JPH1017495A - Pharmaceutical composition of poorly water-soluble drug - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal composition capable of imparting an excellent bioavailability and stability when orally administrated by blending a hardly water-soluble medicine with a specific compound such as fatty acid monoglyceride. SOLUTION: This composition comprises (A) a hardly water-soluble medicine having low water solubility, (B) a fatty acid monoglyceride, (C) a polyoxyethylene sorbitan fatty acid ester and (D) polyethylene glycol. The component (A) is a medicine having <=0.1mg/ml solubility to water and pharmacological activity and e.g. dihydropyridine derivatives can be preferably examplified as the component A. It is preferable that the blend ratio of each component in the composition is 1-20 pts.wt. component (A), 10-100 pts.wt. component (B), 10-100 pts.wt. component (C) and 1-20 pts.wt. component (D). The composition is preferably used in a state absorbed into a pharmaceutically permissible porous inorganic substance. Dosage of the hardly water-soluble medicine can be decreased to alleviate pain of patients to which the medicine is administered thereby.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a pharmaceutical composition for oral administration of a poorly water-soluble drug. The pharmaceutical composition for oral administration provided by the present invention is characterized in that it absorbs poorly water-soluble drugs from the digestive tract into the blood.

[0002]

2. Description of the Related Art Since poorly water-soluble drugs, for example, dihydropyridine derivatives, have poor absorbability from the digestive tract, it is desired to develop a formulation of a drug having good absorbability as a clinical formulation. . Therefore, as a method of increasing the absorption, it is necessary to add an absorption accelerator or the like and to devise the dosage form itself. In general, fine powdering of crystals, amorphization, addition of a surfactant, inclusion of cyclodextrin, etc. , Emulsification, dissolution in polyethylene glycol and vegetable oil, and the like. However, none of them has sufficient absorption from the digestive tract into the blood.

According to Japanese Patent Application Laid-Open No. 4-217921,
Pharmaceutical compositions containing poorly water-soluble drugs, unsaturated fatty acid monoglycerides and polyoxyethylene sorbitan fatty acid esters, as well as pharmaceutical compositions containing medically acceptable porous inorganic substances are described. In addition, Japanese Unexamined Patent Publication No.
No. 16537 describes a pharmaceutical composition using saturated fatty acid monoglycerides instead. These compositions can provide a composition having excellent absorption and stability.

In order to solve the above problems, an object of the present invention is to
An object of the present invention is to provide a composition having improved absorption by oral administration of a poorly water-soluble drug.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies on a pharmaceutical composition for oral administration which can effectively absorb a poorly water-soluble drug from the digestive tract into the blood. When a composition obtained by blending monoglyceride, polyoxyethylene sorbitan fatty acid ester and polyethylene glycol, and a composition obtained by adsorbing these on a porous inorganic substance, excellent bioavailability during oral administration ( BA = Bioavailability) and stability were obtained and found to be suitable as a pharmaceutical composition for oral administration.

The present invention has been completed on the basis of the above findings, and is a pharmaceutical composition for oral administration obtained by dissolving a poorly water-soluble drug in fatty acid monoglyceride, polyoxyethylene sorbitan fatty acid ester and polyethylene glycol. The present invention relates to a pharmaceutical composition for oral administration obtained by adsorbing the composition on a pharmaceutically acceptable porous inorganic substance, and a pharmaceutical composition for oral administration obtained by packaging the composition in PTP.

In the present invention, the poorly water-soluble drug is not particularly limited as long as it has a solubility in water of 0.1 mg / ml or less and has pharmacological activity. Preferably, it is hardly absorbed by oral administration. Specifically, when the drug is pulverized in a mortar with a No. 200 sieve (75 μm) or less and suspended in a 0.5% carboxymethylcellulose sodium salt aqueous solution, BA is administered. (%) Is 10 or less, preferably 5 or less, more preferably 3 or less, and is a drug having high solubility in fatty acid monoglyceride, polyoxyethylene sorbitan fatty acid ester and polyethylene glycol, such as a dihydropyridine derivative.

Preferred examples of the dihydropyridine derivative include compounds represented by the following general formula (1). General formula (1)

[0009]

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Wherein R ¹ , R ² and R ³ are the same or different and are alkyl, cycloalkyl or alkoxyalkyl, and R ⁴ and R ⁵ are the same or different and are a hydrogen atom, halogen, nitro, halogenated alkyl, X represents alkylsulfonyl, halogenated alkoxy, alkylsulfinyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl or alkylthio (provided that R ⁴ and R ⁵ are not hydrogen atoms at the same time);
Represents a group represented by vinylene or azomethine, A represents an alkylene, and B represents —N (R ⁶ ) ₂ or a general formula

[0011]

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(Wherein, R ⁶ and R ⁷ each represent a hydrogen atom, alkyl, cycloalkyl, aralkyl, aryl or pyridyl, Ar represents aryl or pyridyl, and n represents an integer of 0 to 2). Shows the group represented. A dihydropyridine derivative or an acid addition salt thereof (JP-A-63-225356).

The alkyl represented by R ¹ , R ² and R ³ is preferably a lower alkyl having 1 to 6 carbon atoms, particularly preferably a lower alkyl having 1 to 4 carbon atoms. These alkyls may further have a lower cycloalkyl having 3 to 6 carbon atoms at the terminal. As cycloalkyl, lower cycloalkyl having 3 to 6 carbon atoms is preferable. As the alkoxyalkyl, those having a total of 3 to 7 carbon atoms are preferable.

The substituents represented by R ⁴ and R ⁵ are preferably those which are 2-position and / or 3-position with respect to the bonding position with the dihydropyridine ring. As the halogen for R ⁴ and R ⁵ , a fluorine atom and a chlorine atom are particularly preferred. As the alkyl and cycloalkyl, those exemplified above as R ^{1 to} R ³ are preferable. Alkoxy and alkylthio have 1 to 3 carbon atoms, respectively.
Those having a lower alkyl group are preferred. Alkoxycarbonyl includes those having 2 to 4 carbon atoms. The same applies to the halogen of the halide. The alkyl halide and the alkoxy halide may be those in which some of the hydrogen atoms are halogenated or those in which all of the hydrogen atoms are halogenated. Examples of the alkyl in the alkylsulfonyl and the alkylsulfinyl include those exemplified above for R ^{1 to} R ³ . As R ⁴ and R ⁵ , cyano and alkyl halide (particularly, trifluoromethyl) are preferable.

R⁶And R⁷Alkyl represented by
As the loalkyl, the above-mentioned R¹~ R ^ThreeWhat was exemplified in
No. Aralkyl is phenyl C_1-3Archi
And aryls such as phenyl and naphthyl.
These aromatic rings may be identical or identical at any position.
May have different substituents. On these aromatic rings
Examples of the substituent include, for example, R^FourAnd R^FiveAs
Examples are given. 2-pyridyl as pyridyl
Jill, 3-pyridyl and 4-pyridyl,
These are the R^FourAnd R^FiveHaving the substituents exemplified as
May be.

The alkylene represented by A may be linear or branched having 2 to 4 carbon atoms.

The aryl and pyridyl represented by Ar include those exemplified for R ⁶ and R ⁷ above, and may have the same substituent.

A 4-position substituent of dihydropyridine

[0019]

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When X is vinylene (-CH = CH-), it represents a benzene ring, and when azomethine (-CH = N-), it means pyridine, and these are optional. At position 4 of dihydropyridine
It may be bonded to a position. The substituents R ⁴ and R ⁵ are preferably substituted at the ortho-position and / or the meta-position with respect to the carbon atom bonded to the 4-position of dihydropyridine.

The following compounds are exemplified as such compounds. 2- (p-dimethylaminophenyl) ethyl methyl
2,6-dimethyl-4- (4-cyano-2-pyridyl)
-1,4-dihydropyridine-3,5-dicarboxylate and its 1 or 2 hydrochloride

2- (p-dimethylaminophenyl) ethyl methyl 2,6-dimethyl-4- (2-trifluoromethyl-3-pyridyl) -1,4-dihydropyridine-3,5-dicarboxylate and its 1 Or dihydrochloride

2- (p-dibenzylaminophenyl) ethyl methyl 2,6-dimethyl-4- (4-cyano-
2-pyridyl) -1,4-dihydropyridine-3,5-
Dicarboxylate and its 1 or 2 hydrochloride

2- (p-dibenzylaminophenyl) ethyl methyl 2,6-dimethyl-4- (2-trifluoromethyl-3-pyridyl) -1,4-dihydropyridine-3,5-dicarboxylate and its 1 or 2
Hydrochloride

2- [p- (4-benzhydrylpiperazino) phenyl] ethyl methyl 2,6-dimethyl-4
-(4-cyano-2-pyridyl) -1,4-dihydropyridine-3,5-dicarboxylate and its 1 or 2 hydrochloride

2- [p- (4-benzhydrylpiperazino) phenyl] ethyl methyl 2,6-dimethyl-4
-(2-trifluoromethyl-3-pyridyl) -1,4
-Dihydropyridine-3,5-dicarboxylate and its 1 or 2 fumarate

2- [p- (4-benzhydrylpiperazino) phenyl] ethyl methyl 2,6-dimethyl-4
-(3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate and its 1 or 2 hydrochloride

The fatty acid monoglyceride in the present invention is
It may be either a saturated fatty acid monoglyceride or an unsaturated fatty acid monoglyceride. The saturated fatty acid monoglyceride is a monoester of a saturated fatty acid and glycerin, and the saturated fatty acid is preferably a fatty acid having 6 to 12 carbon atoms, more preferably 8 to 10 carbon atoms. As saturated fatty acids,
Specifically, caproic acid (C6), caprylic acid (C8),
Examples include capric acid (C10) and lauric acid (C12). As the saturated fatty acid, a saturated fatty acid having the above carbon number may be used alone or as a mixture.

The unsaturated fatty acid monoglyceride is a monoester of an unsaturated fatty acid and glycerin. The unsaturated fatty acid preferably has 14 to 28 carbon atoms, more preferably 1 to 28 carbon atoms.
6 to 18 fatty acids with an unsaturated number (especially double bonds)
Is preferably 1 or 2. Specific examples include palmito oleic acid, oleic acid, linoleic acid, and linoleic acid. The unsaturated fatty acids having the above carbon number may be used alone or as a mixture.

The polyoxyethylene sorbitan fatty acid ester of the present invention has a fatty acid moiety having 10 to 1 carbon atoms.
8 [eg, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate,
Polyoxyethylene sorbitan monolaurate etc.] can be used. The polyethylene glycol in the present invention has a molecular weight of about 100 to 1,000. The above-mentioned saturated fatty acid monoglyceride, unsaturated fatty acid monoglyceride, polyoxyethylene sorbitan fatty acid ester and polyethylene glycol have an action as a nonionic surfactant.

The composition of the present invention may further contain nonionic surfactants other than the above four kinds, such as polyoxyethylene sorbite fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyglycerin fatty acid ester. Can be illustrated. The nonionic surfactant used in the present invention is not particularly limited as long as it is acceptable as a pharmaceutical additive. The HLB value (Hydr
ophile-Lipophile Balance) is 3 or more, especially 10-20
Is preferred.

The solubility of the poorly water-soluble drug in fatty acid monoglycerides and nonionic surfactants is 10 to 10.
It is about 500 mg / ml.

In the present invention, the porous inorganic substance is
Fatty acid monoglyceride, polyoxyethylene sorbitan fatty acid ester and the composition obtained by blending polyethylene glycol is efficiently adsorbed, as long as it is pharmacologically acceptable, there is no particular limitation, magnesium aluminate silicate, Silicon dioxide (for example, light anhydrous silicic acid, hydrous silicon dioxide) and the like are used.

The mixing ratio of the various components in the above-mentioned pharmaceutical composition for oral administration is not particularly limited, and is appropriately adjusted depending on the type of the poorly water-soluble drug.

For example, 10 to 100 parts by weight of fatty acid monoglyceride (preferably 20 to 50 parts by weight) and 10 to 100 parts by weight of polyoxyethylene sorbitan fatty acid ester (preferably 20 to 20 parts by weight) are used for 1 to 20 parts by weight of the poorly water-soluble drug.
To 50 parts by weight) and polyethylene glycol 1 to 20
Those consisting of parts by weight (preferably 5 to 10 parts by weight) are preferred.

When another nonionic surfactant is used in combination, 10 to 100 parts by weight (preferably 20 to 20 parts by weight) of fatty acid monoglyceride is added to 1 to 20 parts by weight of a poorly water-soluble drug.
50 parts by weight), 10 to 100 parts by weight (preferably 20 to 50 parts by weight) of polyoxyethylene sorbitan fatty acid ester, 1 to 20 parts by weight (preferably 5 to 10 parts by weight) of polyethylene glycol and other nonionic surfactants Those comprising 1 to 20 parts by weight (preferably 5 to 10 parts by weight) of the agent are preferred.

In the pharmaceutical composition for oral administration obtained by adsorbing the porous inorganic substance, 1 to 100 parts by weight, preferably 2 to 100 parts by weight of the porous inorganic substance is added to 10 parts by weight of the pharmaceutical composition for oral administration. One compounded with 10 parts by weight is exemplified.

The pharmaceutical composition of the present invention is usually prepared by dissolving a poorly water-soluble drug in fatty acid monoglyceride, polyoxyethylene sorbitan fatty acid ester and polyethylene glycol. The composition may further contain additives such as a stabilizer, a preservative, and an extender. The composition is usually formulated as a capsule, especially a soft capsule.

The pharmaceutical composition obtained by adsorbing a porous inorganic substance is usually prepared as a powder, and the adsorption is carried out by a method known per se. If necessary, a formulation excipient such as lactose may be added to make a powder formulation, or a capsule may be filled or tableted by a conventional method. In order to improve the hygroscopicity of the composition of the present invention, PTP (Press Through Pack) packaging may be performed. Examples of the material include PVDC (polyvinylidene chloride) coated PVC (polyvinyl chloride), PP (polypropylene), and PP-based multilayer. PTP packaging is used in combination with aluminum packaging.

[0040]

EXAMPLES The present invention will now be described specifically with reference to examples, but the present invention is not limited to these examples. Example 1 2- [p- (4-benzhydrylpiperazinophenyl) ethyl methyl 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate] hydrochloric acid 220 g of the salt were mixed with 2413 g of oleic acid monoglyceride (“EXOEL O-95R” manufactured by Kao Corporation; the same applies hereinafter) and polyoxyethylene sorbitan monooleate (“TO-10” manufactured by Nippon Chemical Co., Ltd.).
M "and the same hereinafter. ) 2413 g and 536 g of polyethylene glycol (“Macrogol 400” manufactured by NOF CORPORATION, the same applies hereinafter). The mixture was dissolved and stirred at 40 to 50 ° C. to obtain 5582 g of a solution.

5245 g of the solution thus obtained was mixed with 3235 g of magnesium metasilicate aluminate (“Neucillin US ₂ ” manufactured by Fuji Chemical Industry Co., Ltd .; the same applies hereinafter) and stirred. Further, 254 g of croscarmellose sodium A type (manufactured by Asahi Kasei Corporation, the same applies hereinafter) was mixed and stirred.
Thereafter, the mixture was sieved with a No. 42 to 200 sieve to prepare 8734 g of fine particles for capsule filling.

The fine granules thus obtained were treated with 2- [p-
(4-benzhydrylpiperazinophenyl) ethyl methyl 2,6-dimethyl-4- (3-nitrophenyl)
[-1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride was filled into a No. 4 capsule so as to give 2 mg (92 mg as a filling amount), and packaged in PTP.

Example 2 2- [p- (4-Benzhydrylpiperazinophenyl) ethyl methyl 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxy Rate] hydrochloride was added to 2365 g of oleic acid monoglyceride, 2365 g of polyoxyethylene sorbitan monooleate and 526 g of polyethylene glycol, and dissolved and stirred at 40 to 50 ° C. to obtain 5584 g of a solution.

5245 g of the solution thus obtained and 3235 g of magnesium aluminate metasilicate were mixed and stirred. In addition, croscarmellose sodium A type 25
4 g were mixed and stirred. Thereafter, the mixture was sieved with a No. 42 to 200 sieve to prepare 8734 g of fine particles for capsule filling.

The fine granules thus obtained were treated with 2- [p-
(4-benzhydrylpiperazinophenyl) ethyl methyl 2,6-dimethyl-4- (3-nitrophenyl)
[-1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride was filled into a No. 3 capsule so as to be 4 mg (122 mg as a filling amount), and packaged in PTP.

Example 3 2- [p- (4-Benzhydrylpiperazinophenyl) ethyl methyl 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxy Rate] hydrochloride (445 g) was added to oleic acid monoglyceride (2312 g), polyoxyethylene sorbitan monooleate (2312 g) and polyethylene glycol (514 g), and the mixture was dissolved and stirred at 40 to 50 ° C. to obtain a solution (5853 g).

5245 g of the solution thus obtained and 3235 g of magnesium aluminate metasilicate were mixed and stirred. In addition, croscarmellose sodium A type 25
4 g were mixed and stirred. Thereafter, the mixture was sieved with a No. 42 to 200 sieve to prepare 8734 g of fine particles for capsule filling.

The fine granules thus obtained were treated with 2- [p-
(4-benzhydrylpiperazinophenyl) ethyl methyl 2,6-dimethyl-4- (3-nitrophenyl)
[1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride was filled in a No. 2 capsule so as to be 8 mg (180 mg as a filling amount), and packaged in a PTP.

Example 4 2- [p- (4-benzhydrylpiperazinophenyl)
Ethyl methyl 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride (91 g) was converted into oleic acid monoglyceride (496 g), polyoxyethylene sorbitan monooleate (496 g) and In addition to 53 g of polyethylene glycol, the mixture was dissolved and stirred at 40 to 50 ° C. to obtain a solution (1105 g in total).

EXPERIMENTAL EXAMPLE 1 Absorbency at Oral Administration The absorbability of the pharmaceutical composition of the present invention at oral administration was examined.
The absorptivity evaluation is about 10 kg body weight fasted for 20 hours before administration.
Was administered one capsule prepared in Example 3 and blood was collected from a vein over time until 24 hours after the administration. The collected blood is centrifuged to collect plasma, subjected to deproteinization treatment, and then subjected to quantitative analysis of the drug by HPLC using a reversed-phase column (ODS system) to determine BA from the blood concentration curve. Calculated. As a result, BA was 15%.

Experimental Example 2 Storage Stability The pharmaceutical composition prepared in Example 3 was subjected to a storage test for 4 weeks in an airtight state at 60 ° C. in order to examine the stability of the drug. The drug content, its related substances (decomposed substances of the drug) content, and appearance were confirmed. Table 1 shows the results. The present composition was hardly decomposed, and was stable under the storage conditions of 60 ° C. in an airtight state for 4 weeks.

[0052]

[Table 1]

Experimental Example 3: Dissolution degree The dissolution degree of the pharmaceutical composition prepared in Example 3 was examined. The dissolution test was performed in accordance with the second method of the dissolution test of the 11th revised Japanese Pharmacopoeia, and the drug dissolution after 60 minutes was measured. As a result, the elution degree (D60) was 75%.

[0054]

The oral pharmaceutical composition of the present invention is a poorly water-soluble drug such as 2- [p-
(4-benzhydrylpiperazinophenyl) ethyl methyl 2,6-dimethyl-4- (3-nitrophenyl)-
[1,4-dihydropyridine-3,5-dicarboxylate] hydrochloride is excellent in stability, solubility, absorption from the gastrointestinal tract into blood and the like in a preparation (solution or powder).

By using the oral pharmaceutical composition of the present invention, the dose of a poorly water-soluble drug such as a dihydropyridine derivative can be reduced, thereby reducing the pain and side effects of the patient when taking the drug.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Nobuo Kondo, Inventor 2-25-1, Invitational Otani, Hirakata City, Osaka Prefecture Inside the Green Cross Research Institute, Ltd. (72) Inventor Yasuo Ueda 2-25, Invitation Otani, Hirakata City, Osaka Prefecture No. 1 Inside the Green Cross Central Research Institute

Claims (3)

[Claims] 1. A poorly water-soluble drug, a fatty acid monoglyceride,
A pharmaceutical composition for oral administration comprising a polyoxyethylene sorbitan fatty acid ester and polyethylene glycol. 2. The pharmaceutical composition according to claim 1, which is adsorbed on a pharmaceutically acceptable porous inorganic substance. 3. The method according to claim 1, which is packaged in PTP.
The pharmaceutical composition according to any one of the preceding claims.