Stabilized pharmaceutical compositions containing derivatives of vitamins D2 and D3

Abstract: 1. A solid state pharmaceutical composition which comprises at least ingredients (a), (b) and (c) of the following ingredients (a), (b), (c) and (d), namely: (a) at least one active component selected from pharmaceutically active derivatives of vitamin D2 and vitamin D3; (b) at least one pharmaceutically acceptable antioxidant; (c) at least one pharmaceutically acceptable polyoxyalkyl stabilizer; (d) at least one solid pharmaceutical excipient or carrier in an amount sufficient to impart the characteristics of a solid to the composition.

Description: FIELD AND BACKGROUND OF THE INVENTION The present invention relates to stabilized solid state pharmaceutical compositions containing an active component selected from pharmaceutically active derivatives of vitamin D 2 and vitamin D 3 . Derivatives of vitamin D 2 and vitamin D 3 , which generally possess at least the activity of their underivatized precursors, have been found to be useful in medicine, e.g. they increase the serum calcium level, inhibit parathyroid hormone, and affect bone formation; they may also inhibit the proliferation of psoriatic and certain cancer cells. In particular, they are used to treat symptoms such as chronic renal failure, hypoparathyroidism, vitamin-D-resistant rickets, osteomalacia, osteoporosis and psoriasis, However, such derivatives have the disadvantage of low stability under ordinary storage conditions. Moreover, refrigeration, protection against actinic radiation and replacement of the ambient atmosphere have not been found to be satisfactory a a means of stabilization and are often costly. Consequently, various stabilization methods have been proposed. Thus, by way of example, EP 413828A teaches dispersion of active ingredient in an excipient readily soluble in orgahic solvent and a basic substance, EP 387808A uses a stabilizer selected from polyvinylacetal diethylaminoacetate and hydroxypropylcellulose, while JP 258722/91 discloses compositions containing crystalline cellulose and butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA), as antioxidant. JP 074123/92 discloses compositions containing active forms of vitamin D 3 and gelatin in the same phase; in an example of a liquid phase composition, a polyoxyethylene hardened castor oil derivative was also present. All of these exemplary solid pharmaceutical compositions show unsatisfactory stability at elevated temperatures or/and humidities. Consequently, there is a great need for improved stabilized solid state pharmaceutical compositions containing the ingredients referred to above. Solid vitamin D containing compositions are also described, by WO-A-9209271 and WO-A-9116899, which however require the use of HPMC or mannitol as a stabiliser. Accordingly, it is an object of the invention to provide solid pharmaceutical compositions containing an active component selected from pharmaceutically active derivatives of vitamin D 2 and vitamin D 3 , which exhibit improved stability for a prolonged period of time. Other objects of the invention will appear from the description which follows. SUMMARY OF THE INVENTION The present invention accordingly provides a solid state pharmaceutical composition consisting essentially of: (a) at least one active component selected from pharmaceutically active derivatives of vitamin D 2 and vitamin D 3 ; (b) at least one pharmaceutically acceptable antioxidant selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, propyl gallate, β carotene and ascorbic acid; (c) at least one pharmaceutically acceptable polyoxyalkyl stabiliser selected from polyethyleneglycols, polyethyleneglycol ethers, polyethyleneglycol esters, polyoxyethylated castor oil, polyoxyethylated hydrogenated castor oil, polyoxyethylated sorbitan fatty acid esters and polyoxyethylated glycerol fatty acid esters; (d) at least one solid pharmaceutical excipient or carrier in an amount sufficient to impart the characteristics of a solid to the composition, and selected from lactose, sorbitol and calcium phosphate. In another aspect, the present invention provides a process for preparing the pharmaceutical composition as defined in the preceding paragraph, which comprises the sequential steps of: (i) dissolving ingredients (a) and (b) in a solvent; (ii) thoroughly mixing the solution formed in step (i) with ingredients (c), and with ingredient (d) and (iii) removing the solvent. DETAILED DESCRIPTION OF THE INVENTION The product of the process just described may be granulated; if desired, the granulate may then be formed into a dosage form selected from tablets, sachets and gelatin capsules (e.g. hard gelatin capsules). A lubricant such as magnesium stearate and/or calcium stearate may be added at any convenient stage. It will be appreciated that in the alternative, the product of the process described above need not be granulated, but may be obtained as a uniform dry powder, which is then mixed with lubricant if desired, and then made into dosage forms such as those specified above. In order to avoid premature deterioration of the composition, it is preferred to remove the solvent under mild conditions, e.g. at ambient temperature, and in the presence of an inert atmosphere (such as nitrogen) or in vacuum. Presently preferred ingredients of the solid state pharmaceutical composition of the invention are: (a) 1α-hydroxycholecalciferol (1α-(OH)D 3 ), 24-hydroxycholecalciferol (24-(OH)D 3 ), 25-hydroxycholecalciferol (25-(OH)D 3 ), 1α,25-dihydroxycholecalciferol (1α,25-(OH) 2 D 3 ), 1α,24-dihydroxycholecalciferol (1α,24-(OH) 2 D 3 ), 24,25-dihydroxycholecalciferol (24,25-(OH) 2 D 3 ), 1,24,25-trihydroxycholecalciferol (1,24,25-(OH) 3 D 3 ), 1α-hydroxyergocalciferol (1α-(OH)D 2 ) and 1α,25-dihydroxyergocalciferol (1α,25-(OH) 2 D 2 ); (b) butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, propyl gallate, β-carotene and ascorbic acid; (c) polyethyleneglycols, polyethyleneglycol ethers, polyethyleneglycol esters, polyoxyethylated castor oil, polyoxyethylated hydrogenated castor oil (e.g. Cremophor RH, a Trade Mark of BASF AG), polyoxyethylated sorbitan fatty acid esters and polyoxyethylated glycerol fatty acid esters; (d) lactose, sorbitol and calcium phosphate. As regards the proportions of the ingredients which may be used in the solid state pharmaceutical compositions of the invention, it will be evident that since use of a pharmaceutical excipient or carrier, is conventional, the proportions in which it may be used, if desired, in the present invention are also conventional. The essential ingredients (a), (b) and (c) may be used in proportions which may be varied within wide ranges. Active ingredient (a), used in a composition of the invention intended for direct therapeutic application (in the usual dosage forms), may be present in an amount within the range of e.g. 0.0000025 to 5.0 wt.%, but more usually 0.0005 to 1.0 wt.%. However, it is also within the contemplation of the present invention that the compositions may be in the form of concentrates of active ingredient, prior to preparation of finished dosage forms, in which case up to 25, or even up to 50 wt% of ingredient (a), may be present. Antioxidant ingredient (b) may be present in an amount within the range of e.g. 0.0000025 to 10.0 wt.%, but more usually 0.0025 to 1.0 wt.%. As is of course well known in the pharmaceutical art, the amount of antioxidant used Will also take account of the relative toxicity of a particular antioxidant. Polyoxyalkyl stabilizer, ingredient (c), may be present in an amount within the range of e.g. 0.01 to 50 wt.% in a composition intended for therapeutic administration. In this connection, reference may be made the Examples set forth below in which the amount of ingredient (c) varies between 3 and more than 21 wt.% of the total composition. However, as may also be seen from the Examples, the proportion of ingredient (c) may approach 100%, when ingredient (d) is omitted. It is presently preferred that, the compositions comprise (by weight) 0.00003 to 0.8% (a), 0.01 to 0.1% (b) and 0.03 to 30% (c);. In other words, according to a presently preferred embodiment, the relative weight ratio ranges of ingredients (a), (b) and (c) are 0.00003 to 0.8 (a) : 0.01 to 0.1 (b) : 0.03 to 30 (c), respectively, whether or not ingredient (d) is present. The invention will now be illustrated by the following non-limitative Examples. EXAMPLE 1 Butylated hydroxyanisole (557 mg) and 1α-OH-D 3 (5.1 mg) were dissolved in ethanol (300 g). The solution was mixed for 20 minutes with sorbitol (1.8 kg) and polyoxyethylated hydrogenated castor oil (55.69 g) in a high speed mixer, the residual ethanol solution being washed into the mixer with an additional 50 g ethanol. The resulting wet mass was removed and dried on trays under vacuum with a nitrogen bleed at ambient temperature, to give dry granules which were screened (30 mesh) and mixed with magnesium stearate (4.64 g). These granules can be packed into sachets or hard gelatin capsules, or pressed into tablets, by conventional methods. The product contained the ingredients in the following percentages by weight: polyoxyethylated hydrogenated castor oil 2.99 % 1α-OH-D 3 0.00027% butylated hydroxyanisole 0.0299 % sorbitol 96.73 % magnesium stearate 0.25 % Examples 2-5 were carried out similarly (except where indicated), but contained the ingredients as described below, in which the stated percentages are by weight. EXAMPLE 2 In this Example, the lactose and magnesium stearate are omitted prior to the drying step. The lactose- and magnesium stearate-free product is then thoroughly mixed with these two ingredients prior to tabletting. polyethylene glycol 6000 21.25 % 24,25(OH) 2 D 3 0.011% butylated hydroxyanisole 0.04 % lactose 78.47 % magnesium stearate 0.25 % EXAMPLE 3 polyoxyethylated hydrogenated castor oil 3.0 % 24,25(OH) 2 D 3 0.088% butylated hydroxyanisole 0.03 % sorbitol 96.63 % magnesium stearate 0.25% EXAMPLE 4 polyoxyethylated hydrogenated castor oil 3.0 % 24,25(OH) 2 D 3 0.01 % butylated hydroxyanisole 0.03 % sorbitol 96.71 % magnesium stearate 0.25% EXAMPLE 5 polyoxyethylated hydrogenated castor oil (Cremophor RH40) 4.0 % 1α-OH-D 3 0.000373% butylated hydroxyanisole 0.04 % sorbitol 95.96 % STABILITY TESTS The exemplified solid state pharmaceutical compositions in tablet form were stored at 40°C and 75% relative humidity. Assay of the active ingredient at monthly intervals gave the following results, expressed as a percentage of the initial assay. Months Example 1 Example 2 Example 3 Example 4 0 100.0 100.0 100.0 100.0 1 105.0 - 99.1 100.0 2 101.7 - 95.9 102.0 3 98.98 91.3 96.0 98.8 4 102.0 - 98.2 97.4 5 98.15 - - - 6 99.2 - 91.2 95.1 The excellent results of stability tests shown above by solid state pharmaceutical compositions in accordance with the present invention may be contrasted with the above-mentioned prior art, which may be summarized as follows, from which it may also be noted that no results were given for any period of time longer than one month. EP 413828A: at 40°C and 75% relative humidity (as in the present stability tests), assay was 95-100% at 7 days, 93-99% at 14 days and 91-94% at 30 days. EP 387808A: at 50°C, assay was 98.0-98.8% at two weeks and 95.7-97.5% at four weeks. JP 258722/91: after one month at 40°C, assayed 97.82 or 97.18% vitamin D 3 , which is not directly comparable with the present active compounds (data on exemplified 1α-OH-D 3 not supplied). JP 074123/92: after 7 and 14 days at 60°C, a liquid phase composition assayed 95.4 or 81.7% 1α-OH-D 3 .

Claims: A solid state pharmaceutical composition consisting essentially of: (a) at least one active component selected from pharmaceutically active derivatives of vitamin D 2 and vitamin D 3 ; (b) at least one pharmaceutically acceptable antioxidant selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, propyl gallate, β carotene and ascorbic acid; (c) at least one pharmaceutically acceptable polyoxyalkyl stabiliser selected from polyethyleneglycols, polyethyleneglycol ethers, polyethyleneglycol esters, polyoxyethylated castor oil, polyoxyethylated hydrogenated castor oil, polyoxyethylated sorbitan fatty acid esters and polyoxyethylated glycerol fatty acid esters; and (d) at least one solid pharmaceutical excipient or carrier in an amount sufficient to impart the characteristics of a solid to the composition, and selected from lactose, sorbitol and calcium phosphate. A pharmaceutical composition according to Claim 1 wherein the pharmaceutically active derivative of vitamin D 2 and vitamin D 3 is selected from 1α hydroxycholecalciferol, 24-hydroxycholecalciferol, 25-hydroxycholecalciferol, 1α 25-dihydroxycholecalciferol, 1α 24-dihydroxycholecalciferol, 24,25 dihydroxycholecalciferol, 1,24,25 trihydroxycholecalciferol, 1α-hydroxyergocalciferol and 1α,25-dihydroxyergocalciferol. A pharmaceutical composition according to Claim 1 wherein the pharmaceutically active derivative of vitamin D 2 and vitamin D 3 is selected from 1α hydroxycholecalciferol and 24,25-dihydroxycholecalciferol. A pharmaceutical composition according to any of the preceding claims wherein the composition additionally comprises a lubricant. A pharmaceutical composition according to Claim 4 wherein the lubricant is selected from magnesium stearate and calcium stearate. A pharmaceutical composition according to any of the preceding claims wherein the relative weight ratio ranges of components (a), (b) and (c) are 0.00003 to 0.8 component (a) 0.01 to 0.1 component (b) 0.03 to 30 component (c) respectively. A pharmaceutical composition according to any of the preceding claims wherein the composition is in a form selected from powdered form and granulated form. A pharmaceutical composition according to any of the preceding claims wherein the composition is constituted in a dosage form selected from tablets, sachets and gelatin capsules. A process for preparing the solid state pharmaceutical composition as defined in Claim 1, which comprises the sequential steps of: (i) dissolving components (a) and (b) in a solvent; (ii) thoroughly mixing the solution formed in step (i) with component (c), and with component (d) and; (iii) removing the solvent. A process according to Claim 9, wherein step (iii) is carried out at ambient temperature, in an inert atmosphere or in a vacuum.

Inventors: SILVER DAVID ISAAC, SILVER, DAVID ISAAC
Applicants: TEVA PHARMA, TEVA PHARMACEUTICAL INDUSTRIES, LTD.
Application year: 1993
Main classification: A61K31
IPC codes: A61K31, A61K9, A61P3, A61K47