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Process for producing sustained-release preparation

a technology of sustained release and preparation, which is applied in the direction of prosthesis, peptide/protein ingredients, drug compositions, etc., can solve the problems of not having a description on the process of producing microcapsules using a solution, no suggestion on application to the other bases, and no suggestion on the application of microcapsules to achieve the effect of suppressing initial release, simple and convenient, and suppressing initial releas

Inactive Publication Date: 2001-08-16
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] It is preferable for sustained-release preparations using biodegradable polymers to suppress initial release of an excess amount of a physiologically active substance, in particular release of an excess amount of the same within one day after administration thereof, and to releases stably a constant amount of the physiologically active substance for a long time. The present invention is to provide a simple and convenient process for producing uniform sustained-release microcapsules which maintain physiological activity of the physiologically active substance, suppress initial release, and release stably a constant amount of the physiologically active substance.
[0008] The present invention have intensively studied to solve the above problems and, as a result, have found that in a process for producing sustained-release microcapsules of a water-soluble physiologically active substance, it is possible to produce very useful sustained-release microcapsules which suppress initial release of an excess amount of the physiologically active substance right after administration and release stably a constant amount of the physiologically active substance for a long time, by adding about 3% to about 30% of a fat and oil to an organic solvent solution of said biodegradable polymer and using the thus obtained uniform solution as an oil phase. Further diligent studies based on this finding have reached the accomplishment of the present invention.

Problems solved by technology

Most of the microcapsules so far reported have the following drawbacks: (1) in the manufacturing process, the amount of the water-soluble drug leaked to the outer aqueous phase is relatively large to invite a relatively low entrapment ratio of the drug, (2) the resulting microcapsules are generally porous and cause a relatively large initial release, and (3) in the manufacturing process, the physiologically active substance is denatured to invite insufficient bioavailability.
Thus, at the present stage, sustained release of the drug over a desirable long period have not yet been succeeded.
However, there is no suggestion on application to the other bases nor on preparation of microcapsules using a solution of the active ingredient.
However, there is no description on a process for producing microcapsules using a solution of a drug as an inner aqueous phase nor on a method using metal complex of a water-soluble physiologically active peptide.
However, there is no description on a process for producing microcapsules using a solution of a drug as an inner aqueous phase nor on a method using metal complex of a water-soluble physiologically active peptide.

Method used

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  • Process for producing sustained-release preparation
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  • Process for producing sustained-release preparation

Examples

Experimental program
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Effect test

working example 1

[0171] In distilled water 1 ml were dissolved (S)-4-(4-guanidinobenzoylami-no)acetyl-3-[3-(4-guanidinobenzoyl-amino)]propyl-2-oxopiperazine-1-acetic acid (hereinafter, briefly referred to as Compound A) hydrochloride 500 mg and L-arginine 150 mg to give an inner aqueous phase. In methylene chloride 7.5 ml were dissolved lactic acid / glycolic acid copolymer (lactic acid / glycolic acid=50 / 50 (mole %), weight-average molecular weight 8,000) 3850 mg and vitamin E 500 mg to give an oil phase. The oil phase was added to the inner aqueous phase, and the mixture was emulsified with small homogenizer (Polytron) to give a W / O type emulsion. The W / O emulsion was emulsified in 0.1% PVA solution 800 ml (an outer aqueous phase) containing 2.7% NaCl which was cooled to 15.degree. C. with using homomixer to give a W / O / W type emulsion. Then, the W / O / W type emulsion was slowly stirred with a conventional propeller agitator for 3 hours. After hardening of the microcapsules with evaporation of methylene ...

working example 2

[0172] In distilled water 1 ml were dissolved Compound A hydrochloride 500 mg and L-arginine 150 mg to give an inner aqueous phase. In methylene chloride 8 ml were dissolved lactic acid / glycolic acid copolymer (lactic acid / glycolic acid=50 / 50 (mole %), weight-average molecular weight: 8,000) 4100 mg and vitamin E 250 mg to give an oil phase. The oil phase was added to the inner aqueous phase, and the mixture was emulsified with small homogenizer (Polytron) to give a W / O type emulsion. The W / O emulsion was emulsified in 0.1% PVA solution 800 ml (an outer aqueous phase) containing 2.7% NaCl which was cooled to 15.degree. C. with using homomixer to give a W / O / W type emulsion. Then, the W / O / W type emulsion was slowly stirred with a conventional propeller agitator for 3 hours. After hardening of the microcapsules with evaporation of methylene chloride, the microcapsules were collected by centrifugation. The collected microcapsules were washed with purified water, to which was added manni...

working example 3

[0173] In distilled water 2 ml were dissolved Compound A hydrochloride 750 mg and L-arginine 150 mg to give an inner aqueous phase. In methylene chloride 10 ml were dissolved lactic acid / glycolic acid copolymer (lactic acid / glycolic acid=50 / 50 (mole %), weight-average molecular weight: 9,000) 3600 mg and vitamin E 500 mg to give an oil phase. According to a similar method described in Working Example 2 the W / O type emulsion was prepared, and thereafter the W / O / W type emulsion was prepared, and finally freeze dried microcapsules was prepared. In the prepared microcapsules, content of arginine and vitamin E was respectively 1.5% (w / w) and 10% (w / w).

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Abstract

The present invention is to provide sustained-release microcapsules which contains high amount of a drug, suppresses initial release and shows stable release, and the production method of which comprises adding a physiologically active substance to biodegradable polymer in an organic solvent containing a fat and oil (in particular, vitamin E) and dispersing and emulsifying the mixture.

Description

[0001] The present invention relates to a sustained-release microcapsule which suppresses initial release of an excess amount of a physiologically active substance right after administration of the microcapsule and releases stably a constant amount of the physiologically active substance for a long time from right after administration of the microcapsule, and a production method thereof.[0002] On sustained-release microcapsules of various physiologically active polypeptides or low molecular water-soluble drugs, many reports have been made [Critical Reviews in Therapeutic Drug Carrier Systems, 12, 1-9 (1995); JP-A H2(1990)2-503315; EP-A-0586238; J. Pharm. Sci., 75, 750-755 (1986); JP-A S57(1987)-118512]. Most of the microcapsules so far reported have the following drawbacks: (1) in the manufacturing process, the amount of the water-soluble drug leaked to the outer aqueous phase is relatively large to invite a relatively low entrapment ratio of the drug, (2) the resulting microcapsule...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/16A61K9/52A61K31/495
CPCA61K9/1617A61K9/1647A61K31/495Y10S514/937Y10S514/938Y10S514/962Y10S514/963
Inventor SHIGEYUKI, TAKADAKEIKO, TAIRASUSUMU, IWASA
Owner TAKEDA PHARMA CO LTD
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