Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From carboxylic acid or derivative thereof
Reexamination Certificate
1998-12-23
2002-04-16
Dodson, Shelley A. (Department: 1616)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From carboxylic acid or derivative thereof
C424S078080, C424S451000, C424S457000, C528S322000, C528S328000, C528S363000
Reexamination Certificate
active
06372880
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a copolymer which is a novel compound useful as a base material for a sustained releasing drug and which has both of a succinimide unit and/or an aspartic acid unit as well as a lactic acid unit and/or a glycolic acid unit, and a process for preparing the above copolymer.
2. Description of the Related Art
Heretofore, there has been the approach of applying a biologically absorbable polymer to a DDS (a drug delivery system). The DDS means a system in which a drug including the biologically absorbable polymer as a base material can be sustaining-released by a proper technique.
Here, typical examples of the above proper technique include a method of blending the biologically absorbable polymer with the drug, a method of microcapsulating the drug with the biologically absorbable polymer, and a method of immobilizing the drug on the biologically absorbable polymer.
Typical examples of the above biologically absorbable polymer include poly-&agr;-hydroxy acids such as a polylactic acid (PLA) and a polyglycolic acid (PGA).
For example, Japanese Patent Application Laid-Open No. 64824/1987 discloses a method which comprises subjecting, to a ring opening polymerization, glycolide (GLD) which is a cyclic dimer of glycolic acid and lactide (LTD) which is a cyclic dimer of lactic acid, thereby obtaining a low-molecular weight polydisperse lactic acid-glycolic acid copolymer (PLGA) useful as the base material for a sustained releasing drug.
On the other hand, in the DDS just described, the sustained releasing behavior of the drug in which the biologically absorbable polymer is used as the base material of the sustained releasing drug is known to variously change on the basis of a specific interaction between the drug and the biologically absorbable polymer. In recent years, therefore, it has been desired to make the drugs having various structures sustained releasable, but only by selecting the biologically absorbable polymer as the base material from already existent polymers such as PLGA, it is often difficult to design the DDS which can express a desired sustained release speed, sustained release period, sustained release pH and the like.
In view of such a technical background, a novel biologically absorbable polymer material has been desired as the base material for the sustained releasing drug.
Furthermore, when the sustained releasing drug having a form of microspheres, microcapsules or the like is manufactured by an emulsion method which has heretofore been used, an organic solvent is used and hence a solvent removal step is required, so that it is necessary to validate that the remaining solvent in the drug is at such a level as to be substantially acceptable.
Accordingly, there is also a demand that a drug formulation can be achieved without using any solvent by thermally melting the polymer and then mixing it with the drug. However, for example, an optically active PLA has a melting point of 160 to 180° C., and if it is molten at this temperature, there exists a problem that the drug thermally decomposes. If the molecular weight of the PLA is reduced, the melting point also lowers, but according to the knowledge of the present inventors, the PLA has a high melting point of 120° C. or more even at a molecular weight of about 2000 to 3000. On the other hand, if the molecular weight of the PLA is less than the above level, the PLA becomes a syrup state, which makes it difficult to prepare the microspheres or the like. Therefore, it has been desired that the biologically absorbable polymer which can be used particularly as the base material for the sustained releasing drug among medical materials has a low melting point.
Ganpat L. Jain et al. disclose a certain kind of random copolymer of lactic acid and aspartic acid [Ganpat L. Jain et al., Makromol. Chem., Vol. 182, p. 2557-2561 (1981)]. Herein, Jain et al. describe a technique in which aspartic acid and lactic acid are subjected to dehydration-polycondensation at an aspartic acid/lactic acid ratio of 2:1 to 0.5:1 at 150° C. under reduced pressure for 5 hours to obtain a lactic acid-aspartic acid copolymer of aspartic acid:lactic acid=9:1 to 1.77:1.
However, when lactic acid is copolymerized with aspartic acid by this technique, a low-molecular weight random copolymer having a wide molecular weight distribution is merely obtained, and its yield is also low. In addition, this polymer has a high melting point, and it is poor in melting workability and moldability and its use as a medical material is restricted.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a novel copolymer and process for preparing the same, which is suitable as, for example, a base material for a sustained releasing drug, can typically be softened or molten in such a low temperature range that a drug for use in a DDS does not thermally decompose, is an unsticky solid at ordinary temperature (e.g., 25° C., or less than 40° C.), and is soluble in various kinds of solvents.
The present inventors have intensively investigated with the intention of achieving the above objects, and as a result, it has been found that when aspartic acid is heated together with lactide, glycolide or the like to perform polymerization, a novel biologically absorbable copolymer having both of a hydroxycarboxylic acid unit and a succinimide unit in its structure can be obtained, and this copolymer is solid at ordinary temperature, is molten at 100° C. or less, is soluble in various kinds of solvents, and shows a particular hydrolysis behavior. In consequence, the present invention has been completed.
That is to say, the present invention is directed to a copolymer having a weight-average molecular weight of 1,000 to 100,000 which comprises, as repeating structure units, both of a succinimide unit represented by the structural formula (1)
and a hydroxycarboxylic acid unit represented by the structural formula (2)
wherein R is a methyl group or a hydrogen atom.
Furthermore, the present invention is directed to a process for preparing a copolymer which comprises a polymerization step of heating a mixture of aspartic acid and a cyclic ester compound to obtain the copolymer having both of a succinimide unit and a hydroxycarboxylic acid unit as repeating structural units.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The structure of a copolymer according to the present invention which has at least both of a succinimide unit and a hydroxycarboxylic acid unit as repeating structure units can be confirmed by a known analytical means such as a nuclear magnetic resonance (NMR) spectrum measurement or an infrared absorption (IR) spectrum measurement.
For example, according to the IR spectrum measurement, there can be observed characteristic absorptions of a carbonyl bond of the succinimide unit as well as another carbonyl bond of a lactic acid unit and/or a glycolic acid unit.
Furthermore, for example, according to the NMR spectrum measurement, there can be clearly confirmed peaks derived from a methylene proton and a methine proton of the succinimide unit as well as peaks derived from a methyl proton and a methine proton of the lactic acid unit and/or a methylene proton of the glycolic acid unit. When an NMR measuring device having a high resolving power is used, there can be slightly observed fine peaks such as peaks derived from a proton of an amide group and a methyl proton adjacent to the amide group as well as peaks derived from branches and chain sequences (inclusive of groups adjacent to the succinimide unit, the aspartic acid unit, the lactic acid unit and/or the glycolic acid unit).
A typical example of the copolymer according to the present invention is a copolymer having a highly dimensional structure which is called a block polymer, a graft polymer, a graft block polymer or a hyper branched polymer in this polymeric chemical field. More concretely, the example of the copolymer is a copolymer having a structure in which a polysuccinimide segment mainly havi
Asou Yukiko
Shinoda Hosei
Tamatani Hiroaki
Burns Doane Swecker & Mathis L.L.P.
Dodson Shelley A.
Mitsui Chemicals Inc.
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