Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-07-09
2001-09-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S451000, C424S452000, C424S457000, C514S937000, C514S938000, C514S962000, C514S963000, C514S002600
Reexamination Certificate
active
06287587
ABSTRACT:
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
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 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.
In JP-A S61(1986)-63613, improvement of sustained release of microspheres was reported. That is, there is described that for the purpose of preventing decrease of release rate of the active ingredient a certain hour after administration of microspheres whose base is polylactic acid, in an organic solvent of polylactic acid to which the active ingredient is dispersed, an oil soluble additive (medium chain fatty acid triglyceride, a lower fatty acid triglyceride, etc.) which is soluble in said solvent and which is biodegradable is uniformly dissolved. However, there is no suggestion on application to the other bases nor on preparation of microcapsules using a solution of the active ingredient.
In JP-A H8(1996)-151321 [EP-A-0709085], there is disclosed microcapsules which contains an amorphous type water-soluble physiologically active substance and polymer, and which are produced from a S/O/W type emulsion. 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.
In EP 0765660, there is disclosed microcapsules which contains an amorphous type 2-piperazinone-1-acetic acid derivative, and in a production method thereof, a S/O/W type emulsion is employed. 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.
In general, in a process for producing microcapsules of a water-soluble physiologically active substance, it is more advantageous to employ a W/O type emulsion than a S/O type emulsion where the drug is used as solid substances in view of equivalency of drug content or operation, and it is desired to employ a W/O type emulsion in an industrial manufacture with large scale.
OBJECT OF THE INVENTION
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.
SUMMARY OF THE INVENTION
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.
The present invention relates to
(1) A process for producing a sustained-release microcapsule of a water-soluble physiologically active substance, which comprises forming a w/o type emulsion comprising a solution containing a water-soluble physiologically active substance as an inner aqueous phase and an uniform organic solvent solution containing (i) a biodegradable polymer and (ii) a “fat and oil” as an oil phase, and removing the organic solvent;
(2) A process as described in the above (1), wherein the w/o type emulsion is dispersed in an aqueous phase, and the organic solvent is removed by in-water drying;
(3) A process as described in the above (1), wherein the inner aqueous phase is a solution containing a water-soluble physiologically active substance and a basic substance;
(4) A process as described in the above (1), wherein the water-soluble physiologically active substance is a polypeptide the molecular weight of which ranges from about 200 to about 80,000;
(5) A process as described in the above (1), wherein the water-soluble physiologically active substance is an integrin antagonist;
(6) A process as described in the above (5), wherein the integrin antagonist is a GPIIb/IIIa antagonist;
(7) A process as described in the above (6), wherein the GPIIb/IIIa antagonist is a 2-piperazinone-1-acetic acid derivative represented by the formula (I):
wherein A
1
and A
2
are independently a proton-accepting group or a group convertible into a proton-accepting group, D is a spacer having a 2- to 6-atomic chain optionally bonded through a hetero atom and/or a 5- or 6-membered ring (provided that the 5- or 6-membered ring is counted as 2- or 3-atomic chain, depending on its bonding position), R
1
is a hydrogen atom or hydrocarbon group, R
2
is a hydrogen atom or a residual group formed by removing —CH(NH
2
)COOH from an &agr;-amino acid, or R
1
and R
2
may be combined to form a 5- or 6-membered ring, P is a spacer having a 1- to 10-atomic chain optionally bonded through a hetero atom and/or a 5- or 6-membered ring (provided that the 5- or 6-membered ring is counted as 2- or 3-atomic chain, depending on its bonding position), Y is an optionally esterified or amidated carboxyl group, and n is an integer of 0-8; or a salt thereof;
(8) A process as described in the above (7), wherein the 2-piperazinone-1-acetic acid derivative (I) is (S)-4-(4-guanidinobenzoylamino)acetyl-3-[3-(4-guanidinobenzoylamino)]propyl-2-oxopiperazine-1-acetic acid or a salt thereof;
(9) A process as described in the above (7), wherein the 2-piperazinone-1-acetic acid derivative (I) is (S)-4-(4-guanidinobenzoylamino)acetyl-3-[3-(4-guanidinobenzoylamino)]propyl-2-oxopiperazine-1-acetic acid hydrochloride;
(10) A process as described in the above (7), wherein the 2-piperazinone-1-acetic acid derivative (I) is (S)-4-(4-guanidinobenzoylamino)acetyl-3-[3-(4-guanidinobenzoylamino)]propyl-2-oxopiperazine-1-acetic acid dihydrochloride;
(11) A process as described in the above (1), wherein the biodegradable polymer is an aliphatic polyester;
(12) A process as described in the above (11), wherein the aliphatic polyester is a lactic acid/glycolic acid copolymer;
(13) A process as described in the above (1), wherein the fat and oil is an oil soluble vitamin;
(14) A process as described in the abov
Keiko Taira
Shigeyuki Takada
Susumu Iwasa
Channavajjala Lakshmi S.
Fitzpatrick ,Cella, Harper & Scinto
Page Thurman K.
Takeda Chemical Industries Ltd.
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