors and cytoplasmic androgen receptor binding agents.

Description

Change the method for hair growth

This invention is that some medicament of selecting from contain 5-alpha-reductase inhibitors and endochylema androgen receptor bonding agent class material of a kind of local application is to change the novel method of androgen stimulating hair growth speed and feature.

About the existing a large amount of medical researches of the effect of hormonal system in the human hair growth.According to these results of study, it is generally acknowledged: the childhood covers the very thin and light hair of big portion body surface, finally becomes under the influence of growth hormone and androgen than what slightly deceive, becomes the terminal hair of the many genius locis of health of growing up.

At each position of health, the feature of last hair growth not only depends on the sensitivity of the topknot at the level of circulation androgen and this position to androgen, but also depends on the be exposed length of time of pieces.Pubes and armpit hair all occur in early days in adolescence, but along with old androgen begins deficiency and reduces.On the other hand, the growth of beard and coming off begins at late adolescence, and more lasting than reducing naturally of androgen.Owing to want to find to control method and the hope that relies on the androgen condition, caused a large amount of relevant androgen metabolic researchs in skin.

The result of these researchs shows all steroid, comprises testosterone, and promptly the main androgen of circulation is diffused into target tissue by quilt in the male blood plasma.In some tissues, as intramuscular, testosterone directly is attached on the cytoplasmic receptor albumen, makes hormone be entered nucleus.

In case enter in the karyon, the testosterone receptor complex just causes that it is essential protein to expressing male phenomenon that these cells synthesize some.

In other tissue, as skin, intracellular testosterone with receptors bind and consequential nuclear translocation before, at first be reduced to dihydrotestosterone by enzyme one steroid 5-5 alpha-reductases, therefore, in the processing of androgen adjusting condition, available two kinds of methods reduce the amount that enters nuclear androgen in to skin.

At first, serum testosterone changes into dihydrotestosterone and can be blocked by enzyme one steroid 5-alpha-reductase inhibitors.Secondly, some chemical compound can be competed cytoplasmic receptor with testosterone or dihydrotestosterone.Our invention proves first by having changed the growth of beard and hair for man's local application antiandrogen (5-alpha-reductase inhibitors and/or cytoplasmic receptor bonding agent).The effect of the antiandrogen chemical compound in this skin also can influence masculinity beard and hair growth course among the secretion of sebaceous gland and the women, and they also are used to treat acne and female hirsutism thus.The ideal antiandrogen agent that is used to change the beard and hair growth should be that a kind of part is quick-acting, does not have the material of remarkable side effect.Though the existing technically report of the quick-acting antiandrogen preparations in several parts, it is effective not having a kind of male's beard is grown.

United States Patent (USP) the 4th, 039 has been described for No. 669 with 17-α-R-androstane-4-alkene-17-β-alcohol-3-ketone or its ester, and R wherein is n-propyl group or n-butyl, the local usage of relevant dermatosis such as the acne that control and androgen are regulated.

United States Patent (USP) the 4th, 139, No. 638 and 4,151, described for No. 540 some 4 '-replace and 3 ', 4 '-substituted polyaniline compound is for the application of dependence androgen diseases such as treatment such as female hirsutism and acne.

United States Patent (USP) the 4th, 191 shows for No. 775, some 3,4-replaces side chain-fluoridize benzamide and can be used for the disease that topical therapeutic relies on androgen, as acne, female hirsutism and seborrhea.

United States Patent (USP) the 4th, describe the local usage of the 17-alpha-substituted steroid of certain androgen for 344, No. 941, as be used for the treatment of acne, seborrhea, the 17-β hydroxyl of alopecia and female hirsutism-1-Alpha-Methyl-17-α-(1-methyl-2-acrylic)-5-α-androstane-3-ketone.

United States Patent (USP) the 4th, 367 has been described a kind of skin sebum secretion that is used for slowing down for No. 227, the cosmetics of being made up of the alcoholic solution of acetic acid chlorine hydroxyl methylene progesterone.

West Germany OLS2, described for 840, No. 144 progesterone and acetic acid chlorine hydroxyl methylene progesterone or with chlormadinone acetate in the inductive hormonal disorder of androgen, for example alopecia, the use in conjunction of the topical therapeutic aspect of female hirsutism and acne.

Japan KOKai has described by local application for 58-57308 number and has resembled stabilized chlorine dioxide, Potassium bromate., or the ozone oxidation thing suppresses the enzymatic activity of 5-5 alpha-reductases and makes bald head long hair again.

Patented technology has disclosed the method for many minimizing human hair growths opposite with conventional measure of removing hair such as cutting, shave, pull out.One of these class methods are at United States Patent (USP) the 3rd, 426, description have been arranged in No. 137, and this method is about by to a kind of replacement benzophenone that contains of alopecia skin area local application, as the synthetic of 2-amino-5-chlorobenzene ketone and the process of hair growth inhibition.Example in the patent has shown rabbit back and slowing down for hair growth on the examination male arm.

At United States Patent (USP) the 4th, 370, the another kind of method that is used for long-term depilation has been described in No. 315.Comprise in this method that a kind of composition of lipoxidase that contains is with the local application of linoleic acid or derivatives thereof.This patent is described, and the women uses about six weeks behind this type of synthetic for examination person's parts of body, and most of people regrow with regard to high-visible hair.

We have found two class antiandrogens, i.e. steroid 5-alpha-reductase inhibitors and endochylema androgen receptor bonding agent, and they can be used for changing the speed of growth and the feature of the complete beard that sexual maturity man androgen stimulates.For reaching partial result, these antiandrogens are contained in external in the skin acceptable carrier, and the allomeric function that other androgen that causes because of general action is regulated changes seldom.In the present invention's the practice of preferentially carrying out, the synthetic that contains steroid 5-alpha-reductase inhibitors has used with a kind of endochylema androgen receptor bonding agent.

We have found that the normal speed of male's beard and hair growth can be slowed down, and makes it become the hair shape by the antiandrogen chemical compound of topical application 5-alpha-reductase inhibitors or endochylema androgen receptor bonding agent class.By the suitable selection of antiandrogen chemical compound and using method thereof, can reduce or avoid unnecessary interference to some processes of other androgen adjusting.

In our invention practice, fail to prove the synthetic active antagonism of androgen for one of the both sides abdomen organ suitable synthetic of local application of ripe male hamster.

Handle abdomen organ's hair growth minimizing (relevant) that the side androgen relies on, but offside is promptly used the vehicle treated side, and the variation of statistical significance is not arranged with dosage.Carried out similar research with female hamster, stimulated the hair growth on the abdomen organ to these suitable androgen of female hamster subcutaneous injection.

A kind of new method of screening local antiandrogen is established, this method is based on a biochemical indicator relevant especially with the androgen stimulation of pilosebaceous unit target tissue, utilizes the abdomen organ that androgen and antiandrogen are replied the active change of middle ODC Ornithine decarboxylase (ODC) and provide one method of screening antiandrogen in the body rapidly.In several researchs, optionally reduced the ODC activity of handling side for male hamster abdomen organ one-sided local application antiandrogen 17-α-Topterone and 17-α-pi-allyl testosterone, and uncastrated complete side ODC activity is unaffected.The local female hamster that has stimulated with acetic acid chlorine hydroxyl methylene progesterone or progesterone processing androgen also suppresses the ODC activity.

About a series of further research of androgen, be intended to test some prescriptions of local antiandrogen use in conjunction to the active regulating action of ODC among the hamster abdomen organ.Antiandrogen, be robust hormone binding inhibitors (acetic acid chlorine hydroxyl methylene progesterone for example, chlormadinone acetate, 17-α-Topterone, and 17-α-acrylic testosterone) and the 5-alpha-reductase inhibitors, can both suppress ODC activity among the abdomen organ such as progesterone, when use the part.But progesterone and binding inhibitors use in conjunction have improved the inhibiting intensity of ODC and have been reduced to the dosage that reaches the necessary binding inhibitors of maximum partial result.It seems that the associating compatibility that contains the androgen binding inhibitors of low dosage be to produce high local efficacy and the most effective local antiandrogen of low offside effectiveness.The prescription that contains progesterone and 17-α-Topterone or 17-α-acrylic testosterone has produced maximum local inhibitory action, compares with other prescriptions, and it does not cause any to side effect.

What sum up below is several result of experiment, and these experiments have been compared several chemical compounds in the effect that reduces the complete male hamster abdomen organ hair of growing up.In each experiment, hamster is located 15 days (from MONDAY to FRIDAY) 21 days interim.Removed abdomen organ's hair at first day and the 6th day that handles.During last 14 days of 21 intervals, abdomen organ's hair, the hair that representative regrows out.Below shown in the percentile result of inhibition be based on that abdomen organ that experimental animal handled goes up number of hairs and the control animal egagropilus quantity crossed with vehicle treated between relatively obtain.

Ⅰ / 1000 30 500 2617-α- 6 2617-α- 6 + 1000 39 500 + 1000 52Ⅱ / 500 38 50 234--3--17B- 400 29 50+4--3--17B- 400 41 500+4--3--17B- 400 54Ⅲ / 1000 57 500 41 500 45 500 + 1000 69Ⅳ / 1000 4817-α- 5017-α- 20 2917-α- 50 5017-α- 100 50

The part use antiandrogen with the speed and feature that change the beard and hair growth in, can be separately or unite mutually and use various 5-alpha-reductase inhibitors and endochylema androgen receptor bonding agent.Available progesterone in the 5-alpha-reductase inhibitors; (5 α, 20-R)-4-diazo-21-hydroxyl-20-methyl alkane-3-ketone of being pregnent; (4R)-and the nor-alkane of being pregnent-4 of 5-10-open loop-19-, 5-diene-3,10,20-triketone; 4-androstene-3-ketone-17B-carboxylic acid, and methyl ester; 17-B-N, N-diethylamino formyl-9-methyl isophthalic acid 4-aza-5 alpha-androstane alkane-3-ketone; 11-Alpha-hydroxy-progesterone; 17-Alpha-hydroxy progesterone and 20-Alpha-hydroxy-progesterone.For function that other androgen is regulated is very little because of the change that causes by general action, we are willing to progesterone or 4-androstene-3-ketone-17-carboxylic acid.As discussed below, the concentration of these materials and level should be to use about 10-10 on every square centimeter of skin in the synthetic of making by prescription, and the active substance of 000 microgram is advisable.We like reaching about 100-1 with those, the synthetic of 000 microgram/square centimeter.

In the cytoplasmic receptor bonding agent, that can mention has an acetic acid chlorine hydroxyl methylene progesterone, chlormadinone acetate, 17-α-Topterone, 17-α-pi-allyl testosterone, α, α, α-three fluoro-2-methyl-4-nitro--propionyl is for toluidines, 6 alpha-brominated-17B-hydroxyl-17 Alpha-Methyls-4-oxa-5 alpha-androstane-3-ketone; 17B-acetate-4 α, 5 ring-A-height-B-are nor--5 α-androstane-1-alkene-3-ketone; And spironolactone.Be the change minimum that the function that androgen is regulated causes by general action, we are willing to 17-α-Topterone or 17-α-pi-allyl testosterone.The concentration of these materials and level should be about 0.1-5 in the synthetic of making by prescription as discussed below, 000 microgram/square centimeter skin.We are willing to can reach with those compositions of about 1.0-500 microgram/square centimeter.

We are willing to unite use 5-alpha-reductase inhibitors and endochylema androgen receptor bonding agent, because the 5-alpha-reductase inhibitors seemingly can strengthen the effect of endochylema androgen receptor bonding agent, thereby can use lower concentration to reduce the danger of whole body side reaction.When the two use in conjunction, the concentration of 5-alpha-reductase inhibitors and endochylema androgen receptor bonding agent all should be within the scope that they use separately respectively.

In practice of the present invention, be used for partial preparation synthetic, can use acceptable substrate of any skin or carrier.But must carefully use substrate or carrier, they should make antiandrogen be only limited to local absorption and not have tangible general to absorb in principle.The proficiency skills of preparation cosmetic creaming can be used for the preparation of compositions in the present invention's practice.For example, the derivant of known many lanolines has fabulous emulsification property, thereby can be used for the preparation of the Emulsion of strict stability.Lanoline also is believed to be helpful in active substance and is absorbed into skin.Though active substance can be attached to various cosmetics such as single solution, Emulsion, suspension, in the gel, but the advantage of same oil-water type Emulsion is can directly contact with the skin lipoids, thereby an approach that makes active antiandrogen slowly continue to absorb is provided.

In our invention practice, when preparation contained the synthetic of 5-alpha-reductase inhibitors, this inhibitor can be less to 0.1% or nearly 10.0% by weight.We preferentially select the content of 1.0-4.0% for use.When preparation contains the synthetic of cytoplasmic receptor bonding agent, same by weight available 0.1-10.0%.But Dichlorodiphenyl Acetate chlorine hydroxyl methylene progesterone, we select 0.5-5.0% for use chlormadinone acetate and spironolactone, and other cytoplasmic receptor bonding agent is selected 0.2-0.5% for use.

Use contains the antiandrogen synthetic to improve people's beard and hair growth, and every day, the compositions with capacity was coated on face and the bearded skin of cervical region, just can keep the aforesaid level of using.Use will cause beard and hair to reduce and gradate to the hair state continuously.But this change at utmost has an individual variation.

Following Example is the compositions in explanation the present invention practice, but not as limitation of the present invention.

Embodiment 1-skin detergent composition weight percent progesterone 2.2+ six alkanols 4.0 atoleines 4.0 isopropyls+four alkanoic acids, 1.0 dimethicones, (Dimethicone) 1.0 lanolin alcohol 0.5Glycerol monosterate, 1.0 sodium lactates, (60% aqueous solution) 1.4 dimethyl chlorinations two ammoniums, (75% activity)-Arquad 2H,T75 2.0 propyleneglycoles 3.0 methyl Paraben 0.2 propyl group Paraben 0.1 titanium dioxide 0.1 spices 0.1 water 77.4 100.0

Program: deionized water and propylene diethanol are heated to 70 ℃, under high-speed stirred, add methyl Paraben.In another container, make lubricating oil, emulsifying agent, the dimethyl chlorination diammonium of preheating, active component and propyl group Paraben combination.Under agitation heat and keep 70 ℃ 30 minutes.Be added to water in the oil phase and agitation as appropriate.Adding titanium dioxide also mixed 60 minutes.Slowly be cooled to 55 ℃, add sodium lactate (60%) and under agitation continue to slowly cool to room temperature.

Embodiment 2-Emulsion concentrate weight percent A. acetic acid chlorine hydroxyl methylene progesterone 2.2 stearic acid xxx 7.6Amerchol L-101 5.0Modulon 2.0+ six alkanols 3.0 propyl group Parasept 0.1B. glycerol 4.0 methyl Paraneb 0.15 water 75.95

Program: mix each composition of (A) and be heated to 70 ℃.Mix each component of (B) respectively and be heated to 72 ℃.Join in (A) in quick stirring following (B), be cooled to room temperature then.

Embodiment 3-aerosol spray concentrate weight percent A. Magnesiumaluminumsilicate (V-type glue K) 1.5 propyleneglycoles 3.0 water 86.0B. chlormadinone acetic acid divinyl ethylene glycol monostearates 3.0 silicone 556 liquid 1.0+ six alkanols 0.5 acetyl lanolin alcohol 2.0 antiseptic 0.2

Program: under stirring fast, V-type glue slowly is added to the water, till mixing well.Add remaining (A) composition and be heated to 80 ℃.(B) composition is mixed and be heated to 75 ℃.Join in (B) while mixing with (A) and be cooled to room temperature.90 portions of concentrate are mixed with 10 parts of hydro carbons spray A-46 be aerosol.

Embodiment 4-aerosol foam concentrate weight percent A. progesterone 2.0 acetic acid hydroxyl methylene progesterone 0.2+ six alkanols 5.2 poly-hydroxyalkyl vinyl (401 stearates (MYRJ52)) 3.0B. propyleneglycoles 4.0 water 85.4 antiseptic 0.2

Program: the composition of (A) is mixed and be heated to 70 ℃.The composition of (B) is mixed respectively and be heated to 72 ℃.Join in (A) while mixing with (B) and be cooled to room temperature.Make aerosol with 7 parts of hydrogen spray A-31 and 93 portions of concentrate.

Embodiment 5-alcoholic solution concentrate weight percent 17-α-Topterone 2.2 propyleneglycoles 4.0 dimethicone 1.0SDA-40 alcohol 92.8

Program: mix each composition and packing while stirring.

Claims (8)

1. Cosmetic method for altering the growth rate and character of androgen-stimulated beard hair in intact, sexually mature men, characterized by applying to the skin a cosmetic composition containing at least one 5-alpha-reductase inhibitor or a cytoplasmic androgen receptor binding agent or a mixture thereof, and a dermatologically acceptable carrier, the formulation of the carrier mentioned and the concentration of the antiandrogen are selected so as to effectively alter the complete Androgen-stimulated hair growth rate and characteristics in sexually mature men, but it only produces local effects, and has little effect on other androgen-stimulated overall functions through systemic effects. 2. The method according to claim 1, wherein the 5-alpha-reductase inhibitor is from progesterone; (5alpha, 20R)-4-diazo-21-hydroxyl-20-methylpren-3-one ; (4R)-5-10-cyclo-19-norpregna-4,5-diene-3,10,20-trione; 4-androstene-3-one-17B-carboxylic acid, or its methyl ester; 17-B-N,N-diethylcarbamoyl-9-methyl-4-aza-5α-androstan-3-one; 11-α-hydroxy-progesterone; 17α -Hydroxy-progesterone; or a selected one from 20-alpha-hydroxy-progesterone. 3. The method of claim 2, wherein the antiandrogen is selected at a concentration of about 10 to 10,000 micrograms of 5-alpha-reductase inhibitor per square centimeter of skin. 4. The method of claim 2, wherein the antiandrogen is selected at a concentration of about 100 to 1,000 micrograms of 5-alpha-reductase inhibitor per square centimeter of skin. 5. The method according to claim 1, wherein the cytoplasmic androgen receptor binding agent is chlormadinone acetate; chlormadinone acetate; 17-alpha-propyl testosterone; 17-alpha-allyl testosterone ; α-α-α-trifluoro-2-methyl-4-nitro-m-propionyl toluidine; 6α-bromo-17B-hydroxy-17α-methyl-4-oxa-5α-androgen Stan-3-one; 17B-acetyl-4α,5cyclo-A-homo-B-nor-5α-androst-1-en-3-one; or spironolactone selected from. 6. The method of claim 5, wherein the antiandrogen is selected at a concentration of about 0.1 to 5,000 micrograms of cytosolic androgen receptor binding agent per square centimeter of skin. 7. The method of claim 5, wherein the antiandrogen is selected at a concentration of about 1.0 to 500 micrograms of cytosolic androgen receptor binding agent per square centimeter of skin. 8. A method according to any preceding claim, wherein the 5-alpha-reductase inhibitor is used together with a cytoplasmic androgen receptor binding agent.