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Biodegradable biopolymers, method for their preparation and functional materials constituted by these biopolymers

This application is a divisional of application Ser. No. 10/458,277, filed Jun. 11, 2003, the entire specification and claims of which are incorporated herewith by reference.

The present invention relates to a biodegradable biopolymer material, which is degraded while being decomposed by the action of an enzyme and which is thus converted into small molecules and a method for the preparation of the biodegradable biopolymer material as well as a functional material containing the material such as a metal ion-adsorbing material, a sustained release carrier for a useful substance, a biological cell-growth substrate and a biodegradable water-absorbing material.

It is quite a long time since materials consisting of organic polymers and possessing biodegradability came on to the market. In the medical field, there have frequently been used materials, which are biologically decomposed and degraded through the action of an enzyme to thus form small molecules. Materials recently widely put into practical use include, as typical examples, poly(oxy-acids) such as poly(lactic acid) and poly(glycolic acid) among the biodegradable organic polymers and these materials have widely been used as implanting materials to be embedded in the living bodies, materials for the in vivo delivery or carriers for sustained release of medicines.

These poly(lactic acid) and poly(glycolic acid) show excellent resistance to chemicals. Poly(lactic acid) and poly(glycolic acid) are non-toxic and quite susceptible to hydrolysis and accordingly, they have widely been used as materials capable of being decomposed and absorbed in vivo. Moreover, poly(glycolic acid) can be prepared as a very high molecular weight polymer and therefore, it is useful as a material, which should have excellent mechanical or dynamic characteristic properties such as high tensile strength. Specifically, poly(lactic acid) and poly(glycolic acid) have been used as, for instance, biodegradable and bioabsorbable suture.

Moreover, in the medical field, silk sutures from domesticated silkworm have long been used as sutures for surgical operations. The use of the silk fiber from domesticated silkworm as sutures for surgical operations, for the first time, dates away back to the beginning of the eleventh century. The total volume of the sutures traded in this country is equivalent to about six billion yens a year (in 1985), 46% of which corresponds to the volume of the silk sutures. The silk fiber is excellent in, for instance, tensile strength and knot strength and can easily be sterilized. For this reason, the silk fiber has favorably been used as sutures. Therefore, even when judging from the actual conditions of the use of the conventional silk sutures, the silk fiber can quite easily be sterilized, it is never biologically decomposed within a short period of time when embedded in the living body and when it is implanted in the living body, it only insignificantly causes an antigen-antibody reaction with the biological tissues.

The cocoon fiber (the silk fiber) is a protein fiber produced and spun by matured larvae of silkworm. The silkworms are divided into two groups or domesticated silkworms reared in farmhouses and wild type ones. Silk fibroin fibers are those obtained by removing sericin as an adhesive substance, which covers the surface of the cocoon fiber, by treating the cocoon fiber with, for instance, an alkali.

The silk fibers from wild silkworm in general mean those produced and spun by, for instance, Antheraea pernyi, Antheraea yamamai, Antheraea militta, Antheraea assama, Philosamia cynthia ricini and Philosamia cynthia pryeri.

The foregoing silk suture is a non-absorbent material, it is never decomposed within a short period of time and accordingly, it would remain in the living body even after the suture. For this reason, it has been used for the purposes different from those of the threads for suture made from poly(oxy-acids) such as poly(lactic acid) and poly(glycolic acid), which are absorbed in the body and decomposed into water and carbon dioxide within several weeks after the suture.

With respect to the foregoing metal ion-adsorbing material and sustained release carrier for useful substances consisting of the aforementioned biodegradable biopolymer, there has not yet been proposed any product having satisfactory characteristic properties.

As has been discussed above in detail, poly(lactic acid) has widely been used as a biodegradable and bioabsorbable material, but it suffers from a problem in that the production cost thereof is too high. Moreover, poly(glycolic acid) has been used as a biodegradable and bioabsorbable material because of the advantages described above. On the other hand, it is too expensive, has high crystallizability, is too hard and is inferior in the compatibility with soft tissues. Moreover, it also suffers from problems such that the rate of decomposition thereof cannot easily be controlled and that the control of the biodegradability thereof is likewise difficult even if this material is chemically modified.

Further, fibrous poly(lactic acid) has a glass transition temperature similar to that of, for instance, polyethylene terephthalate fiber and accordingly, the poly(lactic acid) fibers possess mechanical properties quite resemble to those observed for the polyethylene terephthalate fibers. In this respect, however, poly(lactic acid) or the like has a crystallization velocity slower than that observed for polyethylene terephthalate and fibers of, for instance, poly(lactic acid) are not sufficiently oriented and are not satisfactorily crystallized even when they are passed through the usual spinning and/or orientation steps. For this reason, additional problems arise when putting them into practical use, for instance, the tensile strength and dimensional stability of poly(lactic acid) are insufficient.

In addition, the higher the molecular weight of the foregoing poly(oxy-acids), the slower the rate of the decomposition thereof. In this connection, it is necessary to produce poly(lactic acid) and poly(glycolic acid) whose molecular weight is controlled for the control of the decomposition speed of these polymers, but the production of such polymers requires much labor and the use of highly advanced techniques requiring a great deal of skill. For this reason, the use of poly(oxy-acids) has presently been limited to medical applications such as absorbent sutures and cosmetic applications and accordingly, there has strongly been desired for the establishment of a production process, which is not expensive or is economical and does not require any skilled technique.

As has been discussed above, the suture of silk differs from sutures of poly(oxy-acids) such as poly(lactic acid) and poly(glycolic acid), which are finally decomposed into water and carbon dioxide in the living body. Accordingly, there has strongly been desired for the development of a biodegradable material whose biodegradability in vivo can be controlled, which does not suffer from any problem concerning the biological safety and whose production cost is very low and which can biologically be decomposed without producing any cytotoxic products, does not form any harmful substance such as formaldehyde as a by-product and which is thus safe to the biological tissues.

The silk protein as a biopolymer from an insect, which can be used as a raw material for the foregoing silk suture is a naturally occurring polymer material produced through the biosynthesis of silkworms, excellent in the biological compatibility with the biological tissues and has good molding properties. Therefore, if by-products of silk obtained in the process for preparing raw silk and silk products are used as starting material for the sutures, one can save the cost of raw materials. Moreover, silk proteins include a large number of active sites rich in chemical reactivity and therefore, the fields of applications thereof (such as the use as medical materials) can considerably and widely be extended if a technique, which permits the control of the biodegradability or biochemical properties of silk fibroin through, for instance, hybrid processings and/or chemical modification treatments, can be developed. For this reason, there has strongly been desired for the development of a novel biodegradable material, which can effectively be used in the medical field, using such biopolymers from insects as starting materials and secondary substances capable of being combined (hereunder also referred to as hybrid or hybridized with the former (composite (materials)).

Accordingly, it is generally an object of the present invention to solve the problems associated with the foregoing conventional techniques and more specifically to provide a biodegradable biopolymer material consisting of a silk protein excellent as a polymeric substrate; a hybridized biodegradable biopolymer material comprising the silk protein and a specific secondary substance hybridized together and having unique characteristic properties, which are not observed for the silk protein alone; a method for the preparation of the same; and functional materials consisting of the foregoing biodegradable biopolymer materials, such as a metal ion-adsorbing material, a sustained release carrier for a useful substance, a biological cell-growth substrate and a biodegradable and water absorbable material.

The silk fibers from domesticated silkworm and those from wild silkworm are fibrous materials produced and spun by silkworm and they have strong resistance to chemicals even to the action of, for instance, chemical agents and enzymes since they have fibrous structures as determined by the X-ray diffraction analysis. This is the reason why the silk fiber from domesticated silkworm is classified as the biologically non-absorbent material. Thus, the inventors of this invention have conducted various studies to provide a material comprising such a silk protein having good biodegradability while making the most use of the excellent biochemical properties of the silk protein and to develop a technique for preparing a novel material whose biodegradability can be controlled by using silk fibroin from domesticated silkworm as a starting material and combining the starting material with a specific secondary substance. The inventors have further inspected for the degradation behavior observed for a novel composite material obtained during the process for the development when acting an enzyme on the composite material, have found that a biopolymer material possessing biodegradability can be provided and have thus completed the present invention.

The biodegradable biopolymer material of the present invention is characterized in that it consists of silk fibroin from domesticated silkworm; silk fibroin from wild silkworm; a composite material comprising silk fibroin from domesticated silkworm and silk fibroin from wild silkworm; or a composite material comprising either silk fibroin from domesticated silkworm or silk fibroin from wild silkworm and at least one secondary substance selected from the group consisting of cellulose, chitin, chitosan, chitosan derivatives, keratin from wool and polyvinyl alcohol.

In this respect, the biodegradable biopolymer material may be one capable of being biologically degraded by the action of at least one enzyme selected from the group consisting of proteases, collagenases and chymotrypsin.

The shape of the biodegradable biopolymer material may be any one such as a fibrous, membrane-like, powdery, gel-like or porous shape.