JPS58116414A - Composition for pharmaceutical of prolonged release containing nicardipine and preparation thereof - Google Patents

Abstract

PURPOSE:To obtain the titled spherular granule capable of exhibiting improved prolonged effect as a remedy for cerebrovascular disorder, hypertension and angina pectoris, by coating a spherular core with a shapeless nicardipine or a salt thereof and a pH dependent-additive and/or water-soluble high polymer. CONSTITUTION:A spherular granule obtained by coating a spherular core with (A) shapeless nicardipine or a salt thereof, (B) a pH dependent-additive and/or a water-soluble high polymer and if desired further a surfactant, and coating the resultant spherular granule with if necessary (C) a substance permeable to chemicals, having smaller variation of concentration in blood between individuals, capable of keeping the minimal effective concentration in blood for a longer time than the conventional same kinds of pharmaceuticals, and giving the aimed composition having the desired prolonged effect. The granule is obtained by spraying and coating a solution of the nicardipine or a salt thereof and the component (B) in an organic solvent on the spherular core, and if necessary spraying and coating a solution of the component (C) in an organic solvent on the resultant spherular granule.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides nicardipine [chemical name: 2,6-dimeteru-4]
-(3'-ditrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-
[beta]-(N-benzyl-N-methylamine) ethyl ester) acid product for long-acting preparations.

Nicardipine has coronary and cerebral vasodilator effects and is a useful drug as a therapeutic agent for cerebrovascular disorders, hypertension, and angina pectoris. This nicardipine and its salts are Japanese Pharmacopoeia X
Since the solubility in the first liquid is good, ordinary preparations can sufficiently express their medicinal efficacy, but they are poorly soluble in the second liquid and have poor enteric properties, making it difficult to create long-lasting preparations. It was difficult.

Since long-acting preparations have many medical advantages, such as reducing the number of drug administrations and maintaining effective blood concentration, various general long-acting preparations have been developed. Preparations containing a large amount of substances that are difficult to disintegrate in water, preparations containing drug granules or tablets coated with water-repellent substances,
Pharmaceutical preparations in which a drug is coated with a semipermeable membrane, and preparations in which a poorly soluble or hydrophilic polymer compound is mixed or adsorbed with the drug to gradually release the drug have been developed. However, in the case of drugs with low solubility in intestinal fluids, such as nicardipine and its salts, conventional long-acting preparations cannot be expected to provide a sustained effect, and may only lead to a decrease in peri-appellivity. In the case of such drugs, it was necessary to incorporate additives to improve dissolution in order to improve their solubility in intestinal fluid.

The present inventors have conducted various studies on long-acting preparations of nicardipine under the above state of the art, and have found that (a)
with amorphous nicardipine or its salts.

(b) pH-dependent additives and/or water-soluble polymers.

A spherical granular composition (composition A) in which a small particle core is coated with a surfactant if desired, and a spherical granular composition (composition B) in which a drug-permeable substance is further coated thereon are excellent. The present invention has been completed based on the discovery that it exhibits a sustained effect. The composition of the present invention has excellent absorption from the intestinal mucosa and can maintain a stable effective blood concentration of nicardipi over a long period of time, despite the low solubility of nicardipi in intestinal fluid. Ta.

Composition A in the present invention is prepared by dissolving (a′l nicardipine or a salt thereof, (blpH-dependent additive and/or water-soluble polymer, and optionally a surfactant) in an organic solvent, and dissolving this solution in a small volume. It can be produced by spray coating particulate nuclei.

Composition-B can also be produced by spray coating the thus obtained composition AK and a solution containing a drug-permeable substance dissolved in an organic solvent.

More specifically, 1 composition A comprises (a') nicardipine or a salt thereof, and (b) a pH-dependent additive and/or a water-soluble polymer, optionally further a surfactant, in methanol, ethanol, indica, etc. Dissolve in organic solvents such as propatool, chloroform, acetone, methylene chloride, etc. alone or in an appropriate mixture.

This solution is mixed with small particulate nuclei made of sucrose, crystalline cellulose, sucrose-starch mixture, crystalline cellulose-lactose mixture, etc. [for example, Nonpareil
) (trade name, manufactured by Freund Sangyo Co., Ltd.)] by a spray coating method such as a centrifugal fluid coating method or a fluidized bed coating method to form a crude drug-containing film, and Composition B can be obtained in this way. A drug-permeable film can be obtained by further coating Composition A with a solution of a drug-permeable substance dissolved in the organic solvent described above by a spray coating method to form a drug-permeable film.

During such a manufacturing process, nicardipine or its salt changes into an amorphous form.

Examples of the pH-dependent additives mentioned above are:

Hydroxyprobyl methylcellulose phthalate.

Eudragit - L and S
(Product name.

Examples of the surfactant include Tween 80 (trade name) manufactured by Rohm &Haas;

Manufactured by Kao Atlas Co., Ltd., Ingredients: Polyoxyethylene sorbitan monooleate), Renex 30
(-Product name, manufactured by ICI, component: polyoxyethylene alkyl ether), Nilcol (N1kkol) HC
Examples of water-soluble polymers include O-60 (trade name, manufactured by Nikko Chemicals, component: polyoxyethylene hydrogenated castor oil), and RPC (trade name, manufactured by Shin-Etsu Chemical Co., Ltd., component: hydroxypropyl cellulose). .

Carbowax (Japanese Pharmacopoeia X, ingredient: polyethylene glycol), Methocel (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.).

Examples of drug-permeable substances include Eudragit-RL and R8 (trade name, manufactured by Rohm and Haas, ingredient: methacrylic acid).
methacrylic acid ester copolymer).

Examples include Ethocel (trade name, manufactured by Dow Chemicals, component: ether cellulose), TC-5 (trade name, manufactured by Shin-Etsu Chemical, component: hydroxypropyl methyl cellulose), and mixtures thereof.

In composition A, the ratio of coating to small particulate core was 1:2 at °C.
-1:10, and in composition B, the ratio of drug-permeable coating to composition A is suitably 15:85-1:99.

The present invention also includes a mixture of one composition A and one composition B. Because of the difference in dissolution rates between Composition A and Composition B, the use of a mixture of these results in higher effective blood concentrations of nicardipine over a longer period of time than when using each composition alone. It becomes possible to sustain it.

This mixture consists of composition A and composition B in a ratio of 1:0.5 to 1.
:19 by mixing in a conventional manner.

The composition of the present invention can be administered as it is, or it can be administered in the form of a capsule by filling it into a commonly used capsule by a conventional method.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Nonpareil 103 (trade name, manufactured by Freund Sangyo Co., Ltd., main ingredient: sugar) 728.
Put 6 g into a 5 kg capacity centrifugal flow device and add 80 g of dicalcibia hydrochloric acid.

Hydroxypropyl methylcellulose fist phthalate [H
Methanol/methylene chloride solution (1:1.φ) in which 80 g of p-55 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) and 8020 g of Tween-8 were completely dissolved (1:1.φ) x 2k
g is sprayed using a conventional method to form 1 spherical granular material. If necessary, add an appropriate amount of talc to prevent the spherical granules from adhering to each other. After drying this product at 40 tl' for 4 hours, it is filled into capsules by a conventional method to prepare capsules.

Example 2゜Example 10 After drying the spherical granular material at 4 Orr for 4 hours, 90 g of 8% Eudragi was added per 500 g of the spherical granular material.
(Eudragid) RL-100・Acetone・
A drug-permeable coating is applied using the isopropanol solution in the same manner as in Example 1. Add a small amount of talc if necessary 1
Prevents mutual agglomeration of spherical granules. 40 of this stuff
After drying at tll' for 4 hours, it is filled into capsules by a conventional method to prepare capsules.

Example 3゜The spherical granular materials prepared in Example ↓ and Example 2 were
= 7 (φ) in a conventional manner to form capsules.

Example 4゜Nonpareil 10368
2 g, 80 g of nicardipine hydrochloride, Eudragit L
-10080g and Tween-802
methanol/methylene chloride solution in which 0 g was completely dissolved (
1:1 w'w ) 1.8 kg was treated in the same manner as in Example 1 to form 1 spherical granular material. If necessary, add an appropriate amount of talc to prevent the nine spherical granules from adhering to each other. After drying this product at 40C for 4 hours, it is filled into capsules by a conventional method to prepare capsules.

Example 5゜ Example 40 After drying the spherical granular material at 40C for 4 hours.

For this 500g, 10g of Eudragit RL
-100 was completely dissolved in acetone/isoprono(nol solution (1:1 lW)) in the same manner as in Example 1.

Apply a drug-permeable coating. If necessary, add an appropriate amount of talc to prevent the spherical granules from adhering to each other. This product is dried in the same manner as in Example 4 and filled into capsules by a conventional method to prepare capsules.

Example 6゜The spherical granules prepared in Example 4 and Example 5 were
Mix well in a conventional manner at a ratio of near (φ).

Claims (1)

[Claims] jll (a) amorphous nicardipine or a salt thereof;
b) pH-dependent additives and/or water-soluble polymers,
A composition for a long-acting preparation of nicardipine in the form of spherical granules, in which a small particle core is optionally coated with a surfactant. (2) (a) amorphous nicardipine or its salt;
b) Nicardipine in the form of spherical granules coated with a small particulate core coated with a pH-dependent additive and/or a water-soluble polymer, optionally a surfactant, and (C) a drug-permeable substance. Composition for long-acting preparations. (3) (-amorphous nicardipine or its salt; (b
) A spherical granular composition in which a small particulate core is coated with a pH-dependent additive and/or a water-soluble polymer, and optionally a surfactant; The spherical granule composition coated with the agent and/or
Alternatively, a water-soluble polymer and optionally a surfactant are dissolved in an organic solvent, and the solution is spray coated onto small particle cores to produce a composition for a long-acting nicardipine preparation in the form of spherical granules. Law. (5) (a) nicardipine or its salt; and (b)
A pH-dependent additive and/or a water-soluble polymer, and optionally a surfactant, are dissolved in an organic solvent, this solution is spray coated onto the small particulate cores, and a drug-permeable substance is added to the organic solvent. A method for producing a composition for a long-acting preparation of nicardipine in the form of spherical granules, which comprises spray coating a solution dissolved in nicardipine.