Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-11-14
2002-06-04
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S401000, C424S423000, C424S426000, C424S499000, C424S501000, C424S502000, C424S422000, C424S451000
Reexamination Certificate
active
06399103
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method of producing a sustained-release preparation comprising a physiologically active polypeptide.
BACKGROUND ART
It is known that physiologically active polypeptides or their derivatives exhibit a variety of pharmacological activities in vivo. Some of these have been produced on a large scale by utilizing
Escherichia coli
, yeasts, animal cells or host animals such as goat and hamsters using recently developed genetic engineering and cell technology, and put to medicinal use. However, these physiologically active polypeptides must be frequently administered because of the generally short biological half-life. The repeated injections takes a significant physical burden on patients.
For instance, growth hormone (hereafter sometimes referred to as GH), a representative hormone which is originally produced and secreted in the anterior portion of the pituitary gland, is a physiologically active polypeptide having widely diverse physiological activities such as promotion of growth in the body, metabolism of glucose and lipids, anabolism of protein, and cell proliferation and differentiation. And GH is produced on a large scale by utilizing
Escherichia coli
using genetic recombination technology, and put to medicinal use clinically and worldwidely. However, GH must be frequently administered in order to maintain an effective blood concentration because of the short biological half-life. Especially, in the case of pituitary dwarfism, a daily subcutaneous administration to infants or young patients over a long period of time ranging from a few months to at least 10 years is conducted practically.
To overcome this problem, various attempts have been made to develop a sustained-release preparation comprising a physiologically active polypeptide.
JP-A 3055/1996 (EP-A 633020) discloses a method of producing a sustained-release preparation which comprises permitting a water-soluble polypeptide to permeate into a biodegradable matrix comprising a biodegradable polymer and a metal salt of a fatty acid in an aqueous solution, and a sustained-release microcapsules (hereafter sometimes referred to as MC) prepared by this method.
JP-A 217691/1996 (WO 96/07399) discloses production of a water-insoluble or slightly water-soluble polyvalent metal salt by using a water-soluble peptide type of physiologically active substance and an aqueous solution of zinc chloride etc., and a method of producing a sustained-release preparation containing this salt and a biodegradable polymer.
WO 94/12158 discloses addition of a polymer erosion rate modulating agent such as zinc hydroxide in an amount of 0.1 to 30% (w/w) relative to the polymer to a polymer solution, as a method of producing a sustained-release preparation comprising human GH and biodegradable polymer. This publication further discloses a method of producing MC as porous particles by spraying a solution of human GH and a polymer in an organic solvent into liquid nitrogen with biological activity retained.
WO 92/17200 and Nature Medicine, Vol. 2, p. 795 (1996) disclose a method of producing a sustained-release preparation by using a zinc salt of human GH.
WO 95/29664 discloses a method of producing MC which comprises the steps of dispersing a metal salt such as zinc carbonate in a solid state in a polymer solution, adding a physiologically active substance such as hormones, and dispersing the physiologically active substance and a metal cation component separately through a biodegradable polymer.
Although, as described above, various attempts have been made to produce a sustained-release preparation with a physiological activity of a physiologically active polypeptide retained, a clinically satisfying preparation has not been obtained yet since some physiologically active polypeptides have problems such as a low entrapment ratio of the physiologically active polypeptide in the preparation, an excess release at an initial stage after administration, an unattained constant release over a long period of time, and an unretained satisfying blood concentration over a long period of time. Further, production methods, in many cases, are not suitable for industrialization which premises a large-scale production in the present situation.
DISCLOSURE OF INVENTION
Through intensive investigation to resolve the above problems, the present inventors found that co-presence of lactic acid/glycolic acid copolymer (hereafter sometimes referred to as PLGA) used as a MC base and zinc oxide in an organic solvent unexpectedly provides dissolution of zinc oxide which itself is insoluble in an organic solvent, and yields PLGA-zinc oxide complex efficiently in high contents, and that a direct dispersion of a physiologically active polypeptide in a solution of the PLGA-zinc oxide complex in an organic solvent and subsequent molding yields a sustained-release preparation having excellent properties such as an enhanced entrapment ratio of the physiologically active polypeptide, a reduced initial burst after administration, and an excellent sustained-release. Further, the present inventors found that this production method has reduced a number of steps and is a quite suitable method for industrialization. After further investigations, the present inventors developed the present invention.
Namely, the present invention relates to
(1) a method of producing a sustained-release preparation which comprises dispersing a physiologically active polypeptide into a solution of a biodegradable polymer and zinc oxide in an organic solvent, followed by removing the organic solvent;
(2) the method according to the above (1), wherein the physiologically active polypeptide is growth hormone;
(3) the method according to the above (1), wherein the biodegradable polymer is lactic acid/glycolic acid copolymer;
(4) the method according to the above (3), wherein a molecular composition ratio of lactic acid/glycolic acid in the lactic acid/glycolic acid copolymer is about 85/15 to about 50/50;
(5) the method according to the above (3), wherein the weight-average molecular weight of the lactic acid/glycolic acid copolymer is about 8,000 to about 20,000;
(6) the method according to the above (1), wherein the content of zinc relative to the biodegradable polymer in the organic solvent solution is about 0.001 to about 2% by weight;
(7) the method according to the above (1), wherein the mean particle diameter of the sustained-release preparation is about 0.1 to about 300 &mgr;m;
(8) the method according to the above (1), wherein the sustained-release preparation is for injection;
(9) the method according to the above (1), wherein an o/w emulsion comprising a dispersion prepared by dispersing growth hormone into a solution of lactic acid/glycolic acid copolymer and zinc oxide in an organic solvent as an oil phase is subjected to in-water drying;
(10) the method according to the above (1), wherein the preparation is a microcapsule;
(11) a solution of lactic acid/glycolic acid copolymer and zinc oxide in an organic solvent;
(12) a lactic acid/glycolic acid copolymer-zinc oxide complex which is soluble in an organic solvent and which is obtained by co-presence of lactic acid/glycolic acid copolymer and zinc oxide in an organic solvent;
(13) a dispersion which is prepared by dispersing a physiologically active polypeptide into a solution of lactic acid/glycolic acid copolymer and zinc oxide in an organic solvent;
(14) the dispersion according to the above (13), wherein the physiologically active polypeptide is growth hormone; and
(15) the sustained-release preparation which is produced by the method according to the above (1).
Preferable examples of the biodegradable polymers used in the present invention include polymers synthesized from one or more &agr;-hydroxycarboxylic acids (e.g., glycolic acid, lactic acid), hydroxydicarboxylic acids (e.g., malic acid), hydroxytricarboxylic acids (e.g., citric acid) etc. by catalyst-free dehydration condensation polymerization and having a free terminal carboxyl group, mixtures thereof, poly-&agr;-cyanoacrylates, po
Iwasa Susumu
Misaki Masafumi
Yamagata Yutaka
Chao Mark
Page Thurman K.
Ramesh Elaine M.
Takeda Chemical Industries, Inc.
Tran S.
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