Pharmaceutical composition containing slightly water-soluble drug

Abstract: The orally administrable pharmaceutical compositions containing a slightly water-soluble drug, characterized by improved stability and improved absorption of the drug from digestive tract into blood. The use of the compositions of the present invention enables decrease of the dose amount of a slightly water-soluble drug, which eventually leads to alleviation of pains and side effects on the part of patients.

Description: BACKGROUND OF THE INVENTION The present invention relates to orally administrable pharmaceutical compositions containing a slightly water-soluble drug. The pharmaceutical compositions for oral use according to the present invention are based on the characteristic properties of improved absorption from digestive tract into blood and improved stability. Due to poor absorption of slightly water-soluble drugs, particularly dihydropyridine derivatives and lipoxygenase inhibitors, from digestive tract, there has been a strong demand for the development of pharmaceutical formulations which afford good absorption in clinical applications. In order to improve absorption, addition of an absorbefacient and improvement of dosage form designs are necessary, and generally employed means of formulation are pulverization of crystals, noncrystallization, addition of surfactants, cyclodextrin inclusion, emulsification, dissolution in polyethylene glycol and vegetable oil. However, none of these affords sufficient absorption from digestive tract. In addition, dihydropyridine derivatives are specifically unstable to light, and for this reason, they are prepared into light-resistant preparations or colored preparations and stored in light-resistant containers. Further, EP-A-0 179 583 discloses adsorption of anhydrous compositions comprising a poorly water-soluble drug and a surfactant onto an adsorber. However, said adsorption is not associated with an improvement in stability of an unstable drug. SUMMARY OF THE INVENTION In an attempt to solve the aforementioned problems, an object of the present invention is to provide compositions containing a slightly water-soluble dihydropyridine derivative which improve absorption by oral administration. Another object of the invention is to provide compositions wherein an unstable dihydropyridine derivative is stabilized therein. The present inventors have conducted intensive studies to provide effective absorption of a slightly water-soluble drug from digestive tract and found that excellent bioavailability (BA) in oral use and stability of the drug can be achieved when the slightly water-soluble drug is formulated into a non-micelle composition by adding a fatty acid monoglyceride and/or a polyoxyethylenesorbitan fatty acid ester to the slightly water-soluble drug, or formulated into a composition by further adsorbing same onto a porous inorganic substance, and that the thus-obtained composition serves well as a pharmaceutical composition for oral use. The present invention has been completed on the basis of such findings, and the present invention relates to a pharmaceutical composition for oral administration comprising: (1) a slightly water soluble drug being a dihydropyridine derivative set forth below; (b) at least one surfactant selected from a fatty acid monoglyceride and a polyoxyethylenesorbitan fatty acid ester; and (c) a pharmaceutically acceptable porous inorganic substance. DETAILED DESCRIPTION OF THE INVENTION The slightly water-soluble drug in the invention is a dihydropyridine derivative which has a solubility of 0.1 mg/ml or below in water and is pharmacologically active. Specifically, the dihydropyridine derivative is slightly absorbed by oral administration, has BA (%) of 10 or below, preferably 5 or below, more preferably 3 or below, when orally administered after pulverization with a mortar [into 200 mesh (75 µm) or below] and suspending same in an aqueous solution of 0.5 % sodium carboxymethylcellulose, and is easily dissolved in a fatty acid monoglyceride and a polyoxyethylenesorbitan fatty acid ester. The dihydropyridine derivate is a compound of the formula: wherein R 1 , R 2 and R 3 are the same or different and are an alkyl, a cycloalkyl or an alkoxyalkyl; R 4 and R 5 are the same or different and are hydrogen, halogen, nitro, a halogenated alkyl, an alkylsulfonyl, a halogenated alkoxy, an alkylsulfinyl, an alkyl, a cycloalkyl, an alkoxy, cyano, an alkoxycarbonyl or an alkylthio, provided that R 4 and R 5 are not hydrogen at the same time; X is a group of vinylene or azomethine; A is an alkylene; and B is -N(R 6 ) 2 or where R 6 and R 7 are respectively hydrogen, an alkyl, a cycloalkyl, an aralkyl, an aryl or pyridyl, Ar is an aryl or pyridyl and n is an integer of 0 to 2; or their acid addition salts (USP 4886819, EP 257 616). The alkyl represented by R 1 , R 2 or R 3 is preferably a lower alkyl having 1 to 6 carbon atoms, with further preference given to that having 1 to 4 carbon atoms. The lower alkyl may have a lower cycloalkyl having 3 to 6 carbon atoms on the alkyl terminal. As the cycloalkyl, a lower cycloalkyl having 3 to 6 carbon atoms is preferable. As the alkoxyalkyl, preferred are those having 3 to 7 carbon atoms. The substituent represented by R 4 or R 5 is preferably at the 2- and/or 3-position to the binding site with the dihydropyridine ring. As the halogen at R 4 or R 5 , particularly preferred are fluorine or chlorine atom, and as the alkyl and cycloalkyl, preferred are those mentioned as R 1 to R 3 . The alkoxy and the alkylthio preferably possess a lower alkyl having 1 to 3 carbon atoms. As the alkoxycarbonyl, there may be mentioned those having 2 to 4 carbon atoms. The halogen in halogenides is exemplified by those mentioned above, and the halogenated alkyl and the halogenated alkoxy may be that where some of the hydrogen atoms are halogenated or all of the hydrogen atoms are halogenated. The alkyl in alkylsulfonyl and alkylsulfinyl includes those exemplified as R 1 to R 3 . As R 4 and R 5 , preferred are cyano and halogenated alkyl (specifically, trifluoromethyl). The alkyl and the cycloalkyl represented by R 6 and R 7 include those exemplified as R 1 to R 3 . Phenyl C 1-3 alkyl is preferred as the aralkyl, and phenyl and naphthyl are preferred as aryl. These aromatic rings may have the same or different substituents at an optional position. The substituents on the aromatic ring include those mentioned as R 4 and R 5 . The pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl, which may have the substituents mentioned above as R 4 and R 5 . The alkylene represented by A includes those having 2 to 4 carbon atoms, which may be a straight- or branched-chain. The aryl and the pyridyl represented by Ar include those exemplified as R 6 and R 7 and may have the same substituents. The ring represented by which is the 4-position substituent of dihydropyridine, means a benzene ring when X is vinylene (-CH=CH-) and pyridine when X is azomethine (-CH=N-). An optional position of the ring may bind to the 4-position of the dihydropyridine. The substituents R 4 and R 5 are preferably at the ortho- and/or meta-position to a carbon atom binding to the 4-position of the dihydropyridine. As such compounds, the following can be mentioned: 2-(p-Dimethylaminophenyl)ethyl methyl 2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride 2-(p-Dimethylaminophenyl)ethyl methyl 2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride 2-(p-Dibenzylaminophenyl)ethyl methyl 2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride 2-(p-Dibenzylaminophenyl)ethyl methyl 2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride 2-[p-(4-Benzhydrylpiperazino)phenyl]ethyl methyl 2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride 2-[p-(4-Benzhydrylpiperazino)phenyl]ethyl methyl 2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its fumarate 2-[p-(4-Benzhydrylpiperazino)phenyl]ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride The fatty acid monoglyceride is a monoester of fatty acid and glycerin where the fatty acid preferably has 14 to 28 carbon atoms, more preferably 16 to 18 carbon atoms and the number of unsaturated bonds, particularly double bonds, when the fatty acid is unsaturated is 1 or 2. Specific examples of unsaturated fatty acid include palmitoleic acid, oleic acid, linoleic acid and linolenic acid, and examples of saturated fatty acid include myristic acid, palmitic acid, stearic acid, behenic acid and heptacosanoic acid. As the fatty acid, those having the above carbon atoms may be used solely or in mixture, with preference given to unsaturated fatty acids. In the present invention, the fatty acid moiety of the polyoxyethylenesorbitan fatty acid ester preferably has 10 to 18 carbon atoms, which is exemplified by polyoxyethylenesorbitan fatty acid esters such as polyoxyethylenesorbitan monooleate, polyoxyethylenesorbitan monostearate, polyoxyethylenesorbitan monopalmitate and polyoxyethylenesorbitan monolaurate. Further, a nonionic surfactant other than the above-mentioned polyoxyethylenesorbitan fatty acid esters may be co-used, and examples of such surfactants include polyoxyethylenesorbit fatty acid ester, polyoxyethylene hydrogenated castor oil and polyglycerin fatty acid ester. The nonionic surfactant to be used in the present invention is not particularly limited and those acceptable as pharmaceutical additives may be used. The HLB value (hydrophile-lipophile balance) is preferably not less than 3, preferably 10 to 20. The solubility of the slightly water-soluble drug in a fatty acid monoglyceride and a nonionic surfactant is 10-500 mg/ml. No limitation is posed on the porous inorganic substance of the present invention as long as the substance efficiently adsorbs the non-micelle compositions obtained by adding a fatty acid monoglyceride and/or a polyoxyethylenesorbitan fatty acid ester and is pharmacologically acceptable, and examples include magnesium aluminate silicate, silicon dioxides such as light silicic acid anhydride and silicon dioxide hydrate. The proportion of each ingredient in the non-micelle compositions is not particularly limited but adjusted suitably depending on the kind of the slightly water-soluble drug. For example, when either the fatty acid monoglyceride or the polyoxyethylenesorbitan fatty acid ester is used solely, it is preferably used in an amount of 1 to 100 parts by weight, preferably 5 to 60 parts by weight per 1 part by weight of the slightly water-soluble drug. When the fatty acid monoglyceride and the polyoxyethylenesorbitan fatty acid ester are used combinedly, they are preferably used in an amount of 1 to 100 parts by weight, preferably 10 to 50 parts by weight per 1 part by weight of the slightly water-soluble drug. Further, when a nonionic surfactant other than the polyoxyethylenesorbitan fatty acid ester is also used, a fatty acid monoglyceride and/or a polyoxyethylenesorbitan fatty acid ester and a nonionic surfactant are used in an amount of 1 to 100 parts by weight, preferably 10 to 50 parts by weight per 1 part by weight of the slightly water-soluble drug. In the pharmaceutical composition for oral administration prepared by adsorption onto the porous inorganic substance, the porous inorganic substance is used in an amount of 1 to 100 parts by weight, preferably 2 to 10 parts by weight per 10 parts by weight of the aforementioned non-micelle composition comprising slightly water-soluble drug and surfactant. The non-micelle compositions are normally prepared by dissolving a slightly water-soluble drug in a fatty acid monoglyceride and/or a polyoxyethylenesorbitan fatty acid ester, and a nonionic surfactant other than the polyoxyethylenesorbitan fatty acid ester. Other additives such as stabilizers, antiseptics and extenders, may be further added to the composition. The pharmaceutical compositions of the invention prepared by adsorption onto a porous inorganic substance is normally in the form of powders and granules and the adsorption is conducted by a method known per se. That is, the pharmaceutical composition of the invention is prepared by mixing a non-micelle composition with a porous inorganic substance. The powders thus obtained may be formulated into powder preparations by adding an excipient for formulation such as mannitol, packed in capsules or tableted by a conventional method. Example 1 2-[p-(4-Benzhydrylpiperazinophenyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride (20.1 g) is added to unsaturated fatty acid monoglyceride (Kao, "Excel O-95R", 650 g), followed by dissolution and stirring at 40°C to give a non-micelle solution. Example 2 2-[p-(4-Benzhydrylpiperazinophenyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride (20.1 g) is added to polyoxyethylenesorbitan monooleate (Nikko Chemical, "TO-10M", 650 g), followed by dissolution and stirring at 40°C to give a non-micelle solution. Example 3 2-[p-(4-Benzhydrylpiperazinophenyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride (20.1 g) is added to a mixture of unsaturated fatty acid monoglyceride (Kao, "Excel O-95R") and polyoxyethylenesorbitan monooleate (Nikko Chemical, "TO-10M") in a proportion of 1:1 (650 g), followed by dissolution and stirring at 40°C to give a non-micelle solution. Example 4 2-[p-(4-Benzhydrylpiperazinophenyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride (20.1 g) is added to a mixture of unsaturated fatty acid monoglyceride (Kao, "Excel O-95R") and polyethylene glycol (PEG 400) in a proportion of 1:1 (650 g), followed by dissolution and stirring at 40°C to give a non-micelle solution. Comparison Example 1 2-[p-(4-Benzhydrylpiperazinophenyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride (20.1 g) is added to polyethylene glycol (PEG 400, 650 g), followed by dissolution and stirring at 40°C to give a non-micelle solution. Comparison Example 2 2-[p-(4-Benzhydrylpiperazinophenyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride (10 g) is pulverized with a mortar and mixed with lactose (190 g) to give 200 g of a powder for capsules. Example 5 2-[p-(4-Benzhydrylpiperazinophenyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride (20.1 g) is added to unsaturated fatty acid monoglyceride (Kao, "Excel O-95R", 650 g), followed by dissolution and stirring at 40°C to give a non-micelle solution. The thus-obtained solution (600 g) and magnesium alminate metasilicate (Fuji Kagaku Sangyo, "Neusilin US 2 ", 370 g) are mixed with a stirring-granulator. Thereto is added Carmellose sodium A type (30 g) for mixing and stirring, followed by addition of purified water (250 ml) to give granules. The granules are dried at 40°C for 17 hours with a forced-air drier and passed through a sieve of 355-75 µm (42-200 mesh) to give 550 g of fine granules for capsules. Example 6 2-[p-(4-Benzhydrylpiperazinophenyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride (20.1 g) is added to polyoxyethylenesorbitan monooleate (Nikko Chemical, "TO-10M", 650 g), followed by dissolution and stirring at 40°C to give a non-micelle solution. The thus-obtained solution (600 g) and magnesium alminate metasilicate (Fuji Kagaku Sangyo, "Neusilin US 2 ", 370 g) are mixed with a stirring-granulator. Thereto is added Carmellose sodium A type (30 g) for mixing and stirring, followed by addition of purified water (250 ml) to give granules. The granules are dried at 40°C for 17 hours with a forced-air drier and passed through a sieve 355-75 µm (42-200 mesh) to give 550 g of fine granules for capsules. Example 7 2-[p-(4-Benzhydrylpiperazinophenyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5- dicarboxylate] hydrochloride (20.1 g) is added to a mixture of unsaturated fatty acid monoglyceride (Kao, "Excel O-95R") and polyoxyethylenesorbitan monooleate (Nikko Chemical, "TO-10M") in a proportion of 1:1 (650 g), followed by dissolution and stirring at 40°C to give a non-micelle solution. The thus-obtained solution (600 g) and magnesium alminate metasilicate (Fuji Kagaku Sangyo, "Neusilin US 2 ", 370 g) are mixed with a stirring-granulator. Thereto is added Carmellose sodium A type (30 g) for mixing and stirring, followed by addition of purified water (250 ml) to give granules. The granules are dried at 40°C for 17 hours with a forced-air drier and passed through a sieve of 355-75 µm (42-200 mesh) to give 550 g of fine granules for capsules. Experiment Example 1 Absorption by oral administration The absorption and stability of the pharmaceutical compositions as obtained in Examples 1 to 7 and Comparison Examples 1 and 2 are summarized in Table 1. The absorption evaluation was conducted as follows. That is, a composition of the present invention was administered to a beagle weighing about 10 kg after fasted for 20 hours before the administration in a dose of 3 mg/0.1 ml/kg, and sample blood was taken from radialis cutaneous vein at given time intervals up to 24 hours after the administration. The plasma of the blood sample was centrifuged, deproteinized with acetonitrile and determined by high performance liquid chromatography (HPLC) using a reversed-phase column [ODS (C 18 ), 4 µ, 3.9 ⊘ × 150 mm, Japan Waters]. The BA% was estimated on the basis of the blood concentration. Additives used Absorption (BA%) Ex. 1 Excel O-95R 26.0 Ex. 2 TO-10M 24.3 Ex. 3 Excel O-95R+TO-10M (1:1) 25.6 Ex. 4 PEG 400+Excel O-95R (1:1) 21.7 Ex. 5 Excel O-95R/Neusilin 23.0 Ex. 7 Excel O-95R+TO-10M (1:1)/Neusilin 29.4 Comp. Ex. 1 PEG 400 1.2 Comp. Ex. 2 no additive 0.3 Experiment Example 2 Stability of the pharmaceutical composition of the invention Using the pharmaceutical compositions as prepared in Examples 5 to 7, the stability was examined by a storage test at 40°C. The content of analogous substance and appearance 4 weeks later are summarized in Table 2. Additives used Stability (60°C, 4 weeks) content of analogous substance (%) appearance Excel O-95R/Neusilin (Ex. 5) 2.9 colored TO-10M/Neusilin (Ex. 6) 1.2 no change Excel O-95R + TO-10M (1:1)/Neusilin (Ex. 7) 1.6 no change The pharmaceutical compositions for oral administration of the present invention markedly improve absorption of slightly water-soluble drugs such as dihydropyridine etc. as evidenced in Experiment Example 1 and the stability of the slightly water-soluble drugs in a powdery form is excellent as evidenced in Experiment Example 2. The use of the pharmaceutical compositions for oral administration of the present invention enables decreasing of the dose amount of slightly water-soluble drugs, which eventually leads to alleviation of pains and side effects on the part of patients.

Claims: Claims for the following Contracting States : BE, CH, DE, DK, FR, GB, IT, LI, NL, SE A pharmaceutical composition for oral administration comprising: (a) a slightly water-soluble drug being a dihydropyridine derivative of the formula wherein R 1 , R 2 and R 3 are the same or different and are an alkyl, a cycloalkyl or an alkoxyalkyl; R 4 and R 5 are the same or different and are hydrogen, halogen, nitro, a halogenated alkyl, an alkylsulfonyl, a halogenated alkoxy, an alkylsulfinyl, an alkyl, a cycloalkyl, an alkoxy, cyano, an alkoxycarbonyl or an alkylthio, provided that R 4 and R 5 are not hydrogen at the same time; X is a group consisting of vinylene or azomethine; A is an alkylene; and B is -N(R 6 ) 2 or where R 6 and R 7 are respectively hydrogen, an alkyl, a cycloalkyl, an aralkyl, an aryl or pyridyl, Ar is an aryl or pyridyl and n is an integer of 0 to 2; or their acid addition salts, (b) at least one surfactant selected from fatty acid monoglyceride and polyoxyethylenesorbitan fatty acid ester, and (c) a porous inorganic substance. A pharmaceutical composition for oral administration as claimed in Claim 1, wherein the slightly water-soluble drug has bioavailability (%) of 10 or below, when orally administered after pulverization into 200 mesh (75 µm) or below and suspending same in an aqueous solution of 0.5% sodium carboxymethylcellulose. A pharmaceutical composition for oral administration as claimed in Claim 1, which is obtained by (a) dissolving the slightly water-soluble drug in a surfactant to prepare a non-micelle composition and (b) adsorbing the non-micelle composition of step (a) onto the porous inorganic substance. A pharmaceutical composition for oral administration as claimed in Claim 1, wherein the slightly water-soluble drug is selected from 2-(p-Dimethylaminophenyl)ethyl methyl 2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride, 2-(p-Dimethylaminophenyl)ethyl methyl 2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride, 2-(p-Dibenzylaminophenyl)ethyl methyl 2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride, 2-(p-Dibenzylaminophenyl)ethyl methyl 2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride, 2-[p-(4-Benzhydrylpiperazino)phenyl]ethyl methyl 2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride, 2-[p-(4-Benzhydrylpiperazino)phenyl]ethyl methyl 2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its fumarate, and 2-[p-(4-Benzhydrylpiperazino)phenyl]ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride. A pharmaceutical composition for oral administration as claimed in Claim 1, wherein the fatty acid monoglyceride is of a fatty acid having 14 to 28 carbon atoms. A pharmaceutical composition for oral administration as claimed in Claim 5, wherein the fatty acid having 14 to 28 carbon atoms is selected from palmitoleic acid, oleic acid, linoleic acid and linolenic acid. A pharmaceutical composition for oral administration as claimed in Claim 1, wherein the polyoxyethylenesorbitan fatty acid ester is of a fatty acid having 10 to 18 carbon atoms. A pharmaceutical composition for oral administration as claimed in Claim 7, wherein the fatty acid having 10 to 18 carbon atoms is selected from polyoxyethylenesorbitan fatty acid esters such as polyoxyethylenesorbitan monooleate, polyoxyethylenesorbitan monostearate, polyoxyethylenesorbitan monopalmitate and polyoxyethylenesorbitan monolaurate. A pharmaceutical composition for oral administration as claimed in Claim 1, wherein a nonionic surfactant other than the polyoxyethylenesorbitan fatty acid ester is added. A pharmaceutical composition for oral administration as claimed in Claim 9, wherein the nonionic surfactant has HLB (hydrophile-lipophile balance) of not less than 3. A pharmaceutical composition for oral administration as claimed in Claim 9, wherein the nonionic surfactant is selected from polyoxyethylenesorbit fatty acid ester, polyoxyethylene hydrogenated castor oil and polyglycerin fatty acid ester. A pharmaceutical composition for oral administration as claimed in Claim 1, wherein the fatty acid monoglyceride and/or the polyoxyethylenesorbitan fatty acid ester is used in an amount of 1 to 100 parts by weight per 1 part by weight of the slightly water-soluble drug. A pharmaceutical composition for oral administration as claimed in Claim 9, wherein the fatty acid monoglyceride and the nonionic surfactant other than polyoxyethylenesorbitan fatty acid ester are used in an amount of 1 to 100 parts by weight per 1 part by weight of the slightly water-soluble drug. A pharmaceutical composition for oral administration as claimed in Claim 1, wherein the surfactant is a combination of fatty acid monoglyceride and polyoxyethylenesorbitan fatty acid ester. A pharmaceutical composition for oral administration as claimed in Claim 3, wherein the porous inorganic substance is mixed in an amount of 1 to 100 parts by weight per 10 parts by weight of the non-micelle composition. A pharmaceutical composition for oral administration as claimed in Claim 1, wherein the porous inorganic substance is selected from magnesium aluminate silicate and silicon dioxide. Claims for the following Contracting State : ES A process for preparing a pharmaceutical composition for oral administration comprising: (a) a slightly water-soluble drug being a dihydropyridine derivative of the formula wherein R 1 , R 2 and R 3 are the same or different and are an alkyl, a cycloalkyl or an alkoxyalkyl; R 4 and R 5 are the same or different and are hydrogen, halogen, nitro, a halogenated alkyl, an alkylsulfonyl, a halogenated alkoxy, an alkylsulfinyl, an alkyl, a cycloalkyl, an alkoxy, cyano, an alkoxycarbonyl or an alkylthio, provided that R 4 and R 5 are not hydrogen at the same time; X is a group consisting of vinylene or azomethine; A is an alkylene; and B is -N(R 6 ) 2 or where R 6 and R 7 are respectively hydrogen, an alkyl, a cycloalkyl, an aralkyl, an aryl or pyridyl, Ar is an aryl or pyridyl and n is an integer of 0 to 2; or their acid addition salts, (b) at least one surfactant selected from fatty acid monoglyceride and polyoxyethylenesorbitan fatty acid ester, and (c) a porous inorganic substance, which process comprises (i) dissolving the slightly water-soluble drug in a surfactant to prepare a non-micelle composition and (ii) adsorbing the non-micelle composition of step (i) onto the porous inorganic substance. A process as claimed in claim 1, wherein the slightly water-soluble drug has bioavailability (%) of 10 or below, when orally administered after pulverization into 200 mesh (75 µm) or below and suspending same in an aqueous solution of 0.5% sodium carboxymethylcellulose. A process as claimed in claim 1, wherein the slightly water-soluble drug is selected from: 2-(p-Dimethylaminophenyl)ethyl methyl 2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride, 2-(p-Dimethylaminophenyl)ethyl methyl 2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride, 2-(p-Dibenzylaminophenyl)ethyl methyl 2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride, 2-(p-Dibenzylaminophenyl)ethyl methyl 2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride, 2-[p-(4-Benzhydrylpiperazino)phenyl]ethyl methyl 2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride, 2-[p-(4-Benzhydrylpiperazino)phenyl]ethyl methyl 2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its fumarate, and 2-[p-(4-Benzhydrylpiperazino)phenyl]ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride. A process as claimed in Claim 1, wherein the fatty acid monoglyceride is of a fatty acid having 14 to 28 carbon atoms. A process as claimed in Claim 4, wherein the fatty acid having 14 to 28 carbon atoms is selected from palmitoleic acid, oleic acid, linoleic acid and linolenic acid. A process as claimed in Claim 1, wherein the polyoxyethylenesorbitan fatty acid ester is of a fatty acid having 10 to 18 carbon atoms. A process as claimed in Claim 6, wherein the fatty acid having 10 to 18 carbon atoms is selected from polyoxyethylenesorbitan fatty acid esters such as polyoxyethylenesorbitan monooleate, polyoxyethylenesorbitan monostearate, polyoxyethylenesorbitan monopalmitate and polyoxyethylenesorbitan monolaurate. A process as claimed in Claim 1, wherein a nonionic surfactant other than the polyoxyethylenesorbitan fatty acid ester is added. A process as claimed in Claim 8, wherein the nonionic surfactant has HLB (hydrophile-lipophile balance) of not less than 3. A process as claimed in Claim 8, wherein the nonionic surfactant is selected from polyoxyethylenesorbit fatty acid ester, polyoxyethylene hydrogenated castor oil and polyglycerin fatty acid ester. A process as claimed in Claim 1, wherein the fatty acid monoglyceride and/or the polyoxyethylenesorbitan fatty acid ester is used in an amount of 1 to 100 parts by weight per 1 part by weight of the slightly water-soluble drug. A process as claimed in Claim 8, wherein the fatty acid monoglyceride and the nonionic surfactant other than polyoxyethylenesorbitan fatty acid ester are used in an amount of 1 to 100 parts by weight per 1 part by weight of the slightly water-soluble drug. A process as claimed in Claim 1, wherein the surfactant is a combination of fatty acid monoglyceride and polyoxyethylenesorbitan fatty acid ester. A process as claimed in Claim 1, wherein the porous inorganic substance is mixed in an amount of 1 to 100 parts by weight per 10 parts by weight of the non-micelle composition. A process as claimed in Claim 1, wherein the porous inorganic substance is selected from magnesium aluminate silicate and silicon dioxide.

Inventors: HIRAI KENICHI, IWAO TORU, KONDOH NOBUO, YAMANOUCHI KOICHI, YOKOYAMA KAZUMASA, HIRAI, KENICHI, IWAO, TORU, KONDOH, NOBUO, YAMANOUCHI, KOICHI, YOKOYAMA, KAZUMASA, HIRAI, KENICHI, C/O THE GREEN CROSS CORPORATION, IWAO, TORU, C/O THE GREEN CROSS CORPORATION, KONDOH, NOBUO, C/O THE GREEN CROSS CORPORATION, YAMANOUCHI, KOICHI, THE GREEN CROSS CORPORATION, YOKOYAMA, KAZUMASA, THE GREEN CROSS CORPORATION
Applicants: GREEN CROSS CORP, THE GREEN CROSS CORPORATION
Application year: 1991
Main classification: A61K47
IPC codes: A61K9, A61K31, A61K47, A61P43