CA1243609A - Compositions and methods for inhibiting the action of androgens - Google Patents
Compositions and methods for inhibiting the action of androgensInfo
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- CA1243609A CA1243609A CA000481315A CA481315A CA1243609A CA 1243609 A CA1243609 A CA 1243609A CA 000481315 A CA000481315 A CA 000481315A CA 481315 A CA481315 A CA 481315A CA 1243609 A CA1243609 A CA 1243609A
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- blocking agent
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Abstract
COMPOSITIONS AND METHODS FOR
INHIBITING THE ACTION OF ANDROGENS
Abstract of the Disclosure Synergistic compositions for inhibiting the ac-tion of androgens comprise the combination in a single topical preparation of a 5 ?-reductase enzyme inhibitor and an androgen receptor blocking agent in a pharmaceutically and dermatologically acceptable vehicle. The compositions may be topically applied to affected areas of the skin in the treatment or prevention of sebaceous gland hypertrophy, hirsutism and male-pattern baldness in mammals. The inhi-bitor and blocking agent are present in the composition in a weight ratio of about 1:20 to 5:1, with the inhibitor comprising up to about 0.1% w/v of the composition and the blocking agent comprising up to about 1% w/v of the compo-sition.
INHIBITING THE ACTION OF ANDROGENS
Abstract of the Disclosure Synergistic compositions for inhibiting the ac-tion of androgens comprise the combination in a single topical preparation of a 5 ?-reductase enzyme inhibitor and an androgen receptor blocking agent in a pharmaceutically and dermatologically acceptable vehicle. The compositions may be topically applied to affected areas of the skin in the treatment or prevention of sebaceous gland hypertrophy, hirsutism and male-pattern baldness in mammals. The inhi-bitor and blocking agent are present in the composition in a weight ratio of about 1:20 to 5:1, with the inhibitor comprising up to about 0.1% w/v of the composition and the blocking agent comprising up to about 1% w/v of the compo-sition.
Description
3~
COMP~ITIONS AND MET~IUD~ FOR
IN~IBITING T~E ACTIO~ ~F ANDROGENS
Field of the Invention The present invention relates to compositions and methods for inhibiting the action of androgens. More par-ticularly, the invention is directed to synergistic com-binations of a 5 ~-reductase enzyme inhibitor and an andro-gen receptor blocking agent for topical applicatlons to the skin in the treatment and prevention of sebaceous gland hypertrophy, hirsutism and male-pattern baldness.
~ack~round of the Invention The development of acne, hirsutism and male-pattern baldness is dependent upon the presence of andro-gens, particularly testosterone and dihydrotestosterone (DHT). Testosterone is secreted into the blood stream by the adrenals and gonads and enters the cells of the seba-ceous glands or hair follicles. This steroid binds speci-fically to the 5 ~-reductase enzyme whlch converts testos-terone to its most active metabolite D~T~ D~T binds to specific receptor proteins in the cell cytoplasm, and this steroid-protein complex is translocated to the nucleus of ..
.~2~ ?.9 the cell where DHT becomes bound to the nuclear receptor protein. Nuclear binding is followed by the synthesis of specific classes of proteins, eventually leading to hyper-trichosis (hirsutism), alopecia ~male-pattern baldness~ or sebaceous gland hypertrophy ~manifested as acne or other skin inflammations).
The inhibition of testosterone conversion to DHT
by the 5 ~-reductase enzyme and the inhibition of D~T bind-ing to the receptor protein are accepted therapeutic moda-lities. A number or compounds, called antiandrogens, have been developed which can interfere with either testosterone metabolism or D~T binding to the receptor.
The serious side effects (such as decreased libido) produced by the systemic administration of anti-androgens preclude the systemic use of these drugs for the treatment of the above skin disorders. For example, pro-gesterone is a highly active 5 d-reductase enzyme inhibi-tor, but systemically disturbs the menstrual cycle in women, since it must be used on a regular basis in order to be effective. Many studies have shown that individual antiandrogens can be used topically to inhibit the action of androgens. ~owever, applicants are not aware of any prior studies on the effectiveness of combining 5 ~-reduc-~2-~3~
tase inhibitors with androgen receptor blocking agents in a topical preparation.
Brief Summary of_the Invention It has been discovered that certain combinations of a 5 ~-reductase enzyme inhibitor and an androgen recep-tor blocking agent have a synergistic effect in the inhibi-tion of the action of androgens particularly in the treat-ment and prevention of sebaceous gland hypertrophy, hirsu-tism and male-pattern baldness. The compositions of the invention are applied topically to affected areas of the skin of humans and other mammals in therapeutically effec-tive amounts. These combinations of inhibitors and block-ing agents at certain concentrations and ratios act syner-gistically to ~roduce a marked inhibition of the effects of the endogenous androgens on the skin. The steroid combina-tions may be delivered through the skin by means of various topical vehicles.
!, Thus the present invention provides a topical composition for the treatment of sebaceous gland hypertrophy hirsutism and male-pattern baldness comprisiny thera-peutically and synergistically effective arnounts of (a) an inhibitor of the conversion of testosterone to dihydro-testosterone by the 5 ~-reductase enz~me and (b) a blocking agent which blocks the binding of dihydrotestosterone to receptor protein in cell cytoplasm and a pharmaceutically and dermatologically acceptable vehicle for said inhibitor and said blocking agent.
Detailed Description of the Preferred Embodiment There are a number of steroids, steroid pre-cursors and derivatives which are known to be effective as 5 ~-reductase inhibitors and which may be used in the com-positions of the present invention. These include proges-terone, 17~carboxylic acid derivatives of testosterone, -3a-j, ~.
-' ', - ' ' ~3~
desoxycorticosterone, desoxycorticosterone acetate, 19-nor-testosterone, 4-preynen-2U~-ol-3-one and 17c~-hydroxy-progesterone. ~f these, progesterone is preferred since it is the most active inhibitor and has been shown to be topi-cally effective by itself.
Both steroidal and non-steroidal androgen recep~
tor blocking agents (blockers or inhibitors) may be used in the synergistic compositions of the present invention.
Representative examples of steroidal blocking agents in-clude spironolactone, cyproterone acetate, trimethyltri-enolone (available from Roussel Uclaf under the designation RU 2956), canrenone and canrenoic acid. Examples of suit-able non-steroidal blocking agents include flutamide (c~,oC,d~-triEluoro-2-methyl-4'-nitro-m-propionotoluidide) and hydroxy-flutamide (c~,cC,dC-triEluoro-2-n~ethyl-4'-nitro-m-lactoluidide), both available from ~chering Corp~, and RU 23908 (5,5-dimethyl-3-[4-nitro-3(trifluoro-methyl)phenyl]-2~4-imidazolidinedione) and RV 22930 (5,6-dihydro-2-methyl-4-[4-nitro-3-(trifluromethyl)phenyl]-2~-1,2,4-oxadiozin-3-(4H)-one), available from Roussel Uclaf, Generally, the ratios of 5 ~ -reductase inhibitor to androyen receptor blocking agent which have been found to be effective in the compositions of the present inven-tion ranye between about 1:20 and 5:1. Ratios of about 1:1to 2:1 are preferred.
It has also been found that the synergistic ef-fects of the combinations o~ the present invention are rnost pronounced at relatively low concentrations of the 5 ~ -reductase inhibitor and androgen receptor blocker. In particular, optimal concentrations for the 5 ~-reductase inhibitors appear to range from about 0,005% to 0.1~
weight/volume of the total composition, while optimal con-centrations for the androgen receptor blockers appear torange from about 0.01% to 0.5% weight/volume of the total composition. Concentrations below about 0.0~5 5 ~-reduc-tase inhibitor and about 0.01 androgen receptor blocker give very little antiandrogenic response. Concentrations above about 0.1% 5 ~-reductase inhibitor and about 0.5~
androgen receptor blocker are not only unnecessarily waste-ful, expensive and liable to produce adverse side effects, but were also found to have very little syner0istic effect above that obtained by applying either the 5~ -reductase inhibitor or the androgen receptor blocker aloneO
It has been found according to the present inven-tion that when a 5C~-reductase inhibitor is applied to-gether with an androgen receptor blocker as a single topi~
cal preparation, the resulting inhibition of androgens was .; ' ' '.
~2~ 9 greater than the sum total of the effects produced indepen-dently by the 5 ~-reductase inhibitor and the andro~en receptor blocker.
These effects will now be demonstrated an~ des-cribed in more detail with reference to the following spe-cific, non-limitiny examples. The hamster ear sebaceous gland was selected as a test model because of the simila-rities in morphology to human sebaceous glands and in cell turnover time. It is well accepted in the medical literature that antiandrogens which work to inhibit sebaceous glands by topical means should also work to in-hibit the androgenic effects in the hair follicle. Thus, the mechanism of androgenic control is similar for seba-ceous gland hypertrophy, hirsutism and androgenic alopecia.
Example Nos. 1-12 A series of experiments were carried out using 5 or 6 animals for each data point. The various concentra-tions of 5 ~-reductase inhibitor or androgen receptor blocker or both as shown in T~ble I where each dissolved in acetone and 25~1 of each solution was applied unilaterally on the right ventral ear skin of adult male Syrian hamste-s two times a day, five days per week for a total duration of i~``
four weeks. Control animals received topical applications of acetone alone. At the end of the experiment, the an-drogen-sensitive ear skin sebaceous glands of the hamsters were analyæed according to the method of Matias and ~ren~
treich, Journal of Investigative Dermatology, 81:~3 (19~3), with minor modifications. In brief, the ventral ear skin was manually separated from the cartilage and stained for three hours with 0.1~ Sudan Black in propylene glycol.
After rinsing overnight with ~5~ propylene glycol, a de-fined area (medial zone; 5-8mm from the ape~ of the ear) was biopsied. The darkly stained sebaceous glands were visualized from the underside at a magnification of 625X
and quantitated planimetrically using a graphics computer interfaced with the microscope.
The size of the sebaceous glands taken as above from the right ventral ear of each hamster was compared with similar samples taken from the acetone treated right ventral ear of another group of hamsters as controls. The effects of the various inhibitors, as measured by sebaceous glands size, are given in Table I as a percent of the size of the vehicle treated control group. That is, lO0~ means that the treated ear sebaceous glands were the same size as the sebaceous glands of the vehicle treated control ears, and hence there was no inhibition of androgenic activity.
* trade mark.
- . : -. - . , . .
.. ". ~ . ,. ~ -::, ., ~ . -~2~3~
On the other hand, an androgenic activity of 60% means that the sebaceous gland size of the treated ear was 60~ of the size of the sebaceous ylands of the vehicle treated control ear, thus indicating a 40% decrease in androyenic activity.
Generally, a percent activity between about 9~% and :L00~ is considered an insignificant inhibition of androgenic effects on sebaceous glands.
The data in Table I demonstrate that each com-bination of 5c~-reductase inhibitor and androgen receptor blocker produces a synergistic effect as compared to the effects of 5~ -reductase inhibitor and androgen receptor blocker alone. That is, the sum of the individual inhibi-tory activities (1~0 minus androgenic activity) of the 5~ -reductase inhibitor and androgen receptor blocker is considerably less than the inhibitory activity of the com-bined composition of 5 ~-reductase inhibitor and androgen rece~tor blocker. Such reductions in androgen activlty correlate very well to inhibition of acne, hirsutism and male-pattern baldness.
.
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The compositions of the present invention may be applied in any of a wide variety of topical application forms, including solutions such as the acetone solution used in the examples above, tinctures, creams, ointrnents, yels, lotions or aerosol sprays. Such preparations may be either alcohol- or water-based or a combination of alco-hol/water base, Typical examples of topical preparations according to the present invention are set forth in Exam-ples 13-18 below.
Example 13 ~ Solutlon ) %w/v Progesterone 0~025 Spironolactone 0.05 Acetone QS
1()0. 0 Example 14 ; (Tincture) ~w~v Progesterone U.025 Canrenone 0.05 Propylene ylycol 10.0 Water 24.0 Alcohol lQS~.o .. . ... . . . . .. . .
.
.
~2~3ç~
Example 15 ~Cream) Desoxycorticosterone 0.025 Trimethyltrienolone 0.05 il Phase Petrolatum 10.0 Stearyl alcohol 4.0 Polyethylene glycol monostearate 4.0 ~tearic acid 2.0 Water Phase Glycerin 5.0 Triethanolamine 1.0 Preservative (methyl and Propyl parabens) 0.2 Water Q~
100.0 Example 16 (~intment) ~w/ v Progesterone 0.025 Flutamide 0.05 Propylene glycol 12.0 ~orbitan sesquioleate 4,0 Petrolatum QS
1 ()~ . 0 .. .. ~.. ~ . .
:
;..... ... , ~ ;~:
~, . : . :
..
. .
:~2~3~
Example 17 (Gel) ~w/v Desoxycorticosterone acetate 0.025 Non-steroidal antiandrogen (RU 23908) 0 05 Carbomer 940 * 1 0 Triethanolamine 0.4 Isopropyl myristate 5.0 Water 35,0 Alcohol QS
1 00 . O
Example 18 (Aerosol Lotion) %w/v Progesterone 0,025 - Canrenoic acid 0.05 Polyethylene glycol monostearate 2.0 Myristyl myristate 2.0 Polysorbate 20 1.0 Water QS
Alcohol 12.0 Dimethyl ether propellent 10.0 Fluorohydrocarbon propellent 10.0 1 00 . O
It will be recognized by those skilled in the art : that changes may be made to the above-described embodiments of the invention without departing from the broad inventive concepts thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover all modifications * trade mark.
- - -:.
.- -~2'~3~
which are within the scope and spirit of the inventi.on as defined by the appended claims.
.
- , . . .
'.: ' '~ ~
:' ;: ' ~ ' ' '' ~' '~
COMP~ITIONS AND MET~IUD~ FOR
IN~IBITING T~E ACTIO~ ~F ANDROGENS
Field of the Invention The present invention relates to compositions and methods for inhibiting the action of androgens. More par-ticularly, the invention is directed to synergistic com-binations of a 5 ~-reductase enzyme inhibitor and an andro-gen receptor blocking agent for topical applicatlons to the skin in the treatment and prevention of sebaceous gland hypertrophy, hirsutism and male-pattern baldness.
~ack~round of the Invention The development of acne, hirsutism and male-pattern baldness is dependent upon the presence of andro-gens, particularly testosterone and dihydrotestosterone (DHT). Testosterone is secreted into the blood stream by the adrenals and gonads and enters the cells of the seba-ceous glands or hair follicles. This steroid binds speci-fically to the 5 ~-reductase enzyme whlch converts testos-terone to its most active metabolite D~T~ D~T binds to specific receptor proteins in the cell cytoplasm, and this steroid-protein complex is translocated to the nucleus of ..
.~2~ ?.9 the cell where DHT becomes bound to the nuclear receptor protein. Nuclear binding is followed by the synthesis of specific classes of proteins, eventually leading to hyper-trichosis (hirsutism), alopecia ~male-pattern baldness~ or sebaceous gland hypertrophy ~manifested as acne or other skin inflammations).
The inhibition of testosterone conversion to DHT
by the 5 ~-reductase enzyme and the inhibition of D~T bind-ing to the receptor protein are accepted therapeutic moda-lities. A number or compounds, called antiandrogens, have been developed which can interfere with either testosterone metabolism or D~T binding to the receptor.
The serious side effects (such as decreased libido) produced by the systemic administration of anti-androgens preclude the systemic use of these drugs for the treatment of the above skin disorders. For example, pro-gesterone is a highly active 5 d-reductase enzyme inhibi-tor, but systemically disturbs the menstrual cycle in women, since it must be used on a regular basis in order to be effective. Many studies have shown that individual antiandrogens can be used topically to inhibit the action of androgens. ~owever, applicants are not aware of any prior studies on the effectiveness of combining 5 ~-reduc-~2-~3~
tase inhibitors with androgen receptor blocking agents in a topical preparation.
Brief Summary of_the Invention It has been discovered that certain combinations of a 5 ~-reductase enzyme inhibitor and an androgen recep-tor blocking agent have a synergistic effect in the inhibi-tion of the action of androgens particularly in the treat-ment and prevention of sebaceous gland hypertrophy, hirsu-tism and male-pattern baldness. The compositions of the invention are applied topically to affected areas of the skin of humans and other mammals in therapeutically effec-tive amounts. These combinations of inhibitors and block-ing agents at certain concentrations and ratios act syner-gistically to ~roduce a marked inhibition of the effects of the endogenous androgens on the skin. The steroid combina-tions may be delivered through the skin by means of various topical vehicles.
!, Thus the present invention provides a topical composition for the treatment of sebaceous gland hypertrophy hirsutism and male-pattern baldness comprisiny thera-peutically and synergistically effective arnounts of (a) an inhibitor of the conversion of testosterone to dihydro-testosterone by the 5 ~-reductase enz~me and (b) a blocking agent which blocks the binding of dihydrotestosterone to receptor protein in cell cytoplasm and a pharmaceutically and dermatologically acceptable vehicle for said inhibitor and said blocking agent.
Detailed Description of the Preferred Embodiment There are a number of steroids, steroid pre-cursors and derivatives which are known to be effective as 5 ~-reductase inhibitors and which may be used in the com-positions of the present invention. These include proges-terone, 17~carboxylic acid derivatives of testosterone, -3a-j, ~.
-' ', - ' ' ~3~
desoxycorticosterone, desoxycorticosterone acetate, 19-nor-testosterone, 4-preynen-2U~-ol-3-one and 17c~-hydroxy-progesterone. ~f these, progesterone is preferred since it is the most active inhibitor and has been shown to be topi-cally effective by itself.
Both steroidal and non-steroidal androgen recep~
tor blocking agents (blockers or inhibitors) may be used in the synergistic compositions of the present invention.
Representative examples of steroidal blocking agents in-clude spironolactone, cyproterone acetate, trimethyltri-enolone (available from Roussel Uclaf under the designation RU 2956), canrenone and canrenoic acid. Examples of suit-able non-steroidal blocking agents include flutamide (c~,oC,d~-triEluoro-2-methyl-4'-nitro-m-propionotoluidide) and hydroxy-flutamide (c~,cC,dC-triEluoro-2-n~ethyl-4'-nitro-m-lactoluidide), both available from ~chering Corp~, and RU 23908 (5,5-dimethyl-3-[4-nitro-3(trifluoro-methyl)phenyl]-2~4-imidazolidinedione) and RV 22930 (5,6-dihydro-2-methyl-4-[4-nitro-3-(trifluromethyl)phenyl]-2~-1,2,4-oxadiozin-3-(4H)-one), available from Roussel Uclaf, Generally, the ratios of 5 ~ -reductase inhibitor to androyen receptor blocking agent which have been found to be effective in the compositions of the present inven-tion ranye between about 1:20 and 5:1. Ratios of about 1:1to 2:1 are preferred.
It has also been found that the synergistic ef-fects of the combinations o~ the present invention are rnost pronounced at relatively low concentrations of the 5 ~ -reductase inhibitor and androgen receptor blocker. In particular, optimal concentrations for the 5 ~-reductase inhibitors appear to range from about 0,005% to 0.1~
weight/volume of the total composition, while optimal con-centrations for the androgen receptor blockers appear torange from about 0.01% to 0.5% weight/volume of the total composition. Concentrations below about 0.0~5 5 ~-reduc-tase inhibitor and about 0.01 androgen receptor blocker give very little antiandrogenic response. Concentrations above about 0.1% 5 ~-reductase inhibitor and about 0.5~
androgen receptor blocker are not only unnecessarily waste-ful, expensive and liable to produce adverse side effects, but were also found to have very little syner0istic effect above that obtained by applying either the 5~ -reductase inhibitor or the androgen receptor blocker aloneO
It has been found according to the present inven-tion that when a 5C~-reductase inhibitor is applied to-gether with an androgen receptor blocker as a single topi~
cal preparation, the resulting inhibition of androgens was .; ' ' '.
~2~ 9 greater than the sum total of the effects produced indepen-dently by the 5 ~-reductase inhibitor and the andro~en receptor blocker.
These effects will now be demonstrated an~ des-cribed in more detail with reference to the following spe-cific, non-limitiny examples. The hamster ear sebaceous gland was selected as a test model because of the simila-rities in morphology to human sebaceous glands and in cell turnover time. It is well accepted in the medical literature that antiandrogens which work to inhibit sebaceous glands by topical means should also work to in-hibit the androgenic effects in the hair follicle. Thus, the mechanism of androgenic control is similar for seba-ceous gland hypertrophy, hirsutism and androgenic alopecia.
Example Nos. 1-12 A series of experiments were carried out using 5 or 6 animals for each data point. The various concentra-tions of 5 ~-reductase inhibitor or androgen receptor blocker or both as shown in T~ble I where each dissolved in acetone and 25~1 of each solution was applied unilaterally on the right ventral ear skin of adult male Syrian hamste-s two times a day, five days per week for a total duration of i~``
four weeks. Control animals received topical applications of acetone alone. At the end of the experiment, the an-drogen-sensitive ear skin sebaceous glands of the hamsters were analyæed according to the method of Matias and ~ren~
treich, Journal of Investigative Dermatology, 81:~3 (19~3), with minor modifications. In brief, the ventral ear skin was manually separated from the cartilage and stained for three hours with 0.1~ Sudan Black in propylene glycol.
After rinsing overnight with ~5~ propylene glycol, a de-fined area (medial zone; 5-8mm from the ape~ of the ear) was biopsied. The darkly stained sebaceous glands were visualized from the underside at a magnification of 625X
and quantitated planimetrically using a graphics computer interfaced with the microscope.
The size of the sebaceous glands taken as above from the right ventral ear of each hamster was compared with similar samples taken from the acetone treated right ventral ear of another group of hamsters as controls. The effects of the various inhibitors, as measured by sebaceous glands size, are given in Table I as a percent of the size of the vehicle treated control group. That is, lO0~ means that the treated ear sebaceous glands were the same size as the sebaceous glands of the vehicle treated control ears, and hence there was no inhibition of androgenic activity.
* trade mark.
- . : -. - . , . .
.. ". ~ . ,. ~ -::, ., ~ . -~2~3~
On the other hand, an androgenic activity of 60% means that the sebaceous gland size of the treated ear was 60~ of the size of the sebaceous ylands of the vehicle treated control ear, thus indicating a 40% decrease in androyenic activity.
Generally, a percent activity between about 9~% and :L00~ is considered an insignificant inhibition of androgenic effects on sebaceous glands.
The data in Table I demonstrate that each com-bination of 5c~-reductase inhibitor and androgen receptor blocker produces a synergistic effect as compared to the effects of 5~ -reductase inhibitor and androgen receptor blocker alone. That is, the sum of the individual inhibi-tory activities (1~0 minus androgenic activity) of the 5~ -reductase inhibitor and androgen receptor blocker is considerably less than the inhibitory activity of the com-bined composition of 5 ~-reductase inhibitor and androgen rece~tor blocker. Such reductions in androgen activlty correlate very well to inhibition of acne, hirsutism and male-pattern baldness.
.
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W ILJ
K Z
~ LL~ W LL~ W ~U
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C~:l L~-r Z Z Z= 2Z Z Z z -- ~ W
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.. , . . I
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The compositions of the present invention may be applied in any of a wide variety of topical application forms, including solutions such as the acetone solution used in the examples above, tinctures, creams, ointrnents, yels, lotions or aerosol sprays. Such preparations may be either alcohol- or water-based or a combination of alco-hol/water base, Typical examples of topical preparations according to the present invention are set forth in Exam-ples 13-18 below.
Example 13 ~ Solutlon ) %w/v Progesterone 0~025 Spironolactone 0.05 Acetone QS
1()0. 0 Example 14 ; (Tincture) ~w~v Progesterone U.025 Canrenone 0.05 Propylene ylycol 10.0 Water 24.0 Alcohol lQS~.o .. . ... . . . . .. . .
.
.
~2~3ç~
Example 15 ~Cream) Desoxycorticosterone 0.025 Trimethyltrienolone 0.05 il Phase Petrolatum 10.0 Stearyl alcohol 4.0 Polyethylene glycol monostearate 4.0 ~tearic acid 2.0 Water Phase Glycerin 5.0 Triethanolamine 1.0 Preservative (methyl and Propyl parabens) 0.2 Water Q~
100.0 Example 16 (~intment) ~w/ v Progesterone 0.025 Flutamide 0.05 Propylene glycol 12.0 ~orbitan sesquioleate 4,0 Petrolatum QS
1 ()~ . 0 .. .. ~.. ~ . .
:
;..... ... , ~ ;~:
~, . : . :
..
. .
:~2~3~
Example 17 (Gel) ~w/v Desoxycorticosterone acetate 0.025 Non-steroidal antiandrogen (RU 23908) 0 05 Carbomer 940 * 1 0 Triethanolamine 0.4 Isopropyl myristate 5.0 Water 35,0 Alcohol QS
1 00 . O
Example 18 (Aerosol Lotion) %w/v Progesterone 0,025 - Canrenoic acid 0.05 Polyethylene glycol monostearate 2.0 Myristyl myristate 2.0 Polysorbate 20 1.0 Water QS
Alcohol 12.0 Dimethyl ether propellent 10.0 Fluorohydrocarbon propellent 10.0 1 00 . O
It will be recognized by those skilled in the art : that changes may be made to the above-described embodiments of the invention without departing from the broad inventive concepts thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover all modifications * trade mark.
- - -:.
.- -~2'~3~
which are within the scope and spirit of the inventi.on as defined by the appended claims.
.
- , . . .
'.: ' '~ ~
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Claims (9)
1. A topical composition for the treatment of sebaceous gland hypertrophy,hirsutism and male-pattern baldness comprising therapeutically and synergistically effective amounts of (a) an inhibitor of the conversion of testosterone to dihydrotestosterone by the 5?-reductase enzyme and (b) a blocking agent which blocks the binding of dihydrotestosterone to receptor protein in cell cytoplasm and a pharmaceutically and dermatologically acceptable vehicle for said inhibitor and said blocking agent.
2. A composition according to claim 1 wherein said inhibitor and said blocking agent are present in the weight ratio of about 1:20 to 5:1.
3. A composition according to claim 1 wherein said inhibitor and said blocking agent are present in the weight ratio of about 1:1 to 1:2.
4. A composition according to claim 1 wherein said inhibitor comprises up to about 0.1% and said blocking agent comprises up to about 1.0% of the composition, said percentages being on the basis of weight/volume.
5. A composition according to claim 1 wherein said inhibitor is selected from the group consisting of progesterone, 17.beta.-carboxylic acid derivatives of testos-terone, desoxycorticosterone, desoxycorticosterone acetate, 19-nor-testosterone, 4-pregnen-20.beta.-ol-3-one and 17?-hy-droxyprogesterone.
6. A composition according to claim 1 wherein said inhibitor is progesterone.
7, A composition according to claim 1 wherein said blocking agent is selected from the group consisting of spironolactone, cyproterone acetate, flutamide, tri-methyltrienolone, hydroxy-flutamide, canrenone, canrenoic acid, 5,5-dimethyl-3-[4-nitro-3(trifluoromethyl)phenyl]-2,4-imidazolidinedione and 5,6-dihydro-2-methyl-4-[4-nitro-3-(trifluromethyl)phenyl]-2H-1,2,4-oxadiozin-3-(4H)-one.
8. A composition according to claim 1 wherein said vehicle comprises water, alcohol, acetone or a combi-nation thereof.
9. A composition according to claim 1 wherein said vehicle is selected from the group consisting of solu-tions, tinctures, creams, ointments, gels, lotions and aerosol sprays.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60915284A | 1984-05-11 | 1984-05-11 | |
| US609,152 | 1990-11-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1243609A true CA1243609A (en) | 1988-10-25 |
Family
ID=24439556
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000481315A Expired CA1243609A (en) | 1984-05-11 | 1985-05-10 | Compositions and methods for inhibiting the action of androgens |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1243609A (en) |
-
1985
- 1985-05-10 CA CA000481315A patent/CA1243609A/en not_active Expired
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