Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-05-15
2001-07-31
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S422000, C424S489000, C424S499000, C514S002600, C514S003100, C530S350000, C530S389200, C530S388240, C530S399000
Reexamination Certificate
active
06267981
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a sustained-release preparation comprising a biodegradable polymer metal salt and a bioactive polypeptide, and a method of producing thereof.
BACKGROUND ART
It is known that bioactive polypeptides or their derivatives exhibit a variety of pharmacologic activities in vivo. Some of these polypeptides have been produced on a large scale by utilizing
Escherichia coli,
yeasts, animal cells or host animals such as hamsters using recently developed genetic engineering and cell technology, and put to medicinal use. However, these bioactive polypeptides must be frequently administered because of the generally short biological half-life. The repeated injections takes a significant physical burden on patients. To overcome this disadvantage, various attempts have been made to develop sustained-release preparations comprising bioactive polypeptides.
EP-461630 discloses prior art production technologies for sustained-release preparations designed for the enhanced efficiency of entrapment of water-soluble bioactive peptides. These preparations are obtained from an oil/water (o/w) emulsion comprising dissolving a water-soluble bioactive polypeptide, a biodegradable polymer and a fatty acid salt in an organic solvent.
Although various attempts have been made to produce a sustained-release preparation retaining the bioactivity of bioactive polypeptides as mentioned above, there has not been a clinically satisfactory sustained-release preparation with efficiencient entrapment of a bioactive polypeptide into a biodegradable polymer, and suppression of initial drug burst, constant long-term drug release, and so on.
DISCLOSURE OF INVENTION
The present inventors made extensives investigations to resolve the above problems, and found that sustained-release preparations dispersing a bioactive polypeptide in an organic solvent containing a biodegradable polymer pre-converted to a metal salt, and subjecting the resulting dispersion to formulation have unexpected excellent properties such as a surprising enhancement of entrapment of bioactive polypeptides, suppression of initial burst of the polypeptides, constant long-term release, and so on. The present invention has been developed after further elaborations based on the above findings.
The present invention, therefore, is directed to:
(1) a method of producing a sustained-release preparation which comprises dispersing a bioactive polypeptide in an organic solvent containing a biodegradable polymer metal salt, and subjecting the resulting dispersion to formation,
(2) a method according to (1), wherein the metal salt is a polyvalent metal salt,
(3) a method according to (1), wherein the metal salt is selected from the group consisting of a zinc salt and a calcium salt,
(4) a method according to (1), wherein the organic solvent is a mixture of halogenated hydrocarbons and acetonitrile or alcohols,
(5) a method according to (4), wherein the organic solvent mixture ratio of haloganated hydrocarbons to acetonitrile or alcohols is in the range of about 40:1 to about 1:1 (volume/volume),
(6) a method according to (1), wherein the bioactive polypeptide is a hormone,
(7) a method according to (6), wherein the hormone is an insulin,
(8) a method according to (6), wherein the hormone is a growth hormone,
(9) a method according to (1), wherein the bioactive polypeptide is a cytokine,
(10) a method according to (9), wherein the cytokine is an interferon,
(11) a method according to (1), wherein the biodegradable polymer is an aliphatic polyester,
(12) a method according to (11), wherein the aliphatic polyester is an &agr;-hydroxycarboxylic acid polymer,
(13) a method according to (11), wherein the aliphatic polyester is a lactic acid-glycolic acid copolymer,
(14) a method according to (13), wherein the composition ratio (mol %) of lactic acid/glycolic acid of the lactic acid-glycolic acid copolymer is about 100/0 to about 40/60, and the weight-average molecular weight of the lactic acid-glycolic acid copolymer is about 3,000 to about 20,000,
(15) a method according to (1), wherein the sustained-release preparation is a particulate artifact,
(16) a method according to (15), wherein the average particle size of the particulate artifact is about 0.1 &mgr;m to about 300 &mgr;m,
(17) a method according to (1), wherein the sustained-release preparation is for an injection,
(18) a dispersion which comprises a bioactive polypeptide dispersed in an organic solvent containing a biodegradable polymer metal salt,
(19) a sustained-release preparation as produced by the method according to (1),
(20) a sustained-release preparation according to (19), wherein the metal content of the biodegradable polymer metal salt is about 0.01 to about 10% by weight,
(21) a sustained-release preparation according to (19), wherein the concentration of the bioactive polypeptide is about 0.001 to about 30% (w/w), and
(22) a sustained-release preparation according to (19), wherein the bioactive polypeptide is a growth hormone, and so on.
The biodegradable polymer of the present invention has low water soluability or is water-insoluble, and includes aliphatic polyesters, e.g., homopolymers or copolymers synthesized from one or more kinds of &agr;-hydroxycarboxylic acids (e.g., glycolic acid, lactic acid, 2-hydroxybutyric acid, valinic acid, leucic acid, etc.), hydroxydicarboxylic acids (e.g., malic acid, etc.), hydroxytricarboxylic acids (e.g., citric acid, etc.), or their mixtures; poly-&agr;-cyanoacrylic esters, e.g., poly(methyl &agr;-cyanoacrylate), poly(ethyl &agr;-cyanoacrylate), poly(butyl &agr;-cyanoacrylate), etc.; and amino acid polymers, e.g., poly(&ggr;-benzyl-L-glutamate) etc., or their mixtures. The mode of polymerization for these biodegradable polymer may be any of random, block or graft polymerizations technique.
The preferred biodegradable polymers are aliphatic polyesters, e.g., homopolymers or copolymers synthesized from one or more kinds of &agr;-hydroxycarboxylic acids (e.g., glycolic acid, lactic acid, 2-hydroxybutyric acid, etc.), hydroxydicarboxylic acids (e.g., malic acid, etc.) and hydroxytricarboxylic acids (e.g., citric acid, etc.), or their mixtures, and so on.
Among the above-mentioned aliphatic polyesters, the homopolymers and copolymers synthesized from one or more kinds of the &agr;-hydroxycarboxylic acids are preferable in view of biodegradability and biocompatibility. Particularly preferred aliphatic polyesters are copolymers synthesized from two or more kinds of the &agr;-hydroxycarboxylic acids. Furthermore, these copolymers can be used as mixtures.
When the &agr;-hydroxycarboxylic acids are chiral compounds, they may be any of D-, L- and D-, L-configuration. It is preferable that the ratio of the D-/L-configuration (mol %) is in the range of about 75/25 to about 25/75. More preferred is a hydroxycarboxylic acid wherein the ratio of the D-/L-configuration (mol %) is in the range of about 60/40 to about 30/70.
An examples of the above mentioned &agr;-hydroxycarboxylic acid polymer is a lactic acid polymer (hereinafter sometimes referred to as “polylactic acid”).
The &agr;-hydroxycarboxylic acid copolymer includes copolymers of glycolic acid with the other &agr;-hydroxycarboxylic acids such as lactic acid and 2-hydroxybutyric acid.
Preferred &agr;-hydroxycarboxylic acid copolymers are lactic acid-glycolic acid copolymer and 2-hydroxybutyric acid-glycolic acid copolymer.
A particularly preferred &agr;-hydroxycarboxylic acid copolymer is a lactic acid-glycolic acid copolymer.
The polylactic acid may be either D-configuration or L-configuration or a mixture; one with the D-/L-configuration ratio (mol %) of about 75/25 to about 20/80 is preferred. More preferred is a polylactic acid wherein the ratio of the D-/L-configuration (mol %) is in the range of about 60/40 to about 25/75. Most preferred is a polylactic acid wherein the ratio of D-/L-configuration is in the range of about 55/45 to about 25/75.
The polylactic acid preferably has the weight average molecular weight, as defined below, of about 1,500 to about 10,00
Igari Yasutaka
Misaki Masafumi
Okamoto Kayoko
Yamagata Yutaka
Fitzpatrick ,Cella, Harper & Scinto
Page Thurman K.
Seidleck Brian K.
Takeda Chemical Industries Ltd.
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