Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2000-01-10
2001-07-10
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S426000, C514S002600, C514S021800, C524S017000, C524S021000, C525S450000, C528S354000
Reexamination Certificate
active
06258382
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to biomaterials and, more particularly, it relates to biomaterials using a copolymer composition having an excellent biodegradation as a base and exhibiting excellent sustained-releasing and degradation properties such as that polypeptides or the like having a biological activity can be continuously released for a prescribed life span in vivo.
PRIOR ART
Polypeptides which are the hormones being present in small amount in Living body and acting therein have been known already and, since such polypeptides are now able to be produced in large quantities as a result of the progress of incubating technique in recently years instead of isolation of small amount by extraction or the like from living body, they now occupy an important position in various fields of application to living body.
However, stability of polypeptides in vivo is low and, therefore, their dose and frequency of administration become large for achieving the effect whereby occurrence of side effect and physical and mental burdens in the patients are becoming big. Under such a background, there has been a demand for functional materials which release the drug in a proper amount within a programmed period of time whereby many investigations have been carried out.
For example, aliphatic polyesters having hydroxycarboxylic acid such as polylactic acid, copolymer of lactic acid with glycolic acid, polyhydroxybutyric acid and poly (&egr;-caprolactone) showing a biodegradability in vivo as a basic structure and also polymers such as a copolymer by a combination of the above with p-dioxanone or trimethylene carbonate have been known.
However, affinity of those hydrophobic polymers with a polypeptide having a relatively high hydrophilicity is little and there is a problem that the initial elution of the polypeptide from the surface of the polymer matrix is big. In addition, there is a rate-determining relation between elution of the polypeptide and water permeating into the polymer and the polypeptide is eluted independently of the polymer matrix whereby there is no proportional relation between the required released duration and the degradation time in vivo and such a polymer is not suitable as a sustained-released biomaterial. Even in the case of a low molecular weight polymer in such an extent as an oligomer, its disappearance by degradation takes more than one month and that results in an affection to surrounding tissues. Thus, a difficulty in its application produces another problem.
Moreover, in the aliphatic polyester, the terminal group is a carboxyl group and, therefore, in the case of a basic polypeptide, the terminal group is coordinated with the polypeptide by means of ionic bond, etc. whereby there is still another problem that the polypeptide is not released within an expected period.
In place of such a hydrophobic polymer, the use of collagen, gelatin, albumin, fibrin, hyaluronic acid, alginic acid, etc. having a hydrophilicity has been investigated as well. However, since those materials are natural ones, their component, molecular weight, water retentivity, etc. are not constant. There is another problem in view of immunology that, during the purifying process, the substances having antigenicity cannot be removed completely. Still another problem is that a releasing time of the polypeptide from the polymer matrix is short.
Accordingly, for solving the above-mentioned problems, copolymers exhibiting both hydrophobic and hydrophilic properties of a lactic acid/glycolic acid copolymer or polylactic acid with polyethylene glycol, polypropylene glycol and Pluronic as the materials containing no impurities in the base, having no side effect and showing little affection to the surrounding cells have now been receiving public attention and various investigations have been carried out for them.
As an example for such an art, the Japanese Laid-Open Patent Publication Sho-58/191714 discloses a method where graft block polymer having a minimum average molecular weight of 5,000 which is able to form hydrogel by absorption of water under a circumstance of in water or in vivo is used as a pharmaceutical and veterinary composition. In this art, it is mentioned that a polymer obtained by polymerization of polyethylene glycol of molecular weight of 6,000 or 20,0000 and D,L-lactide or glycolide becomes gel by absorption of water within from 4 to 24 hours. However, for the polymer having such a big hydrophilic segment, the polymer swells and its shape gets to be crumbled and, therefore, adjustment between release of the drug and degradation of the polymer is difficult.
As a prior art, the present inventors have disclosed in the Japanese Laid-Open Patent Publication Hei-02/203861 for a biomaterial in which a reaction product of polylactic acid or a lactic acid/glycolic acid copolymer with polyethylene glycol as a carrier for a bone morphogenetic protein. However, although this material is a polymer which has both hydrophilic and hydrophobic properties being dispersed in water at low temperature while, when heated, being separated therefrom, there is still a problem that the said material is difficult in handling because it is in a pasty or waxy form. In another Japanese Laid-Open Patent Publication Hei-03/45265, the present inventors improved the adhesive property of the materials by blending (1) a lactic acid/glycolic acid copolymer and (2) a reaction product of a lactic acid/glycolic acid copolymer with polyethylene glycol. However, properties inherent to the two polymers strongly appear in terms of release of the drug and degradation of the polymer whereby a satisfactory result has not been achieved yet.
Further, Ronnenberger, B., et al. disclosed the use of a triblock copolymer of a lactic acid/glycolic acid copolymer with polyethylene glycol having a molecular weight of 1,000-10,000 as a biomaterial (
J. Biomed. Mater. Res
., 30, 31 (1996)). This polymer ismade into a filmbymethylene chloride, its handling is good, and its molecular weight distribution obtained by dividing the weight average molecular weight by the number average molecular weight is 1.80-2.86. However, in a polymer where the molecular weight distribution is as broad as more than 1.8, the influence by aliphatic polyesters is appeared strongly and, therefore, the polymer is not suitable as a sustained-released biomaterial because of a poor balance between release of the drug and degradation of the polymer.
As mentioned above, many studies have been carried out up to now for the method where the drug such as polypeptide is contained. in a biomaterial and many proposals based upon them have been available but, at present, any biomaterial which is satisfactory in terms of releasing rate of the drug and also in terms of degradability, safety and practical value of the material has not been found yet.
Problems to be Solved by the Invention
In order to solve the above-mentioned problems, the present inventors have carried out an intensive investigation for developing biomaterials which are biodegradable, have both hydrophobic and hydrophilic properties, particularly exhibit excellent property for giving sustained release of polypeptide having a biological activity, show no xenobiotic reaction in vivo and have no affection to the surrounding tissues.
Means for Solving the Problems
As a result, the present inventors have found that a copolymer which is obtained by the reaction of lactic acid and/or glycolic acid and p-dioxanone with polyethylene glycol as main components can be used as excellent biomaterials for solving the above-mentioned problems when it (the copoleymer)is used carrying polypeptide or the like. Based upon such a finding, the present invention has been accomplished.
Thus, the present invention relates to biomaterials which consist of a copolymer obtained by the reaction of lactic acid and/or glycolic acid and p-dioxanone with polyethylene glycol as main components.
BEST MODE FOR CARRYING OUT THE INVENTION
The biomaterials according to the present invention use a copolymer which is obt
Okada Takao
Saito Naoto
Takaoka Kunio
Kolisch Hartwell Dickinson & McCormack & Heuser
Russel Jeffrey E.
Takai Chemical Co.
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