MXPA99011995A - Solutions containing azasteroids - Google Patents

Abstract

The present invention discloses a novel solution comprising a therapeutically effective amount of a pharmaceutically active aza steroid, polyethylene glycol, and propylene glycol. In another aspect, the present invention discloses 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

SOLUTIONS CONTAINING AZASTEROIDS The present invention relates to certain pharmaceutical compositions comprising 4-azasteroids and / or 6-azasteroids. In particular, the present invention relates to solutions comprising a steroid inhibitor of 5-alpha reductase.

The pharmaceutically active compounds can be supplied in a variety of forms, for example in a soft, elastic, gelatin capsule. The methods for the preparation of soft gelatine capsules are well known. See, for example, J.P. Stanley, Soft Gelatin Capsules, Ch. ' 13-Part Two in: The Theory and Practice of Industrial Pharmacy, eds. L. Lachman et. al., 3 rd Ed., pp. 398-412, 1986, and W.R. Ebert, Soft Elastic Gelatin Capsules: A Unique Dosage Form, Pharmaceutical Technology, Vol. 1, No. 5.

The choice of excipients is important to ensure good solubility and good bioavailability of the pharmaceutically active compound. See for example, A. Matso, Excipients Commonly REF .: 32400 Used in Soft Gelatin. 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), M.S. Patel et. al., Advances in. Softgel Formulation Technology, Manufacturing Chemist, August 1989, and I.R. Berry, Improving Bioavailability with Soft Gelatin Capsules, Drug & Cosmetics Industry, pp. 32, 102-108, (September 1993). Particular publications have been described with respect to the formulation of pharmaceutically active hydrophobic compounds, for example in K. Hutchison, Formulation of Softgels For I proved Oral Delivery of Hydrophobic Drugs, Spc. Pub. - R. Soc. Chem., Vol. 161, pp. 133-147 (1995).

Hard gelatin 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).

Azasteroids are an important class of pharmaceutically active compounds. In particular there are some 4-azasteroids and 6-azasteroids known to be inhibitors of the enzyme testosterone of 5-alpha reductase (hereinafter "5AR inhibitors"). Such compounds are appreciated to be useful in the treatment of benign prostatic hyperplasia, prostate cancer and other conditions. See, for example, U.S. Patent 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 (Frye et al.), 5,438,061 (Bergman et al.), 5,543,406 (Andrews et al.), 5,565,467 (Batchelor et al.) And WO 95/07926 (Batchelor et al.). One such 5AR inhibitor, finasteride, is commercially available from Merck & Co. , Inc. under the name PROSCAR ™. These pharmaceutically active compounds are not easy to dissolve. These solubility challenges may affect bioavailability which may result in reduced or unpredictable bioavailability.

Briefly, the present invention describes a novel solution comprising a pharmaceutically effective amount of a pharmaceutically active azasteroid, polyethylene glycol (PEG), and propylene glycol (PG).

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. What turns the steroid from a free powder into a ready solution in the manufacturing process which provides a safer process. There is less risk when working with the solution than with the free solid.

In addition, some of these steroids are prone to oxidation. Gelatin capsule formulations can be much more resistant to oxidation due to oxygen permeation than typical gelatin shells. See, for example, F.S. Hom et al., Soft Gelatin capsules II: Oxygen Permeability Study of Capsule Shells, J. Pham. Sci., Vol. 64 (No. 5), pp 851-887 (1975).

Given the PEG content of the compositions of this invention, the compositions of this invention have a surprisingly short drying time. This surprisingly short drying time is beneficial for manufacturing because with this cut in manufacturing time, packaging and shipping, manufacturing costs are reduced.

The azasteroids useful in this invention can be any pharmaceutically active azasteroid or pharmaceutically acceptable solvate thereof. The preferred classes of azasteroids are the 4-azasteroid class of 5-alpha reductase inhibitors (5AR inhibitors) and the 6-aza class of 5-alpha reductase inhibitors. For example, any of the 5AR inhibitors described in the aforementioned patents. Particularly preferred azasteroids are the 4-azasteroids. Particularly preferred 4-azasteroids include finasteride, 17-beta-N- (2,5-bis (trifluoromethyl)) phenylcarbomoyl-aza-5-alpha-androst-1-en-3-one which is the described steroid in U.S. Patent No. 5,565,467 (batchelor et al.), and 17-beta-Nl- (3,4-methylenedioxy-phenyl) -cyclohexylcarbomoyl-4-aza-5-alpha-androst-1-en-3 ona and 17-beta-N- (1- (p-chlorophenyl)) -cyclopentylcarbomoyl-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 aforementioned patents.

The azasteroid is preferably present in the range from 0.00075 to 0.4% by weight of the solution of this invention, more preferably from 0.0075 to 0.3% by weight of the solution of this invention.

The PEG useful in this invention preferably have an average molecular weight that is within the range of 200-600, in which the PEG is in the liquid state. Particularly preferred is PEG with an average molecular weight of about 400 (PEG 400). Preferably, the PEG is at least 90% by weight of the solution of this invention.

The PG is preferably from 1 to 7.5% by weight of the solution of this invention, more preferably from 4 to 6% by weight of the solution.

It is generally preferable to include a surfactant in the composition. Suitable surfactants include polyoxyethylene monooleate (20) sorbitan (polysorbate 80), sodium dodecyl sulfate, and the sodium salt of dioctylsulfosuccinate (Sodium Docusate). The surfactants can be used alone or in combination. A particularly preferred surfactant is Polysorbate 80. The surfactant or mixture of surfactants is preferably from 0.05 to 1.0% by weight of the composition 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.The antioxidants may 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 a filling formulation for gelatin capsules, more preferably of soft gelatin capsules.

EXPERIMENTS In the following experiments, a 4-azasteroid pharmaceutically activated in several solubility studies. The pharmaceutically active steroid is 17-beta-N- (2,5-bis (trifluoromethyl)) phenylcarbomoyl-4-aza-5-alpha-androst-1-en-3-one. This steroid is described in the '467 patent and can be prepared by known methods including the methods described in the' 467 patent.

The solubility of the steroid was determined by suspending the excess in the amount of the steroid in about 1 mL of various aqueous and organic media. The resulting suspension is stirred in a Vankel® rotating water bath maintained at ° C and protected from light. At the end of an equilibrium time, usually between 1 and 12 days, the excess solids were removed by means of filter centrifugation through 0.22μ filters. The resulting float was then tested for steroid concentration against the external standard. The concentration of the steroid in the float is determined by HPLC analysis using a column II / M of the hewlett Packard 1090 Series with a Two Chem Station. The HPLC conditions are summarized below in Table 1. The solubility results in various aqueous media are summarized in Table 2, and in various organic media are summarized in Table 3. Table 4 summarizes the solubility in various compositions containing a complexing agent (2-hydroxypropyl-beta-cyclodextrin). Table 5 summarizes the solubility in various oils. In the following Tables and experiments, the Milli Q ™ plus water is a reverse osmosis water, THF is tetrahydrofuran, DMSO is dimethyl sulfoxide, Labrafil ™ is a mixture of unsaturated polyglycolized glycerides obtained by partial alcoholysis of corn oil or oil or oil of apricot kernel, consisting of polyethylene glycol glycerides and esters, SDS is sodium dodecyl sulfate, "bile salt model of duodenum", and a mixture of sodium glycocholate, sodium glycocenodeoxycholate, sodium glycodeoxylate, sodium taurocholate, sodium taurocenodeoxycholate, sodium taurodeoxylate, sodium chloride, lecithin, and phosphate buffer, Tween 80 is polyoxyethylene monooleate (20) sorbitan, PEG 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 indicated otherwise, all% are given by weight, for example "v / v" means% by volume. Table 1. HPLC conditions Table 2. Solubility in a Watery Environment Table 3. Solubility in an 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 hydroxypropyl-β-cyclodextrin solutions Table 5. Solubility in Various Oil Based Systems The solubility data show that these types of steroids are very difficult to dissolve. In addition, if these dissolved steroids are to be used in a gelatin capsule, the excipients to be chosen need to be acceptable excipients for use with gelatin capsule systems. Therefore, the following excipients were considered viable components for this formulation: Ethanol Propylene glycol Polysorbate 80 Polyethylene glycol 400 These excipients were then further evaluated to discover the best formulation. The experiment was conducted using a mixture of the following components in the corresponding percentages: Ethanol 0%, 5%, and 10% Propylene glycol 5%, 6.25%, and 7.5% Polysorbate 80 (Tween 80) 0%, 0.05%, and 0.1% Polyethylene glycol 400 QS Then an experiment designed following the design summarized in Table 6 was carried out.

Table 6. Experimental parameters The experimental design includes 14 runs that result in a completely quadratic equation and error detection. To adapt the data, the JPM® system was used. The solubility of the steroid in the various compositions of the designed experiment was evaluated as described below. The results are summarized in Table 7.

Table 7. Solubility Results Run # Solubility (mg / mL) 1 5.95 2 5.82 3 4.84 4 4.21 5 4.57 6 3.26 7 3.65 8 3.97 9 5.42 10 3.92 11 3.80 12 3.90 13 0.87 14 3.14 The data from the designed experiment show that the increase in the concentration of ethanol and polysorbate 80 increases the steroid's solubility. It is also indicated that propylene glycol does not have a significant effect on the solubility at the concentrations studied.

The preferred compositions were then used to prepare filling formulations suitable for use in gelatin capsules. For the manufacture of gelatin capsules of 0.1, 0.5, and 2.5 mg, the propylene glycol was heated to 35-50 ° C. then butyl hydroxytoluene NF was added to the mixture and the mixture was stirred until dissolved. Polyethylene glycol 400 NF was added to the resulting solution and mixed. Then Polisorbate 80 NF was added and mixed. Then the steroid was added and mixed, and heated if necessary at 40-45 ° C, until it dissolves. The solution was desaereated before encapsulation.

The gelatin was prepared by mixing the NF gelatin, USP glycerin, and the purified USP water. The resulting mixture was heated in a "pressurized reactor to melt the gelatin." Then the gelatin was kept in the molten state until it was used for the encapsulation.

The encapsulation was performed using a rotary matrix process. The heated gelatine was fed to an encapsulation machine where it entered two separating boxes that melt the gelatin in a cooling drum, thereby forming two gelatin bands. Each strip of gelatin was lubricated with Fractionated Coconut Oil on the inner side and Fractionated Coconut Oil with 0.1% Lecithin NF on the outer side. Fractionated Coconut Oil prevents gelatin from adhering or sticking to the equipment and Lecithin NF prevents the gelatin from adhering together after manufacturing, and before drying. The bands were then transported to the encapsulation roller. The matrix cavities for forming the capsules are located in the circumferences of the two adjacent rollers, which rotate and pull the gelatin bands between them. The filling solution was injected, by means of a calibrated positive displacement pump, between the gelatin bands that forced them to expand and fill the cavities of the matrix. As the capsules are filled, they are formed simultaneously, sealed and cut from the gelatin web by means of the encapsulation rollers. Then the capsules were transported to the rotary basket dryer.

The capsules were dried by shaking in a rotary basket dryer to remove enough moisture to allow handling. They were then transferred onto trays and allowed to dry until the moisture level of the filling solution was not more than 8% (w / w). The drying time is the time required to reach the humidity level of the Batches were prepared containing 0.1, 0.5, and 2.5 mg per capsule. The compositions are summarized in Table 8.

Then the drying times of the batches were evaluated. The drying time for all the PEG-based compositions that were tested was only 1 day. Those skilled in the art generally expect that soft gelatin capsules containing oil-based (hydrophobic) filler material have drying times of about 3 days, and that PEG-based fillers typically increase the drying time. in comparison with oil-based compositions. Therefore, the shorter drying time of the steroid-based PEG formulation offers an advantage over PEG-based formulations, as well as the typical oil-based formulations. Those skilled in the art will also recognize that although the inclusion of propylene glycol in the formulation typically decreases the migration of water to the filling, propylene glycol typically has no effect on the drying time. In our case, however, propylene glycol results in a greater drying time than expected. These compositions were evaluated for relative bioavailability using standard methods. Volunteers were considered at random to receive the drug in either of the two oral solution presentations of the present invention, a soft gelatin capsule or in a standard tablet. Plasma tests were collected and the pharmacokinetic parameters (AUC, Cmax, Tmax) were compared between the treatment groups. The relative bioavailability from the solution and from the soft gelatin capsule of the present invention was from 80 to 90% compared to 10 to 20% for the same amount of the steroid in a tablet. The request for this description and the claims that form part may be used for priority with respect to any subsequent request. The claims of such a subsequent application may be directed to any novel feature or in combination with 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 to the applicant, to implement said invention is that which is clear from the manufacture of the objects to which it refers.

Claims (21)

1. A solution characterized in that it comprises a therapeutically effective amount of a pharmaceutically active azasteroid, polyethylene glycol, and propylene glycol.

2. The solution of claim 1, characterized in that said steroid is a 4-azasteroid or a 6-azasteroid.

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

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

5. The solution of claim 4, characterized in that said steroid is a 17-beta-N- (t-butyl) -carbamoyl-4-aza-5-alpha-androst-l-en-3-one, 17-beta-N - (2,5-bis (trifluoromethyl)) phenylcarbomoyl-4-aza-5-alpha-androst-l-en-3-one, 17-beta-Nl- (3,4-methylenedioxy-phenyl) -cyclohexylcarbomoyl-4 -aza-5-alpha-androst-l-en-3-one, or 17-beta-N- (1- (p-chlorophenyl)) -cyclopentylcarbomoyl-4-aza-5-alpha-androst-l-en -3-ona.

6. The solution of claim 5, characterized in that said steroid is a 17-beta-N- (2,5-bis (trifluoromethyl) phenylcarbomoyl-4-aza-5-alpha-androst-1-en-3-one.

7. The solution of any of claims 1-6, characterized in that said steroid is from 0.00075 to 0.4% by weight of said solution.

8. The solution of claim 7, characterized in that said asteroid is from 0.0075% to 0.3% by weight of the solution.

9. The solution of any of claims 1-8, characterized in that said polyethylene glycol is at least 90% by weight of said solution.

10. The solution of any of claims 1-9, characterized in that said polyethylene glycol has an average molecular weight from 200 to 600.

11. The solution of any of claims 1-10, characterized in that said propylene glycol is from 1% to 7.5% by weight of said solution.

12. The solution of claim 11, characterized in that said propylene glycol is from 4% to 6% by weight of said solution.

-13. A pharmaceutical composition characterized in that it comprises the solution according to any of the preceding claims.

14. The composition of claim 13, characterized in that it also comprises a surfactant.

15. the composition of claim 14, characterized in that said surfactant is polysorbate 80, sodium dodecyl sulfate, docusate sodium, or mixtures thereof.

16. The composition of claim 14 or 15, characterized in that said surfactant is from 0.05% to 1.0% by weight of said composition.

17. The composition of any of claims 13-16, characterized in that it also comprises an antioxidant.

18. The composition of claim 17, characterized in that said antioxidant is butylated hydroxytoluene, butylated hydroxyanisole, or mixtures thereof.

19. The composition of claim 17 or 18, characterized in that said antioxidant is from 0.001% to 0.5% by weight of said composition.

20. A liquid-filled gelatin capsule characterized in that it comprises the composition according to any of claims 13-19.

21. The gelatin capsule of claim 20, characterized in that it is a soft, gelatin capsule.