MXPA00007074A - Modulation of hair growth - Google Patents

Abstract

Mammalian hair growth may be modulated by applying to the skin a compound that induces or activates the conjugation of an androgen.

Description

MODULATION OF HAIR GROWTH BACKGROUND OF THE INVENTION This invention relates to the modulation of hair growth in mammals. A primary function of the hair of mammals is to provide protection against the environment. However, this function has been largely lost in humans, in whom hair is preserved or removed from various parts of the body essentially for cosmetic reasons. For example, it is generally preferred to have hair on the scalp, but not on the face. Various procedures have been used to eliminate unwanted hair, including shaving, electrolysis, creams or depilatory lotions, application of wax, rra ncarlo and therapeutic antiandrogens. These conventional procedures generally have drawbacks associated with the m is s. Shaving, for example, can cause scratches and cuts, and may leave a perception of an increase in the speed at which the hair grows back. Shaving can also leave a very short, undesirable beard. Electrolysis, on the other hand, can maintain a treated area without hair during REF.121511 extended periods, but can be expensive, painful and sometimes leaves scars. Hair removal creams, although very effective, are typically not recommended for use with frequency due to their high irritation potential. The application of wax and plucking the hair can cause pain, discomfort, and poor elimination of short hair. Finally, a n t i a n d r e g e s - which have been used to treat female hirsutism - can have undesirable secondary effects. It has previously been described that the speed and character of hair growth can be altered by the application, to the skin, of inhibitors of certain enzymes. These inhibitors include the 5-alpha-uctase inhibitors, ornithine decarboxylase, S-adenosylmethionine decarboxylase, g a m a - g I u t a m i I t r a n s p a p t i d a y t a n a g a u a t i n g a s. See, for example, Breuer et al. US Patent No. 4,885,289; Shander, U.S. Patent No. 4,720,489; Ahluwalia, US Patent No. 5,095,007; Ahluwa lia et al., U.S. Patent No. 5,096,911; Shander et al. , US Patent No. 5, 132, 293; and Shander et al., US Patent No. 5, 143,925.

Hair growth results from many complex and interactive processes. In one process, the sex steroid androgens, particularly testosterone, act in, for example, the hair follicles of the beard on the face, to stimulate growth. But these same androgens can inhibit hair growth on the scalp, particularly in those who have a genetic predisposition for male pattern baldness or androgenetic alopecia. Cytochrome P450s, epoxide hydrolases, gIutation - S - 1 transferases, UDP - glucuronosyltransferases (UGTs) and sulfotransferases (STs) are families of enzymes that are involved in the metabolism of xenobiotics and other substances which are endogenous to the human body. In general, enzymes catalyze the conversion of a substrate (e.g., a particular steroid) to a form that is more easily eliminated by the body. For example, the giutathion-S-transferases catalyze the conjugation of the substrate with glutathione; the UGTs catalyze the conjugation of the substrate with glucuronic acid; and the STs catalyze the conjugation of the substrate with a sulfonate group. It is thought that these substrate conjugates are more water soluble than the substrate itself and, therefore, more easily removed from the body. Some of these enzymes can be induced by compounds, such as 3-m e t i I c o I a n t r e n o and phenobarbital. Steroids are substrates for various isoforms of the UGT, with overlapping specifications. For example, UGTr-3, from the liver of the rat, catalyses the glucuronidation of dihydrotestosterone, testosterone and beta-estradiol (β-estradiol I), while, in addition to these steroids, UGTr-2 also catalyzes glucurono with 4-hydroxy-phenyl play, chloramphenicol and 4-methylumbelliferone (Chen et al., Biochem, 32: 10648-10657).

Brief Description of the Invention In one aspect, the invention characterizes the modulation of hair growth by the topical application of a compound that induces or activates the conjugation of an androgen (eg, testosterone), which is involved in hair growth By "induces" or "active", we indicate that the compound increases the levels of conjugating enzyme in hair follicle cells and / or increases the catalytic activity of the conjugating enzyme for conjugation. The compound can, for example, induce or activate the UGT or a ST, for which the androgen serves as a substrate. The modulation of hair growth depends on whether hair growth selected for treatment is hair growth stimulated with androgens (eg, beard hair and torso hair generally in humans) or hair growth that is not stimulated by androgens (eg, hair of the scalp in humans). Topical application of the compound, in a dermatologically acceptable vehicle, to an area of the skin that has hair growth stimulated by androgens generally causes a reduction in hair growth. The topical application of the compound, in a dermatologically acceptable vehicle, to an area of the skin that has hair growth (ie, of the scalp) that is reduced in the presence of androgens (eg, due to androgenic alopecia) generates originates an increase in hair growth. In another aspect, the invention characterizes the modulation of hair growth by the topical application of a compound that induces or activates a UGT. In another aspect, the invention characterizes the modulation of hair growth by the topical application of a compound that induces or activates an ST. In another aspect, the invention characterizes the modulation of hair growth, by the topical application of a compound that induces or activates the conversion of an androgen involved in hair growth into a less active metabolite (eg, more soluble in water). ). Other features and advantages of the invention will become apparent from the description of the Preferred Modalities and the claims.

Description of Preferred Modalities Compounds that activate or induce UGTs. These compounds include ethoxyquin, 5,7-dihydroxy-4'-methoxyflavone, butylhydroxyanisole, f e n b a b i t a, naringenin, b u t i i i i i i i i i i i e r, flavone, thioconazole, t r a n s - 1, 2 - b i s (2 - p i r i d i I) e t i n e, 7,4'-isof lavandiol (equol), galangin, 7-h idroxi-4'-m e t o x i i s or f a a v a n a (formononetin), 5, 4 '- d i h i d r o x i - 7-methoxy isoflavone (prunetin) and daidzein. These compounds induce the UGTs that are important for the gluconon ion of testosterone. Examples of the androgens that can be conjugated include testosterone, dihydrotestosterone, a n d r o s t e n d a n d a n d, a n d r o s t e n d s and dehydroepiandrosterone. It is believed that the compounds act according to the route shown below (in which testosterone is used as an example): Stimulating Hair Growth (beard) Testosterone Reducing Hair Growth (scalp) Induction / Activation of Conjugation Enzymes (UDP-glucuronosyltrapsferase; sulfotransferase) Testosterone conjugate (elimination) Reduced Biological Activity Reduced Hair Growth (beard) Stimulation of Hair Growth (scalp) The compound can induce or activate, for example, UGTs that catalyze the conjugation of testosterone with g-lucic acid (donated by uridin d i f or s f or g I u c u n i c o); or STs that catalyze the conjugation of testosterone with a sulfonate group (donated by 3'-phosphoadenosine 5'-phosphosulfate).

The compound is preferably incorporated into a topical composition that includes a non-toxic, dermatologically acceptable vehicle or carrier that is adapted to be distributed on the skin. Examples of suitable carriers are acetone, alcohols or a cream, lotion, or gel that can effectively distribute the active compound. A vehicle is described in U.S. Patent No. 5,648,394. In addition, a penetration enhancer can be added to the vehicle, to further strengthen the effectiveness of the formulation. The concentration of the compound in the composition can vary in a multiple interval to a saturated solution, preferably from 0.1% to 30%, by weight, or even more; The reduction or increase in hair growth increases as the amount of the inhibitor applied is increased by the unit area of the skin. The maximum amount that is applied effectively is limited only by the speed at which the compound penetrates the skin. The effective amounts may vary, for example, from 10 to 3000 micrograms, or more, per square centimeter of the skin. A composition may include more than one of the compounds.

The composition should be applied topically to a selected area of the body from which it is desired to reduce hair growth (if hair growth is hair growth stimulated by androgens) or increase hair growth (if hair loss is dependent on hair). androgens). For example, in humans, the composition can be applied to the face, particularly to the area of the facial beard, i.e., the cheek, the neck, the upper lip and the chin, to obtain a reduction. in the growth of hair lo. The composition can also be applied to the legs, arms, torso or armpits, to obtain a reduction in hair growth. The composition can be applied to the scalp to obtain an increase in hair growth. The composition is particularly suitable for reducing unwanted hair growth in women suffering from irsutism or other similar conditions. In humans, the composition, for example, can be applied once or twice a day, or even more frequently, for two weeks up to six months (e.g., three months) to achieve an effect that can be perceived. The reduction in hair growth is demonstrated when the frequency of hair removal is reduced or the subject perceives less hair at the treated site, or quantitatively, when the hair weight removed by shaving (ie, hair mass) ) is reduced. The increase in hair growth is demonstrated when the opposite effect is observed. The intact male hamsters, Golden Syrian, are considered as acceptable models for hair growth in the human beard and another type of hair growth stimulated by androgens, in that they show oval shape, one on each side, each one of approximately 8 mm, in its greater diameter, where grows black hair, thick, and rough, similar to the beautiful hair of the human beard. These organs produce hair in response to androgens, in the hamster. To evaluate the effectiveness of a composition to reduce hair growth stimulated by androgens, the flanks of each, of a group of hamsters, are shaved. To one organ of each animal, 10 μL of the composition of the vehicle is applied alone, once a day, while at the other organ of each animal, an equal amount of the composition (including the com ponent or relevant com ponents) is applied. ). After thirteen applications (one application per day, for five days a week), the flanges are shaved and the amount of hair recovered (hair mass) is heavy. The percentage of hair growth reduction is calculated by subtracting the value of the hair mass (mg), from the side treated with the test com, from the value of the hair mass of the side treated with the vehicle.; then, the delta value is obtained by dividing by the hair mass value of the side treated with the vehicle, and the resulting number is multiplied by 100. The test described above will be referred to herein as "the Golden Syrian hamster test". Preferred compositions provide a reduction in hair growth of at least about 30%, more preferably at least about 50% and more preferably at least about 60%, when tested with the Golden Syria n. Several compositions containing compounds that induce or activate the UGTs for which testosterone is a substrate, were evaluated in the Golden Syria n Hamster Test; the results are given in Table I: Table I All compounds were admired as a 10% dose. Vehicle A = ethanol 80%, H20 17.5% 7 dipelargonate propylene glycol 2%, propylene g licol 0.5%; B = 70% ethanol, dimetilsu lfoxa mine 30%; C = propylene glycol 50%, ethanol 25%.

An essay was conducted to evaluate if some of the compounds evaluated in the Golden Syrian Hamster test caused induction of the formation of lucid testosterone. Halogen homogenates were prepared by adding 4 halves in 2 μl of a buffer containing 25 mM Tris / 50 mM sucrose, pH 7.4 and homogenized with a Polytron (Brinkman Instruments), while keeping the mixture on ice. The testosterone g ucuronidation was measured by incubating 20 μL of the ileal protein (1 mg / m L) with 125 μM of testosterone labeled with [l * C] UDP-glucuronic acid (5 mM), in the presence of the buffer containing Tris 0.5 M, pH 7.5 and MgCl2 0.1 M. The total volume of the reaction mixture was 100 μL. The assay mixtures were incubated at 37 ° C for 60 minutes, and the reactions were stopped with the addition of 3.5 mL of methylene chloride. An aqueous carrier was added (250 μL of water) to each reaction mixture, which was then stirred and centrifuged. Testosterone labeled with [1 C], not metabolized, remained in the organic phase, while testosterone glucuronide was divided into the aqueous phase, and quantified by scintillation spectrometry. The results are given in Table II: Table II It was believed that the diversion of testosterone from its biologically active species to a conjugate of glucurone or sulfonate would have effects on the flanks of the Golden Syrian hamster, since it is known that testosterone regulates the existence of these unique organs. The diameter of the flanges was evaluated using a vernier, after the topical treatment of the hamsters with ethoxyquin or 5,7-drhydroxy-4'- m e t or x i f I a v a n a, as described in the section on the test of the mass of the hair. A decrease in the diameter of the flank was demonstrated after the topical application of the compounds (Table III). These data are consistent with the hypothesis that suggests that local induction of conjugation enzymes, such as UGTs, can decrease the biological activity of testosterone.

Table III Other embodiments are included in the claims It is noted that, with respect to this date, the best known method for applying the said invention is that which is clear from the present description of the invention. .

Claims (39)

1. CLAIMS Having described the invention as above, property is claimed as contained in the following re indications. 1. A method for reducing hair growth, stimulated by androgens, in mammals, characterized in that it comprises: - selecting an area of the skin, where the hair grows in response to androgen stimulation, of which you want to reduce hair growth; and applying to the skin area a dermatologically acceptable composition comprising a compound that induces or activates a UDP-glucuronosyltransferase or a sulfotransferase, wherein the compound is presented in the composition in an amount effective to network hair growth.
2. 2. A method for increasing hair growth in mammals, characterized in that it comprises: -selecting an area of the skin, where hair grows not in response to androgens, where it is desired to increase hair growth; and applying to the skin area a dermatologically acceptable composition, comprising a compound that induces or activates a U DP-glucuronosyltransferase or a sulfotransferase, wherein the compound is presented in the composition in an amount effective to increase hair growth.
3. 3. The method, according to claim 1 or 2, characterized in that the compound comprises ethoxyquin.
4. 4. The method according to claim 1 or 2, characterized in that the compound comprises 5,7-dihydroxy-4'-methoxyflavone.
5. 5. The method, according to claim 1 or 2, characterized in that the compound comprises butyl alcohol or sun.
6. 6. The method, according to claim 1 or 2, characterized in that the compound comprises phenobarbital.
7. 7. The method, in accordance with the claim 1 or 2, characterized in that the compound comprises naringenin.
8. 8. The method according to claim 1 or 2, characterized in that the compound comprises butylhydroxytoluene.
9. 9. The method, in accordance with claim 1 or 2, characterized in that the com ponent comprises f a a v o n a.
10. The method, according to claim 1 or 2, characterized in that the compound comprises thioconazole.
11. 11. The method, according to claim 1, characterized in that the compound comprises trans-, 2-bis (2-pyridyl) ethylene.
12. 12. The method according to claim 1 or 2, characterized in that the compound comprises 7, 4 '- i s or f I a v a n d i or I.
13. 13. The method, according to I to claim 1 or 2, characterized in that the compound comprises galangin.
14. 14. The method, according to claim 1 or 2, characterized in that it comprises 7-hydroxy-4'-methoxyisoflavone.
15. 15. The method according to claim 1 or 2, characterized in that it comprises 5,4'-dihydroxy-7-methoxyisoflavone.
16. 16. The method, according to claim 1 or 2, characterized in that the compound comprises daidzein.
17. 17. The method according to claim 1, characterized in that the compound induces or activates a UDP-glucuronosyltransferase.
18. 18. The method, according to claim 2, characterized in that the compound induces or activates a sulfotransferase.
19. 19. The method, according to claim 1 or 2, characterized in that the androgen comprises testosterone.
20. The method, according to claim 1 or 2, characterized in that the concentration of the compound in the composition is between 0.1% and 30%.
21. The method, according to claim 1 or 2, characterized in that the composition provides a reduction in hair growth of at least 15%, when evaluated in the Golden Syrian hamster test.
22. 22. The method according to claim 1 or 2, characterized in that the composition provides a reduction in hair growth of at least 40% when evaluated in the Golden Syrian hamster test.
23. 23. The method, according to claim 1 or 2, characterized in that the mammal is a human.
24. 24. The method, according to claim 1, characterized in that the skin area is on the face of the human.
25. 25. The method, according to claim 24, characterized in that the human is a woman suffering from hirsutism.
26. 26. The method, according to claim 2, characterized in that the area of the skin is on the scalp of a human.
27. 27. A method for reducing hair growth, stimulated by androgens, in mammals, characterized in that it comprises: - selecting an area of the skin, where hair grows in response to stimulation with androgens, of which is desired to reduce hair growth; and applying to the skin area a dermatologically acceptable composition comprising a compound that induces or activates the conjugation of an androgen that stimulates hair growth stimulated by androgens, to produce an androgen binding, where the compound is presents, in the composition, an effective amount to reduce hair growth.
28. 28. The method, according to claim 27, characterized in that the skin area is on the face of a human.
29. 29. A method for increasing hair growth in mammals, characterized in that it comprises: - selecting an area of the skin, where the hair does not grow in response to androgens, from which it is desired to increase the growth of the hair; and applying to the skin area a dermatologically acceptable composition comprising a compound that induces or activates the conjugation of an androgen that retards hair growth, to produce an androgen conjugate, where the compound is present in the hair. com position in an effective amount to increase hair growth.
30. 30. The method, according to claim 29, characterized in that the skin area includes the scalp of a human.
31. 31. The method according to claim 27 or 29, characterized in that the compound is an inducer or an activator of an androgen conjugation enzyme.
32. 32. The method, according to claim 31, characterized in that the androgen comprises testosterone.
33. 33. The method, according to claim 31, characterized in that the androgen comprises dihydrotestosterone.
34. 34. The method, according to claim 31, characterized in that the androgen comprises an androgen which is selected from the group consisting of a n d r o s t e n d a n a n d, a n d r o s t e n o d i o s and dehydroepiandrosterone.
35. 35. A method for reducing hair growth, stimulated by androgens, in mammals, characterized in that it comprises: - selecting an area of the skin, where hair grows in response to androgen stimulation, of which you want to reduce hair growth; and applying to the skin area a dermatologically acceptable composition comprising a compound that induces or activates the conversion of testosterone to a less active metabolite, where the compound is present in the composition in an effective amount to reduce growth of the hair, of the skin area.
36. 36. The method, according to claim 35, characterized in that the skin area is on the face of a human.
37. 37. The method, according to claim 35, characterized in that the less active metabolite comprises a compound that is more water soluble than testosterone.
38. 38. A method for increasing the hair growth of human hair, characterized in that it comprises: - selecting an area of the scalp of a human, from which it is desired to increase hair growth; and - applying to the area of the scalp a dermatologically acceptable compound comprising a compound which induces or activates the conversion of testosterone to a less active metabolite., where the compound is present in the composition in an effective amount to increase hair growth in the leather area.
39. 39. The method according to claim 38, characterized in that the less active metabolite comprises a compound that is more soluble in water than testosterone. SUMMARY OF THE INVENTION The growth of hair of a mammal can be modulated by applying, to the skin, a compound that induces or activates the conjugation of an androgen.