MXPA00004434A - Stable antiandrogenic gel composition - Google Patents

Abstract

Pharmaceutical compositions for the topical treatment of androgen-related conditions, e.g., acne in humans containing an amount of the compound represented by formula (II) effective for the topical treatment of the androgen-related conditions, e.g., acne dissolved in an alcohol-water solvent system, such as ethanol-water [97.6:2.4(w/w)]and having an apparent pH in the range of about 3.5 to 4.5, and containing a gelling agent are disclosed.

Description

COMPOSITION IN STABLE ANTIANDROGEN GEL BACKGROUND OF THE INVENTION This invention relates to stable pharmaceutical compositions in the form of a gel, which are suitable for treating acne and other androgen-related conditions, including seborrhea, hirsutism and androgenic alopecia in humans, and which contain an antiandrogen compound dissolved or suspended in an alcohol-water solvent system and have an apparent pH value of no more than about 5 and a gelling agent. International Publication No. WO 94/26767 published November 24, 1994, discloses anti-androgens represented by formula I: wherein n is an integer of 2 to 3, pharmaceutical compositions containing said antiandrogens, and methods of using said antiandrogens to treat androgen-dependent diseases, including acne. In the course of developing a pharmaceutical composition containing one of the antiandrogen compounds of formula I, it was found that this compound is unstable and decomposes with time even at 25 ° C. Thus, there is a need for a stable pharmaceutical composition containing an antiandrogen useful for the topical treatment of androgen-dependent diseases, including acne, and having an extended storage life suitable for commercial use.

BRIEF DESCRIPTION OF THE INVENTION It has been found that the compounds of formula I (1) are more stable to decomposition in an alcohol-water solvent system containing less than about 5 weight percent water, than in one containing pure alcohol or a system of alcohol-water solvent containing more than about 5 weight percent water, for example, 6.2 weight percent water; and (2) that the presence of a glycol such as propylene glycol in an alcohol solvent system accelerates the degradation of the compounds of formula I; and (3) that an apparent pH of the alcohol-water solvent system of no more than about 5, preferably in the range of more than about 3 to less than about 5.0, improves the stability of the compounds of formula I. This invention provides a pharmaceutical composition for the topical treatment of androgen-related disorders, comprising (a) an amount of a compound represented by formula I effective to topically treat androgen-related disorders wherein n is an integer of 2 to 3; (b) an alcohol-water solvent system containing not more than about 5.0 weight percent water; and (c) a gelling agent in an amount sufficient to maintain the pharmaceutical composition in the form of a gel; and wherein the pharmaceutical composition has an apparent pH equal to about 5 or less. This invention further provides a pharmaceutical composition for the topical treatment of androgen-related disorders, which comprises: a) an amount of the compound represented by formula I effective to topically treat androgen-related disorders where n is an integer from 2 to 3; b) an ethanol-water solvent system containing not more than about 5.0 weight percent water; c) a pH regulator system capable of maintaining an apparent pH of the pharmaceutical composition at a scale value of more than about 3 and less than about 5; and d) an amount of a gelling agent sufficient to maintain the pharmaceutical composition in the form of a gel. This invention further provides a pharmaceutical composition for the topical treatment of androgen-related disorders, which comprises (a) an amount of the compound represented by formula II effective to topically treat androgen-related disorders. (b) an ethanol-water solvent system containing more than about 1.0 to about 4.0 weight percent water; c) a pH regulator system capable of maintaining an apparent pH of the pharmaceutical composition in the range of about 3.5 to about 4.5; and (d) an amount of a gelling agent sufficient to maintain the pharmaceutical composition in the form of a gel. In a more preferred embodiment of this invention, an anti-androgenic gel composition is provided comprising an amount of the compound represented by formula II effective to topically treat androgen-related conditions. and which is named 17-a- (4-iodobutynyl) -17-β-hydroxy-4-androsten-3-one dissolved in an ethanol-water solvent system containing about 2.5 weight percent water and a pH regulator system capable of maintaining an apparent pH of the pharmaceutical composition at a scale value of about 3.5 to 4.5, and an amount of a gelling agent sufficient to maintain the pharmaceutical composition in the form of a gel.

DETAILED DESCRIPTION OF THE INVENTION In the course of developing the stable gel compositions of this invention, it was found that the antiandrogens represented by formulas I and II are soluble in alcohols such as ethanol, isopropanol, oleyl alcohol, propylene glycol, octanol and 2-methyl-1, 4-pentanediol, but they are poorly soluble in water. Stability studies of the preformulation with the most preferred compound of formula II showed that the compound of formula II is rapidly degraded at 50 ° C in pure ethanol, ethanol: water (95: 5, v / v) and ethanol: propylene glycol (90 : 10, v / v). The compound of formula II was stable to decomposition in an alcohol-water solvent system containing no more than about 5.0 weight percent water, preferably from about 1.0 to about 4.0 weight percent water, and more preferably from about 2.0 to about 3.0 weight percent water. The alcohols that have been found to be useful in the present invention include water-soluble alcohols that include straight and branched chain alcohols of C2 to C8. The use of ethanol or 2-propanol is preferred; the use of ethanol is more preferred. By the term "conditions related to androgens in humans", as used herein, is meant those conditions related to androgens that include acne, seborrhea, hirsutism and androgenic alopecia. The pH regulator systems that have been found to be useful in the present invention are those pH regulator systems which are water-soluble pH regulator systems, especially those soluble in the alcohol-water solvent system useful in the present invention, and capable of maintaining an apparent pH of the alcohol-water solvent system of no more than about 5, preferably in the range of more than about 3 to less than about 5, more preferably a pH on the scale of about 3.5 to about 4.5, and most preferably at a pH of about 4. Typically, suitable pH regulator systems include phosphoric acid / sodium phosphate monobasic; citric acid-sodium citrate and acetic acid / sodium acetate. The use of phosphoric acid / sodium phosphate monobasic is preferred. Other pH regulator systems capable of maintaining an apparent pH of about 3.5 to 4.5 in an alcohol-water system containing less than 10% by weight of water can also be used. By the term "apparent pH value", as used herein in relation to the pharmaceutical compositions of the present invention, it is understood that the pH value of the stable pharmaceutical composition of the present invention comprising a solvent system of Water-alcohol is measured using pH electrodes. The gelling agents that have been found to be useful in the present invention include those that can maintain the pharmaceutical composition of the present invention in the form of a gel. Typically, suitable gelling agents include cellulose alkyl and hydroxyalkyl ethers including hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose derivatives, as well as carboxypolymethylene (which is highly ionic and slightly acidic), such as those carboxyvinyl polymers marketed under the names commercial carbomers and carbopol. The use of hydroxypropylcellulose is preferred. The amount of gelling agent that has been found is effective to maintain the pharmaceutical compositions of this invention in the form of a gel, is at least about 2% by weight of the composition, preferably in the range from about 2 to about 5% by weight, and more preferably from about 2 to about 3% by weight, and most preferably about 2.5% by weight of the composition. The topical pharmaceutical composition of the present invention is in the form of a gel containing an amount of the compounds of formulas I or II for the effective topical treatment of acne and other androgen-related disorders, dissolved or dispersed, preferably dissolved, in a alcohol-water solvent system having an apparent pH of less than about 5. In addition to the active ingredient, the alcohol-water solvent, the gelling agent and the pH regulator system, surfactants, preservatives and pharmaceutically acceptable adjuvants. The pharmaceutical compositions of this invention are useful for the topical treatment of androgen related conditions, for example acne, in humans. Typically, the gel compositions would be applied topically twice a day, for example, in the morning and in the evening, on the area of the skin where acne and other androgen-related conditions appear, in an amount sufficient to cover slightly the entire affected area. The affected area of the skin must be thoroughly cleaned before applying the pharmaceutical composition of the present invention. The amount of the compounds represented by formulas I and II effective to topically treat androgen related conditions, for example acne, varies from a dose level of about 0.01 g / cm2 to about 0.1 g / cm2, which can be applied like a thin film twice a day. Typical single doses include 0.3 g / 30 cm2, 0.6 g / 60 cm2, 1.0 g / 100 cm2 and 2 g / 200 cm2. The regimen should be continued for 4 to 16 weeks, or until androgen-related conditions, for example, acne-related injuries, have responded satisfactorily. Once the twice-daily regimen has provided such beneficial beneficial results, a less frequent topical application (eg, once a day) of the pharmaceutical composition of the present invention can be used to maintain the improvement in the related conditions. to androgens, for example, the injuries caused by acne.

Pharmaceutical Compositions The following examples illustrate the formulation and method of manufacture and packaging of the compositions of the present invention. It will be apparent to those skilled in the art that many modifications of the present invention can be made without departing from the purpose and scope thereof.

EXAMPLE 1 The topical gel pharmaceutical compositions of this invention contain the following ingredients present in the indicated amounts.

Ingredient Quantity (mq / q) Compound of formula II1 8.00-12.00 Hydroxypropylcellulose NF2 20.00-30.00 Sodium phosphate monobasic, USP 0.025-0.035 Phosphoric acid, NF 1.60-2.40 Water, purified (USP) 19.0-29.0 Ethanol, USP 929-951 1. The compound of formula II was prepared in accordance with the procedures of example 2 and scheme 2 of WO 94/26767, published on November 24, 1994. 2. Available under the trade name of Klucel ™ NF from Aqualon Company , 2711 Centervill Rd., Wilmington, DE 19850. The following procedure was used to prepare the composition: 1) Charge the water in an appropriate stainless steel container equipped with a suitable mixer. 2) Add the sodium phosphate in the water (step # 1), and mix until dissolved. 3) Charge the alcohol in a large stainless steel container equipped with a suitable mixer. 4) Transfer the aqueous solution (step # 2) into the alcohol container (step # 3) and start mixing. 5) Add the phosphoric acid to the mixing vessel (step # 4), and mix for about 5 minutes. 6) Measure the pH of the alcohol solution / pH regulator (target pH = 4.0 ± 0.2). If the target pH is not obtained, discard the material (alcohol solution / pH regulator). 7) If the target pH is obtained, add the drug of formula II in the mixing vessel (step # 5), and mix until the drug is completely dissolved. 8) Increase the agitation speed, slowly add the Klucel HF in the mixing vessel (avoid the formation of lumps), and mix properly until the batch begins to thicken and the Klucel HF is completely dispersed. 9) Decrease the agitation speed appropriately, and continue mixing for approximately 15 minutes. Stop the agitation and let it rest overnight. 10) Fill in specified aluminum tubes coated with epoxy. 11) Store from 2 to 25 ° C.

EXAMPLE 2 The procedure of Example 1 was used to prepare the topical gel composition mentioned below. 1. The compound of formula II was prepared in accordance with the procedures of example 2 and scheme 2 of WO 94/26767, published on November 24, 1994. 2. The hydroxypropyl cellulose used was Klucel HF available from Aqualon Company, 2711 Centervill Rd. ., Wilmington, DE 19850. The most preferred gel pharmaceutical composition of the present invention prepared in accordance with the procedure of Example 2, was stable to the decomposition of the compound of formula II when stored at a temperature of 25 ° C for 24 hours. months The stability results are summarized in table 1 below.

TABLE 1 Stability of the composition of example 2 at 25 ° C v 60% relative humidity 1 HPLC analysis 2 The overburden of the compound of formula II at 5% was added to the batch The stability of the compound of formula II was measured in ethanohydrate systems [95: 5 (v / v)] containing phosphate pH regulators capable to maintain a pH of 4.0 to 5.0 at temperatures of 30 °, 50 ° and 65 ° C for a period of 12 weeks. The stability of the compound of formula II (measured by HPLC test), did not change significantly on the pH scale from 4 to 5, as shown in table 2 below.

TABLE 2 Stability of the compound of formula II1 in ethanol-water systems2 containing phosphate pH regulators at various pH and temperature values (1) Analysis of the compound of formula I by HPLC with an external standard. (2) The ethane water system is 95: 5, v / v, equivalent to 93.8: 6.2, w / w. The stability of the compound of formula II (1% by weight) dissolved in an ethanohawa solvent system (95: 5) was also measured.; v / v) containing a pH regulator of phosphate in the aqueous phase at temperatures of 30 °, 50 ° and 65 ° C for a period of 12 weeks. The results summarized in Table 3 of the present show that the stability of the compound of formula II is greater than a pH of 4 (maintained by a phosphate pH regulator system) in an ethanol-water solvent system (97.5: 2.5 v / v).

TABLE 3 Stability of the compound of formula II1 in several ethanohawa solvent systems containing a phosphate pH regulator at pH = 4 and at temperatures of 30 °, 50 ° and 65 ° C (1) Analysis of CLAR (2) 96.9: 3.1, p / p (3) 93.8: 6.2, p / p (4) 90.7: 9.3, p / p

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition for the topical treatment of androgen-related disorders, characterized in that it comprises (a) an amount of a compound represented by formula I effective to topically treat androgen-related disorders where n is an integer from 1 to 3; (b) an alcohol-water solvent system containing not more than about 5.0% by weight of water; and (c) a gelling agent in an amount sufficient to maintain the pharmaceutical composition in the form of a gel; and wherein the pharmaceutical composition has an apparent pH equal to about 5 or less.

2. The pharmaceutical composition according to claim 1, further characterized in that the alcohol is ethanol.

3. The pharmaceutical composition according to claim 1, further characterized in that the pH is maintained on the scale of more than about 3 and less than about 5.

4. The pharmaceutical composition according to claim 1, further characterized in that n in formula I is 2.

5. A pharmaceutical composition for the topical treatment of androgen-related disorders, characterized in that it comprises: (a) an amount of the compound represented by the formula I effective for topically treating androgen-related disorders where n is an integer from 2 to 3; (b) an ethanol-water solvent system containing not more than about 5.0% by weight of water; (c) a pH regulator system capable of maintaining an apparent pH of the pharmaceutical composition at a value on the scale of more than 3 to less than about 5; and (d) an amount of a gelling agent sufficient to maintain the pharmaceutical composition in the form of a gel.

6. The pharmaceutical composition according to claim 5, further characterized in that n in formula I is 2.

7. The pharmaceutical composition according to claim 5, further characterized in that the ethanol-water solvent system contains about 1.0 to about 4.0% by weight of water.

8. - The pharmaceutical composition according to claim 5, further characterized in that the apparent pH is in the range of about 3.5 to about 4.5.

9. A pharmaceutical composition for the topical treatment of androgen-related disorders, characterized in that it comprises (a) an amount of the compound of formula II effective for the topical treatment of androgen-related disorders (b) an ethanol-water solvent system containing more than about 1.0 to about 4.0 weight percent water; (c) a pH regulator system capable of maintaining an apparent pH of the pharmaceutical composition in the range of about 3.5 to 4.5; and (d) an amount of a gelling agent sufficient to maintain the pharmaceutical composition in the form of a gel. 10. The pharmaceutical composition according to claim 9, further characterized in that the gelling agent is a hydroxypropylcellulose. 11. The pharmaceutical composition according to claim 9, further characterized in that it comprises the ingredients present in the following amounts (in mg / g): compound of formula II, 8.00-12.00; hydroxypropylcellulose, 20.00-30.00; sodium phosphate monobasic, 0.025-0.035; phosphoric acid, 1.60-2.40; water, 19.0-29.0; and ethanol, 929-951. 12. The pharmaceutical composition according to claim 9, further characterized in that it comprises the ingredients present in the following amounts (in mg / g): compound of formula II,

10. 00; hydroxypropylcellulose, 25.00; sodium phosphate monobasic, 0.03; phosphoric acid, 2.00; water, 24.07; and ethanol, 938.90. 13. The pharmaceutical composition according to claim 9, further characterized in that the ethanol-water solvent system contains from about 2.0 to about 3.0% by weight of water. 14. The pharmaceutical composition according to claim 9, characterized also because the condition related to androgens is acne. 15. The pharmaceutical composition according to claim 9, further characterized in that the condition related to androgens is seborrhea. 16. The pharmaceutical composition according to claim 9, further characterized in that the androgens related condition is hirsutism. 17. The use of the pharmaceutical composition as claimed in claim 1, in the manufacture of a medicament for treating acne in a human. 18. The use of the pharmaceutical composition as claimed in claim 1, in the manufacture of a medicament for treating seborrhea in a human. 19. The use of the pharmaceutical composition as claimed in claim 1, in the manufacture of a medicament for treating hirsutism in a human. 20. The use of the pharmaceutical composition as claimed in claim 1, in the manufacture of a medicament for treating androgenic alopecia in a human.