MXPA99011970A - Pharmaceutical composition - Google Patents

Abstract

The present invention discloses a novel solution comprising a therapeutically effective amount of a pharmaceutically active aza steroid, and a fatty acid ester of glycerol or propylene glycol. In another aspect, the present inventiondiscloses a pharmaceutical composition comprising the solution of the invention. In another aspect, the present invention discloses a gelatin capsule filled with the composition of the present invention.

Description

PHARMACEUTICAL COMPOSITION The present invention relates to certain pharmaceutical compositions comprising 4-aza steroids and / or 6-aza steroids. In particular, the present invention relates to solutions comprising an inhibitor of steroid 5-alpha reductase. The pharmaceutically active compounds can be supplied in a variety of forms, for example in a soft gelatin capsule. Methods for the preparation of soft gelatine capsules are well known. See, for example, J. ~ P. Stanley, Soft Gela tin Capsules, Ch. 13 - Part Two in: The Theory and Practice of Industrial Pharmacy, eds. L. Lachman et. al., 3 / a. Edition, pp. 398-412, 1986, and W .. R. Ebert, Soft Elastic Gela tin Capsules: A Unique Dosage Form, Pharmaceutical Technology, Vol. 1, No. 5. The selection of excipients is important to ensure good solubility and good bioavailability of the pharmaceutically active compound. See for example, A. Matso, Excipients Commonly Used in Soft Gela tin Capsules: Their Analysis and Usefulness, ^ Novel Drug Formulation Systems and Delivery Devices International Seminar, pp. 76-81, (1991). K. Hutchison, Encapsulation in Softgels for Pharmaceutical Advantage, Spec. Pub. - R. Soc. Chem., Vol. 138, pp. 86-97, (1993), REF .: 32401 M.S. Patel et. al., Advances in Softgel Formula tion Technology, Manufacturing Chemist, August 1989, and I.R. Berry, Improving Bioavailabili ty wi th Soft Gela tin Capsules, Drug & Cosmetic Industry, pp. 32, 102-108, (September, 1983). Particular issues or issues with respect to the formulation of pharmaceutically active compounds, hydrophobic, have been described, for example in K. Hutchison, Formulation of Softgels For Improved Oral Delivery of Hydrophobi c Drugs, Spc. Pub. -R. Soc. Chem., Vol. 161, pp. 133-147 (1995). Hard gelatine capsules filled with liquid have also been used. See, for example, D. Cade et. al., Liquid Filled and Sealed Hard Gelatin Capsules, Drug Development and Industrial Pharmacy, 12 (11-13): 2289-2300, (1986). Aza steroids are an important class of pharmaceutically active compounds. In particular, there are 4-aza steroids and 6-aza steroids that are known to be inhibitors of the enzyme testosterone 5-alpha-reductase (hereinafter referred to as "5AR inhibitors"). Such compounds are thought to be useful in the treatment of benign prostatic hyperplasia, prostate cancer and other diseases. See, for example, U.S. Pat. Nos. 4,377,584 (Rasmusson et al.), 4,220,775 (Ras usson et al.), 4,732,897 (Cainelli) et al.), 4,760,071 (Rasmusson), 4,845,104 (Carlin et al.), 4,859,681 (Rasmusson), 5,302,589 (Frie et. al.), 5,438,061 (Berg an et al.), 5,543,406 (Andrews et al.), 5,565,467 (Batchelor et al.), and WO 95/07926 (Batchelor et al.). One of . such 5AR inhibitors, finasteride, is commercially available from Merck & Co., Inc. as PROSCARR. These pharmaceutically active compounds are not easy to dissolve. These drawbacks in terms of solubility can affect bioavailability leading to reduced or unpredictable bioavailability. A mixture of glyceride esters, commercially available from Abitec (P.O. Box 569, Columbus, Ohio) as Capmul® MCM, has been used to dissolve bile duct stones. . See, for example, Cholesterol Stones Dissolved Harmlessly ", Medical World News, page 28 (1978), U. Leüschner and D. Landgraf," Dissolution of Biliary Duct Stones with Mono-Octanoin ", The Lancet, 2 p 8133 (1979) , and JL: Thistle et al., "Monooctanoin, a Dissolution Agent for Retained Cholesterol Bile Duct Stones: Physical Properties and Clinical Application", Gastroenterology 78, pp. 1016-1022 (1980) .The esters of glycerol and / or propylene glycol They have been used in a variety of formulations.

See, for example, U.S. Pat. Nos. 4,316,917 (Antoshkiw et al.) And 4,343,823 (Todd et. Al.). Briefly, in one aspect, the present invention describes a novel solution comprising a therapeutically effective amount of a pharmaceutically active steroid aza, and a fatty acid ester of glycerol or propylene glycol. The fatty acids are preferably carboxylic acids containing from 6 to 12 carbon atoms. Preferably, the ester is a monoester. In another aspect, the present invention describes a pharmaceutical composition comprising the solution of this invention. The composition of this invention is particularly suitable for use as a filling formulation for gelatin capsules. . In another aspect, the present invention describes a gelatin capsule filled with the composition of the present invention. The composition of this invention has improved bioavailability over standard tablets or suspensions. Some of the steroids useful in this invention are potent teratogens. By converting the steroid from a free powder to a solution at the beginning of the manufacturing process, a safer process is provided. There is a lower risk in working with the solution than with the free solid. Also, some of these steroids are prone to oxidation. The formulations of the gelatin capsule can be much more resistant to oxidation due to a low oxygen permeation of the typical gelatin shells or shells. See, for example, F.S. Ho et al., Soft Gelatin capsules II: Oxygen Permeabili ty and Study of Capsule Shells, J. Pharm. Sci., Vol. 64 (No. 5), pp. 851-887 (1975). The esters useful in this invention are preferably derivatives of carboxylic acids containing from 6 to 12 carbon atoms. Particular preference is given to those esters derived from caprylic acid (8 carbon atoms). Although all mono, di, and tri-esters are useful in this invention, monoesters are preferred. In addition, the ester may be part of a mixture comprising different content of carbon atoms in the esters and / or comprising a mixture of monoglycerides, diglycerides, and triglycerides. Commercially available esters are often such mixtures. For example, Capmul® MCM and PG-8 (both available from Abitec Corporation, Janesville, Wisconsin) are such mixtures. The composition of Capmul® MCM is a mixture of fatty acid esters of glycerol and is approximately 95% monoester, 1% glycerin, 2% free fatty acid, and less than 0.5% water and is derived from approximately 85% caprylic acid and 15% capric acid (all percentages are percentages by weight). PG-8 is a mixture of fatty acid esters of propylene glycol and is approximately 96% monoester, 0.05% diester, 1.3% free propylene glycol, and is derived from caprylic acid. The aza steroids useful in this invention can be any pharmaceutically active azaido steroid or pharmaceutically acceptable solvates thereof. The preferred classes of aza steroids are of the 4-azasteroid class and the 6-azasteroid class of 5AR inhibitors. For example, any of the 5AR inhibitors described in the patents cited above. Particularly preferred aza steroids are the 4-aza steroids. Particularly preferred 4-aza steroids include finasteride, 17-beta-N- (2, 5, -bis (trifluoromethyl)) -phenylcarbamoyl-4-aza-5-alpha-androst-1-en-3-one which it is the steroid that is described in Pat. U.S. No. 5,565,467 (Batchelor et al.), And 17-beta-Nl- (3,4-methylenedioxy-phenyl) -cyclohexylcarbamoyl-4-aza-5-alpha-androst-1-en-3-one and 17- beta-N1- (p-chlorophenyl)) -cyclopentylcarbamoy1-4-aza-5-alpha-androst-1-en-3-one which are both described in WO 95/07926 (Batchelor et al.). These steroids can be prepared by well-known methods, for example as described in the patents cited above. The aza steroids are preferably present in the range from 0.0025 to 2.5% by weight of the solution of this invention, more preferably from 0.025 to 1.5% by weight of the solution of this invention. It may also be useful to include an antioxidant in the composition. Suitable antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbic acid. A particularly preferred antioxidant is butylated hydroxytoluene.

Antioxidants can be used alone or in combination. The antioxidant or mixture of antioxidants is preferably from 0.001 to 0.5% by weight of the composition of this invention. The pharmaceutical composition of the present invention is particularly useful as filling formulations for gelatin capsules, more preferably for soft gelatin capsules.

Experiments In the following experiments, a pharmaceutically active steroid 4-aza was used in several solubility studies. The pharmaceutically active steroid used was 17-beta-N- (2, 5, -bis (trifluoromethyl)) phenylcarbamoyl-4-aza-5-alpha-androst-1-en-3-one. This steroid is described in patent 67 and can be prepared by known methods including the methods described in patent 67. The solubility of the steroid was determined by suspending an excess amount of the steroid in about 1 ml of various aqueous and organic media. The resulting suspension was tumbled in a rotating Vankel® water bath maintained at 25 ° C and protected from light. At the end of an equilibrium time, usually between 1 and 12 days, the excess solid was removed by ultracentrifugation through 0.22μ filters. The resulting supernatant was then evaluated to verify the concentration of the steroid against an external standard. The concentration of the steroid in the supernatant was determined by HPLC analysis using a Hewlett Packard 1090 Series II / M with a DOS Chem Station. The conditions of the HPLC are summarized below in Table 1. The solubility results in various aqueous media are summarized in Table 2, and in several organic media are summarized in Table 3. Table 4 summarizes the solubility in several compositions containing a complex forming agent, (2-hydroxypropyl-beta-cyclodextrin). Table 5 summarizes the solubility in various oils and in Capmul® MCM. Table 6 summarizes the solubility results in the mixtures of Capmul® MCM and polyethylene glycol having an average molecular weight of 400 (PEG 400). In the following Tables and experiments, Mili QR plus water is a water for reverse osmosis, CMC is carboxy methyl cellulose. THF is tetrahydrofuran, DMSO is dimethylsulfoxide, PG is propylene glycol, Labrafil.RTM. Is a mixture of unsaturated polyglycolized glycerides obtained by partial alcoholysis of corn oil or apricot kernel oil, consisting of glycerides and polyethylene glycol esters, SDS is dodecyl sulfate of sodium, "bile salts of the duodenum models" is a mixture of sodium glycocholate, sodium glycokenedeoxycholate, sodium glycodeoxycholate, sodium taurocholate, sodium taurokenedeoxycholate, sodium taurodeoxycholate, sodium chloride, lecithin, and phosphate buffer, Tween. 80 is polyoxyethylene (20) monooleate sorbitan, polyethylene glycol 400 was purchased from Union Carbide, Molescusol® is 2-hydroxypropyl-beta-cyclodextrin, and Intralipid is a blend of soybean oil, phospholipids, USP glycerin, and water for injection. Unless stated otherwise, all% are by weight, for example, "v / v" means% by volume.

Table 1. CLAR conditions Table 2. Solubility in the Aqueous Environment Medium Concentration (mg / ml) Water Milu QR plus < 0.0039 0.1N HCl < 0.0039 0.5% CMC < 0.0039 1% LabrafilR Highly degraded 0. 02% SDS < 0.0039 0.01% sodium docusate < 0.0039 0.1% Tween 80 < 0.0039 0.1% Tween 80 / 0.02% SDS < 0.0039 Duodenum bile salts models 0.0386 Table 3. Solubility in the Organic Environment Medium Concentration (mg / ml) Propylene glycol 6.21 Polyethylene glycol 400 3.27 PEG 400, 0.1% Tween 80 3.91 Propylene carbonate 6.24 Ethyl acetate 14.49 THF 225.44 Acetonitrile 7.44 Acetone 46.97 DMSO 130.40 Benzyl Alcohol > 34 Ethanol 45.59 70% aqueous ethanol 2.73 • Isopropanol 29.98 Table 4. Solubility in 2-Hydroxypropyl-β-cyclodextrin Solutions Medium Concentration (mg / ml) 10% Molecusol® 0.03 20% Molecusol® 0.12 40% Molecusol® 0.79 40% Molecusol®, 25% PEG400, 0.08 5% PG 40% Molecusol®, 50% PEG 400 0.56 Aqueous Table 5. Solubility in Various Oil-Based Systems Medium Concentration (mg / ml) Sesame oil 0.52 Safflower oil 0.39 Soybean oil 0.44 Cottonseed oil 0.53 Corn oil 0.56 Castor oil 2.01 Olive oil 0.44 Peanut oil 0.46 Mineral oil 0.007 1% Span 20, cottonseed oil 0.62 10% alcohol benzyl, 2.77 Cotton seed oil Intralipid® 20% 0.009 CapmulR MCM 28.24 Table 6. Solubility in mixtures of Capmul® MCM and PEG Capmul® MCM (%) in PEG400 Concentration (mg / ml) 10 6.95 25 10.01 50 14.11 100 28.24 The solubility data show that these types of steroids are very difficult to dissolve. The data also show that the solubility in Capmul® MCM is significantly higher than in the other systems which were tested. Capmul® MCM was then used to prepare filling formulations suitable for use in gelatin capsules. For the manufacture of soft gelatine capsules of 0.01, 0.05, 0.5, 2.5, 5.0, and 10.0 mg, the Capmul® MCM was heated to approximately 26-28 ° C. The butyl hydroxytoluene was then added. NF is added and the mixture is stirred until it dissolves. The steroid was then added and mixed, and the temperature of the mixture was maintained and checked to ensure that it did not exceed 40 ° C, until it dissolved. The solution was degassed prior to encapsulation. The gelatin was prepared by combining gelatin NF, USP glycerin, special sorbitol and USP purified water. The resulting mixture was heated in a pressurized reactor to melt the gelatin. The gelatin was then kept in the molten state until it was used for the encapsulation. The encapsulation was carried out using a rotary die or die process. The heated gelatine was fed to an encapsulation machine where it was introduced in two dispersing boxes which mold or melt the gelatin on a cooling drum, thus forming two gelatin tapes. Each gelatin belt was lubricated with Fractionated Coconut Oil on the inner side and with Fractionated Coconut Oil with 0.1% Lecithin NF on the outer side. Fractionated Coconut oil prevents the gelatin from sticking to the equipment and lecithin NF prevents the capsules from sticking together after manufacture, prior to drying. The tapes were then transported to the roller or encapsulation cylinder. The cavities of the die or die to form the capsules are located on the circumference of the two adjacent rollers or cylinders, which rotate and pull the gelatin ribbons therebetween. The filling solution was injected, by a measured or metered positive displacement pump, between the gelatin tapes, forcing them to expand and fill the cavities of the die or die When the capsules were filled, they were shaped, sealed and cut simultaneously from the gelatin belt by the rotating rolls or cylinders.The capsules were then transported to the rotary basket dryer.The capsules were tumbled in a rotary basket dryer to remove a sufficient amount of moisture to allow the They were then transferred onto trays and allowed to dry until the moisture level of the filling solution was no more than 2% (w / w) The drying time is the time required to reach the level of moisture of 2% Six batches were prepared containing 0.01, 0.05, 0.5, 2.5, 5.0, or 10.0 mg of steroid, 0.035 mg of hydroxytoluene butyl NF, and sufficient CapMul® MCM to make a total filling composition of 350 mg, except that the 10 mg capsule was made with a total 500 mg. These compositions were evaluated to verify the relative bioavailability using standard methods. The volunteers were randomly assigned to receive the drug either in a soft gelatin capsule of the present invention or in a conventional tablet. Plasma samples were collected and the pharmacokinetic parameters (AUC, Cmax, Tmax) were compared between the treatment groups. The relative bioavailability of the soft gelatine capsule of this invention was 80% to 90% compared to 10% to 20% for the same amount of the steroid in one tablet. The application of which this description and the claims form a part, may be used as a basis for priority with respect to any subsequent request. The claims of such a subsequent application may be directed to any novel feature or to a combination of the features described herein and may include, by way of example and without limitation, one or more of the following claims.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Having described the invention as above, property is claimed as contained in the following

Claims (17)

1. A solution, characterized in that it comprises a therapeutically effective amount of a pharmaceutically active azaido steroid, and a fatty acid ester of glycerol or propylene glycol.

2. The solution according to claim 1, characterized in that the steroid is a steroid 4-aza or 6-aza.

3. The solution according to claim 2, characterized in that the steroid is a 17-beta-substituted carbonyl-4-azaandrost-l-en-3-one or a carbonyl-6-azaandrost-4-en-3-one 17- beta-substituted.

4. The solution according to claim 3, characterized in that the steroid is a 17-beta-substituted carbonyl-4-azaandrost-1-en-3-one.

5. The solution according to claim 4, characterized in that it is 17-beta-N- (t-butyl) carbamoyl-4-aza-5-alpha-androst-l-en-3-one, 17-beta-N- (2, 5, -bis (trifluoromethyl)) -phenylcarbamoyl-4-aza-5-alpha-androst-l-en-3-one, 17-beta-Nl- (3,4-methylenedioxy-phenyl) -cyclohexylcarbamoyl- 4-aza-5-alpha-androst-l-en-3-one, or 17-beta-N- (1- (p-chlorophenyl)) cyclopentylcarbamoii-4-aza-5-alpha-androst-l-en- 3-one.

6. The solution according to claim 5, characterized in that the steroid is 17-beta-N- (2, 5, -bis (trifluoromethyl)) phenylcarbamoyl-4-aza-5-alpha-androst-1-en-3 ona

7. The solution according to any of claims 1-6, characterized in that the steroid is from 0.0025% to 2.5% by weight of the solution.

8. The solution according to claim 7, characterized in that the steroid is from 0.025% to 1.5% by weight of the solution.

9. The solution according to any of claims 1-8, characterized in that the ester is derived from carboxylic acids containing from 6 to 12 carbon atoms.

10. The solution according to claim 9, characterized in that the ester is derived from carboxylic acids which contain 8 carbon atoms.

11. The solution according to any of claims 1-lQ, characterized in that the ester is a monoester. t2.

A rarmaceutic composition, characterized in that it comprises the solution according to any previous claim.

13. A pharmaceutical composition according to claim 12, characterized in that it also comprises an antioxidant.

14. The composition according to claim 13 characterized in that the antioxidant is butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, or mixtures thereof.

15. The composition according to claim 13, characterized in that the antioxidant is from 0.001% to 0.5% by weight of the composition.

16. A gelatin capsule filled with liquid, characterized in that it comprises the composition according to any of claims 12-15.

17. The gelatin capsule according to claim 16, characterized in that the capsule .a is a soft gelatin capsule.