AU700565B2 - 5-alpha-reductase inhibitor formulations - Google Patents
5-alpha-reductase inhibitor formulations Download PDFInfo
- Publication number
- AU700565B2 AU700565B2 AU71834/98A AU7183498A AU700565B2 AU 700565 B2 AU700565 B2 AU 700565B2 AU 71834/98 A AU71834/98 A AU 71834/98A AU 7183498 A AU7183498 A AU 7183498A AU 700565 B2 AU700565 B2 AU 700565B2
- Authority
- AU
- Australia
- Prior art keywords
- butylcarbamoyl
- aza
- tert
- androst
- ene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/63—Steroids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
- A61Q7/02—Preparations for inhibiting or slowing hair growth
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
- A61K2800/782—Enzyme inhibitors; Enzyme antagonists
Description
Inhibitor Formulations The present invention is concerned with the treatment of androgenic alopecia, including male pattern baldness, with compounds that are reductase isozyme 2 inhibitors.
Background of the Invention Certain undesirable physiological manifestations, such as acne vulgaris, seborrhoea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone or similar androgenic hormones in the metabolic system Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own.
The estrogens, for example, not only counteract the effect of the androgens but have a feminising effect as well. Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethylisobutyranilide. See Neri, et al., Endocrinol. 1972, 91 However, these products, though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminise a male host or the male foetus of a female 20 host and/or initiate feed-back effects which would cause hyperstimulation of S the testes.
The principal mediation of androgenic activity in some target organs, eg.
the prostate, is 5a-dihydrotestosterone formed locally in the target Sorgan by the action of testosterone-5a-reductase. Inhibitors of testosterone- 25 5a-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially US 4,377,582. It is now known that a second 5a-reductase isozyme exists, which interacts with skin tissues, especially in scalp tissues. See, eg., G. Harris, et al., Proc. Natl. Acad. Sci.
USA, Vol. 89, pp. 10787-10791 (Nov. 1992). The isozyme that principally interacts in skin tissues is conventionally designated as 5a-reductase 1 (or type while the isozyme that principally interacts within the prostatic tissues is designated as 5a-reductase 2 (or 5a-reductase type 2).
Finasteride (17p-(N-tert-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one), which is marketed by Merck Co., Inc. under the tradename PROSCAR®, is an inhibitor of 5a-reductase 2 and is known to be useful for the treatment of hyperandrogenic conditions. See eg., US.. 4 760 071. Finasteride is currently marketed in the United States and worldwide for the treatment of benign prostatic hyperplasia. Finasteride's utility in the treatment of androgenic alopecia and prostatic carcinoma is also disclosed in the following documents: Libaa/01810 EP 0 285 383; CA. 1 302 2 77; and CA. 1 302 276. The specific dosages exemplified in the above-noted disclosures varied from 5 to 2000mg per patient per day.
In the treatment of androgenic alopecia, which includes both female and male pattern baldness, and other hyperandrogenic conditions, it would be desirable to administer the lowest dosage possible of a pharmaceutical compound to a patient and still maintain therapeutic efficacy. Applicants have surprisingly and unexpectedly discovered that a low daily dosage of a 2 inhibitor is particularly useful in the treatment of androgenic alopecia.
Furthermore, a low daily dosage of a 5a-reductase 2 inhibitor may also be particularly useful in the treatment of the hyperandrogenic conditions of acne vulgaris, seborrhoea, female hirsutism, and polycystic ovary syndrome.
Detailed Description of the Invention The instant invention involves a tablet comprising 17p-(N-tert.-butylcarbamoyl)-4-aza-5aandrost-1-ene-3-one at a unit dosage amount of about 0.05 to 3mg and tabletting ingredients.
It also involves a method of treating and/or reversing androgenic alopecia and promoting hair growth, and methods of treating acne vulgaris, seborrhoea, and female hirsutism, which comprises administering to a patient in need of such treatment a tablet of this invention. A further aspect of the present invention provides the use of 17p-(N-tert.-butylcarbamoyl)-4-aza- 5a-androst-1-ene-3-one for the preparation of a tablet for the treatment or prophylaxis of androgenic alopecia, acne vulgaris, sebhorroea and female hirsutism in a mammal requiring 20 said treatment or prophylaxis wherein the dosage amount is about 0.05 to 3mg. The 17p-(Ntert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one is administered in a dosage amount of from 0.01 to 3.0mg/day. In one class of this embodiment, the 17p-(N-tert.-butylcarbamoyl)-4aza-5a-androst-1-ene-3-one is administered in a dosage amount of from 0.05 to 1.Omg/day, S and in a sub-class of this embodiment, the 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1ene-3-one is administered in dosage amounts of about 0.05 to 0.2mg/day. Illustrating this subclass are dosage amounts of about 0.05, 0.1, 0.15 and 0.2mg/day. Exemplifying the sub-class are dosages of 0.05 and 0.2mg/day.
•The compound 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one is currently available as a prescription pharmaceutical from Merck Co. Inc. The synthesis of 17p-(N-tert.- 30 butylcarbamoyl)-4-aza-5a-androst-1-ene- 3 -one is described in US 4 760 071. A further S synthesis of 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one is described in Synthetic Communications, 30 p.26832690 (1990).
The present invention has the objective of providing methods of treating the hyperandrogenic conditions of androgenic alopecia, including male pattern baldness and female pattern baldness, acne vulgaris, seborrhoea, female hirsutism, and polycystic ovary syndrome by oral, administration of 17p-(N- Libaa/01810 11, 3 tert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one in a dosage amount of 3mg/day or less, and particularly, from about 0.01mg/day to 3.0mg/day, and more particularly 0.05 to 1mg/day. The invention is further illustrated by dosages of about 0.05 to 0.2mg/day and specifically dosages of about 0.05, 0.1, 0.15 and 0.2mg/day. Exemplifying the invention are dosages of 0.05 and 0.2mg/day. The term "treating androgenic alopecia" is intended to include the arresting and/or reversing of androgenic alopecia, and the promotion of hair growth. Also, 17p3-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one, at a dosage under 3mg,/day can be used in combination with a potassium channel opener, such minoxidil or a pharmaceutically acceptable salt thereof, for the treatment of androgenic alopecia, including male pattern baldness. The 17p- (N-tert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one and the potassium channel opener may be given via different administration routes; for example, the 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one may be 15 administered orally while the potassium channel opener may be administered topically.
The tablets can be provided in the form of scored or unscored tablets containing 0.01, 0.05, 0.1, 0.2, 1.0 1, 2.0 and 3.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be 20 treated.
Advantageously, 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-l-ene-3one may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
The dosage regimen utilising 17p-(N-tert.-butylcarbamoyl)-4-aza-5aandrost-l-ene-3-one is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
In the methods of the present invention, the 17p-(N-tert.-butylcarbamoyl)- 4-aza-5a-androst-1-ene-3-one herein described in detail can form the ingredient, and is typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of Libaa/01810 administration, that is, oral tablets consistent with conventional pharmaceutical practices.
Tablets may be prepared by mixing the active ingredient with conventional tabletting ingredients such as calcium phosphate, lactose, corn starch or magnesium stearate. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and colouring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or p-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
15 The following examples illustrate the present invention and as such are not to be considered limiting the invention set forth in the claims appended hereto.
Example 1 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one is known to 20 occur in two distinct polymorphic crystal forms, termed "Form I" an d "Form II".
Form I is the marketed form of 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst- 1-ene-3-one as a 5mg table (PROSCAR®).
17p-(N-tert.-butylcarbamoy)-4-aza-5a-androst--ene-3-one Form I can :be prepared by dissolving 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1ene-3-one in glacial acetic acid (ca. 100mg/mL) and adding water with stirring until the wt% of water equals or exceeds 84%. The resulting solid phase is collected by filtration and dried under vacuum and at about 50°C. The resulting Form I is characterised by a differential scanning calorimetry
(DSC)
curve, at heating rate of 20°C/min and in a closed cup, exhibiting a minor endotherm with a peak temperature of about 232 0 C, an extrapolated onset temperature of about 223°C with an associated heat of about 11 joules/g and by a major melting endotherm with a temperature of about of 261°C, an extrapolated onset temperature of about 258°C with an associated heat of about 89J/g. The x-ray powder diffraction pattern is characterised by dspacings of 6.44, 5.69, 5.36, 4.89, 4.55, 4.31, 3.85, 3.59 and 3.14. The FT-IR spectrum shows bands at 3431, 3237,1692, 1666, 1602 and 688 cm 1 The solubilities in water and cyclohexane at 250C are 0.05±0.02 and 0.27±0.05mg/g respectively. In addition, Form I of 17p-(N-tert.butylcarbamoyl)-4-aza-5-androst-l-ene-3-one can be prepared by Libaa/01810 recrystallisation from dry (H 2 0<lmg/mL) ethyl acetate and isopropyl acetate.
The isolated solids are dried under vacuum at about 50°C and have the same physical characterisation data as given above.
Example 2 Form II 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one can be prepared by dissolving 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1ene-3-one in glacial acetic acid (ca. 100mg/mL) and adding water with stirring until the wt% of water equals about 75% but not in excess of 80%. The resulting solid phase is collected by filtration and dried under vacuum and at about 1000C. The resulting Form II is characterised by a DSC curve, at heating rate of 20°C/min and in a closed cup, exhibiting single melting endotherm with a peak temperature of about of 261°C, an extrapolated onset temperature of, about 258 0 C with an associated heat of about 89J/g. The xray powder diffraction pattern is characterised by d-spacings of 14.09, 10.36, 15 7.92, 7.18, 6.40, 5.93, 5.66, 5.31, 4.68, 3.90, 3.60 and 3.25. The FT-IR spectrum shows bands at 3441, 3215, 1678, 1654, 1597, 1476 and 752 cm 1 The solubilities in water and cyclohexane at 25°C are 0.16±0.02 and 0.42±0.05mg/g respectively. In addition, Form II of 17p-(N-tert.butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one can be prepared by 20 recrystallisation from ethyl acetate containing between 2 to 30mg/mL of water and isopropyl acetate containing between 2 to 15mg/mL of water. The isolated solids are dried under vacuum at about 80°C and have the same physical characterisation data as given above. Form II can also be prepared by heating Form I up to about 150°C, holding for about one hour and cooling back to room temperature. The Form II prepared in this manner has the same physical characterisation data as given above.
Example 3 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one was orally administered for 6 weeks to men with male pattern baldness at doses of 0.2mg/day and 1.0mg/day. The results of this test showed a significant reduction in DHT content in scalp tissue of the test participants.
Libaa/01810 The claims defining the invention are as follows: 1. A tablet comprising 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one at a unit dosage amount of about 0.05 to 3mg and tabletting ingredients.
2. The tablet of claim 1 wherein the 17p-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1ene-3-one is present at a unit dosage of about 1mg.
3. The tablet of claim 2 wherein the tabletting ingredients are calcium phosphate, lactose, corn starch and/or magnesium stearate.
4. The tablet of claim 3 additionally comprising at least one of the following: a binder, a lubricant, a disintegrating agent or a colouring agent.
5. The tablet of claim 4 wherein the binder is starch, gelatin, natural sugars, corn sweeteners, gums, carboxymethylcellulose, polyethylene glycol and/or waxes.
6. The tablet of claim 4 wherein the lubricant is sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate and/or sodium chloride.
7. The tablet of claim 4 wherein the disintegrating agent is starch, methylcellulose, agar, bentonite and/or xanthan gum.
8. A method for the treatment or prophylaxis of androgenic alopecia in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an effective amount of a tablet according to any one of claims 1 to 7.
9. A method for the treatment or prophylaxis of acne vulgaris, seborrhoea, and female 20 hirsutism in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an effective amount of a tablet according to any one of claims 1 to 7.
10. A tablet according to any one of claims 1 to 7 when used for the treatment or prophylaxis of androgenic alopecia in a mammal requiring said treatment or prophylaxis.
11. A tablet according to any one of claims 1 to 7 when used for the treatment or prophylaxis of acne vulgaris, sebhorroea and female hirsutism in a mammal requiring said treatment or prophylaxis.
12. The use of 17p-(N-tert.-butylcarbamoyl)-4-aza-5-androst-1-ene-3-one for the preparation of a tablet useful for the treatment or prophylaxis of androgenic alopecia in a 30 mammal requiring said treatment with prophylaxis wherein the dosage amount is about 0.05 to 13. The use of 17 3-(N-tert.-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one for the treatment or prophylaxis of acne vulgaris, sebhorroea and female hirsutism in a mammal requiring said treatment or prophylaxis wherein the dosage amount is about 0.05 to Dated 12 November 1998 MERCK CO., INC.
Patent Attorneys for the Applicant/Nominated Person
SPRUSON&FERGUSON
Libaa/01810
Claims (1)
- 9. 9 S. 9e 9* 9 9* 9 9 *99 9 9. 9 .9 9* *99999 9 Libaa/01 810
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU71834/98A AU700565B2 (en) | 1993-10-15 | 1998-06-12 | 5-alpha-reductase inhibitor formulations |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13852093A | 1993-10-15 | 1993-10-15 | |
US138520 | 1993-10-15 | ||
US08/214,905 US5547957A (en) | 1993-10-15 | 1994-03-17 | Method of treating androgenic alopecia with 5-α reductase inhibitors |
US214905 | 1994-03-17 | ||
AU79742/94A AU688395C (en) | 1993-10-15 | 1994-10-11 | Method of treating androgenic alopecia with 5-alpha reductase inhibitors |
AU71834/98A AU700565B2 (en) | 1993-10-15 | 1998-06-12 | 5-alpha-reductase inhibitor formulations |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU79742/94A Division AU688395C (en) | 1993-10-15 | 1994-10-11 | Method of treating androgenic alopecia with 5-alpha reductase inhibitors |
Publications (2)
Publication Number | Publication Date |
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AU7183498A AU7183498A (en) | 1998-07-30 |
AU700565B2 true AU700565B2 (en) | 1999-01-07 |
Family
ID=27156357
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Application Number | Title | Priority Date | Filing Date |
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AU71834/98A Expired AU700565B2 (en) | 1993-10-15 | 1998-06-12 | 5-alpha-reductase inhibitor formulations |
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AU (1) | AU700565B2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0285382A2 (en) * | 1987-04-03 | 1988-10-05 | Merck & Co. Inc. | Treatment of androgenic alopecia with 17beta-n-monosubstituted-carbamoyl-4-aza-5alpha-androst-1-en-3-ones |
-
1998
- 1998-06-12 AU AU71834/98A patent/AU700565B2/en not_active Expired
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0285382A2 (en) * | 1987-04-03 | 1988-10-05 | Merck & Co. Inc. | Treatment of androgenic alopecia with 17beta-n-monosubstituted-carbamoyl-4-aza-5alpha-androst-1-en-3-ones |
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AU7183498A (en) | 1998-07-30 |
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