Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From carboxylic acid or derivative thereof
Reexamination Certificate
2001-06-12
2004-06-29
Hightower, P. Hampton (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From carboxylic acid or derivative thereof
C528S359000, C525S411000, C525S413000, C525S415000
Reexamination Certificate
active
06756472
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing a novel biodegradable polymer.
BACKGROUND ART
EP-A-0839525 discloses a sustained-release preparation composed of a physiologically active peptide or its salt and a biodegradable polymer, and its production process, and the biodegradable polymer described in the publication is produced by subjecting a biodegradable polymer produced by a known ring-opening polymerization process to a hydrolysis process which itself is known.
The ring-opening polymerization process uses a cyclic dimer of lactic acid by adding a catalyst while heating, and this process is described by J. H. R. Woodland et al. in the Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 16, page 897 (1973). In addition, a process in which this is performed using a catalyst from a cyclic diester compound such as a lactide or glycolide is described in the Encyclopedic Handbook of Biomaterials and Bioengineering Part A: Materials, Vol. 2, Marcel Dekker, Inc. (1995).
Further, a process of producing a block copolymer in which one polylactide and three dextrans are bonded through citric acid by polymerization of tribenzyl citrate and lactide is described in WO 95/03356.
Since polymers obtained by the above known ring-opening polymerization process do not always have a free carboxyl group at the &ohgr;-end of the resulting polymer, it is difficult to efficiently incorporate a physiologically active substance into a sustained-release preparation. In addition, it is difficult to adjust the molecular weight of the target biodegradable polymer at the raw material loading stage.
Thus, there has been a need to establish a process of producing a biodegradable polymer that allows a physiologically active substance to be efficiently incorporated into a sustained-release preparation and facilitates easy adjustment of the molecular weight of the target biodegradable polymer.
In addition, there has also been a need to establish a production process suited for a biodegradable polymer used in a sustained-release preparation that releases a physiologically active substance over a long time of at least about six months or more.
DISCLOSURE OF THE INVENTION
As a result of intensive study to solve the above problems, the present inventors found a production process of a biodegradable polymer having a free carboxyl group at the &ohgr;-end comprising subjecting a cyclic ester compound to a polymerization reaction in the presence of a hydroxymonocarboxylic acid derivative in which the carboxyl group is protected or a hydroxydicarboxylic acid derivative in which the carboxylic acid groups are protected, and subjecting the resulting polymer having a protected carboxyl group at the &ohgr;-end to a deprotecting reaction. The present inventors further studied and, thus, the present invention was accomplished.
Namely, the present invention relates to the following:
(1) A process for producing a biodegradable polymer having a free carboxyl group at the &ohgr;-end comprising:
subjecting a cyclic ester compound to a polymerization reaction in the presence of a hydroxymonocarboxylic acid derivative in which the carboxyl group is protected, or a hydroxydicarboxylic acid derivative in which the carboxyl groups are protected, and
subjecting the resulting polymer having a protected carboxyl group at the &ohgr;-end to a deprotecting reaction;
(2) The process described in (1), wherein the hydroxymonocarboxylic acid derivative in which the carboxyl group is protected is glycolic acid in which the carboxyl group is protected, L-lactic acid in which the carboxyl group is protected, D-lactic acid in which the carboxyl group is protected, or DL-lactic acid in which the carboxyl group is protected;
(3) The process described in (1), wherein the protecting group of the hydroxymonocarboxylic acid in which the carboxyl group is protected is a tert-butyl group or benzyl group;
(4) The process described in (1), wherein the hydroxydicarboxylic acid derivative in which the carboxyl groups are protected is dibenzyl tartronate or di-tert-butyl 2-hydroxyethylmalonate;
(5) The production process described in (1), wherein the cyclic ester compound is a cyclic monoester compound or a cyclic diester compound;
(6) The production process described in (1), wherein the deprotecting reaction is an acidolysis reaction;
(7) A process for producing a biodegradable polymer having a free carboxyl group at the &ohgr;-end comprising: subjecting a cyclic ester compound to a polymerization reaction in the presence of a hydroxymonocarboxylic acid derivative in which the carboxyl group is protected, and subjecting the resulting polymer having a protected carboxyl group at the &ohgr;-end to a deprotecting reaction;
(8) The process described in (7), wherein an acid hydrolysis reaction is carried out following the deprotecting reaction;
(9) The process described in (1) or (7), wherein the biodegradable polymer is a biodegradable polymer that is used in a sustained-release preparation that releases a physiologically active substance over the course of at least about six months;
(10) A biodegradable polymer obtained by the production process described in (1) or (7);
(11) A sustained-release preparation containing the biodegradable polymer described in (10);
(12) The sustained-release preparation described in (11) further containing a physiologically active substance; and
(13) The sustained-release preparation described in (12), wherein the physiologically active substance is an LH-RH derivative or its salt.
BEST EMBODIMENT FOR CARRYING OUT THE INVENTION
There are no particular restrictions on the physiologically active substance used in the present invention provided it is useful pharmacologically; it may be a non-peptide compound or peptide compound. Examples of non-peptide compounds include agonists, antagonists and compounds having enzyme inhibitory action. In addition, examples of peptide compounds preferably include physiologically active peptides having a molecular weight from about 300 to about 400,000, preferably from about 400 to about 30,000, more preferably from about 500 to about 25,000, and particularly preferably from about 500 to about 20,000.
Examples of the physiologically active peptides include leuteinizing hormone releasing hormone (LH-RH) insulin, somatostatin, growth hormone, growth hormone releasing hormone (GH-RH), prolactin, erythropoietin, adrenocortical hormone, melanocyte stimulating hormone, thyroid hormone releasing hormone, thyroid stimulating hormone, leuteinizing hormone, follicle-stimulating hormone, vasopressin, oxytocin, calcitonin, gastrin, secretin, pancreozymin, cholestokinin, angiotensin, human placental lactogen, human chorionic gonadotropin, enkephalin, endorphin, kyotorphin, tuftsin, thymopoietin, thymosin, thymosthymlin, thymic humoral factor, serum thymic factor, tumor necrosis factor, colony stimulating factor, motilin, dynorphin, bombesin, neurotensin, caerulein, bradykinin, atrial natriuretic factor, neural growth factor, cell growth factor, neurotrophic factor and peptides having endoserine antagonistic action, their derivatives as well as their fragments or derivatives of their fragments.
The physiologically active peptide used in the present invention may itself be a pharmacologically acceptable salt. In the case the physiologically active peptide has a basic group such as an amino group, examples of such salts include the salts of inorganic acids (e.g., carbonic acid, bicarbonic acid, hydrochloric acid, sulfuric acid, nitric acid and boric acid) and organic acids (e.g., succinic acid, acetic acid, propionic acid and trifluoroacetic acid).
In the case the physiologically active peptide has an acidic group such as a carboxyl group, examples of such salts include the salts of inorganic bases (e.g., alkali metals such as sodium and potassium, and alkaline earth metals such as calcium and magnesium), and organic bases (e.g., organic amines such as triethylamine and basic amino acids such as arginine). In addition, the physiologically active peptide may form a metal complex compound
Hata Yoshio
Igari Yasutaka
Hampton Hightower P.
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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