Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active...
Reexamination Certificate
1999-11-24
2002-01-01
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
C424S422000, C424S484000, C514S801000, C514S944000
Reexamination Certificate
active
06335007
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a collagen gel, its production process, a medical material in which it is used or a kit for its production.
BACKGROUND ART
Medical materials in the form of hemostyptics or adhesives for living body must be provided with general requirements including rapid adhesion in the presence of water, adhesion at body temperature and normal pressure, being able to be sterilized and absence of histotoxicity, able to adequately stop bleeding on wound surfaces, and being flexible after curing and not inhibiting healing. Different adhesives have been used clinically as conventional materials that satisfy these requirements to a certain extent, examples of which include synthetic adhesives such as cyanoacrylate compounds such as methyl-2-cyanoacrylateor isobutyl-2-cyanoacrylate, and polyurethane having an isocynate group at the terminal, and natural adhesives such as fibrin paste that promotes wound healing by forming insoluble fibrin from soluble fibrinogen, and gelatin-based adhesives in which gelatin is crosslinked with formaldehyde or resorcinol. In addition, Japanese Provisional Patent Publication No. 7-163860 describes a gelatin-based adhesive in which gelatin and polyanion are crosslinked with carbodiimide.
Cyanoacrylate adhesives have the shortcoming of the tissue opening up again after several days once it has been adhered, as a result that cell dies due to robbing the tissue of water during polymerization, that adhesion procedure is difficult due to the rapid reaction rate, that it is required one year to be absorbed into the tissue due to the hard reaction product formed following adhesion, and that the adhered site lacks flexibility in the manner of living body tissue (see Ikada, Y. et al. ed., Biocompatible Materials, Japan Standards Association, 1993, p. 117)., thereby worsening the wound, and the problem of tissue damage caused by formaldehyde that is formed accompanying decomposition. Isocyanate adhesives had the shortcoming of requiring considerable time for the wound surface to return to normal as a result of remaining in the tissue for one year or more. Although fibrin pastes solve the inherent shortcoming of synthetic adhesives of foreign body reactivity with the tissue, their adhesive strength is somewhat weak and have a complex procedure as a result of having to mix 2 or 4 liquids before use. Moreover, since the material is of human blood origin, there is the risk of HIV, HBs or other viral infection. In addition, since the fibrin begins to dissolve 2-3 days after applied to the wound site and is absorbed into the tissue, despite having to adhere the wound site for a fixed period of time, there was the problem of cases in which the absorption of fibrin paste was faster than healing of the wound (see Pharma Medica's off-print, Pharma Medica Vol. 14, 1996, Medical Review Publishing, p. 157).
Gelatin-based adhesives used in the clinical steps have a limited range of use due to toxicity of the formaldehyde or resorcinol used as crosslinking agent. In addition, although the invention of Japanese Provisional Patent Publication No. 7-163860 uses a crosslinking agent having low toxicity, this invention had such shortcomings that it is typically necessary to adjust consistency by heating an aqueous gelatin solution used as the material to 40° C. or higher during the production of these gelatin-based adhesives, considerable time is required for gelation in order to crosslink the short gelatin molecules,and it is required to use a large amount of crosslinking agent.
DISCLOSURE OF INVENTION
The present invention provides a material suitable for use as a medical material that is adhered easily, has powerful adhesive strength, eliminates the risk of viral infection, has low toxicity for the living body, forms an elastic adhesive layer after curing, and conversely promotes wound healing without impairing healing due to being absorbed and decomposed in the tissue.
Based on the fact that a hydrogel obtained by mixing polyanion and water-soluble carbodiimide with collagen that is commonly added to pharmaceuticals and foods exhibits high adhesiveness with living body tissue even in the presence of water, the inventors of the present invention found that this hydrogel can be applied to the living body as a non-formed medical material such as adhesive for living body, hemostyptic, obstruent or dead space filler, and/or that formed articles of this gel can be applied to the living body as a formed medical material such as blood vessel substitute and so forth, thereby leading to completion of the present invention.
Namely, the present invention relates to a collagen gel obtained by crosslinking collagen with polyanion and carbodiimide and its production process, and more particularly, to a production process of a collagen gel comprising adding water-soluble carbodiimide to an aqueous solution containing collagen and polyanion followed by crosslinking the collagen and polyanion, or by reacting olyanion and water-soluble carbodiimide in an aqueous solution containing both and adding an aqueous solution of collagen to this followed by crosslinking the collagen with polyanion. Alternatively, the present invention relates to medical materials comprised of this collagen gel, including adhesive for living body, hemostyptic, obstruent, dead space filler and medical formed articles such as blood vessel substitute, or a kit for producing those materials.
The collagen used in the present invention is collagen such as Type I, Type III or Type I+III collagen that has been removed of the strongly antigenic telopeptide portion either by, for example, alkaline treatment of insoluble collagen extracted from various animals, or by treating with enzyme such as pepsin, trypsin, chymotrypsin, papain or pronase. There are no particular restrictions on the origin of the collagen, and typically collagen can be used that is obtained from the skin, bone, cartilage, tendon or organs, etc. of birds or mammals such as cows, pigs, rabbits, sheep and mice. Differing from gelatin, since this collagen allows the obtaining of a suitable consistency without heating, preparation can be made easily in the case of gelation. In addition, since this collagen has a higher molecular weight than gelatin, it more closely resembles living body tissue, has considerable physiological activity, and therefore promotes healing in the case of using on a wound, resulting in a favorable contrast to the tendency of gelatin to conversely inhibit tissue regeneration. This collagen is flexible after curing and requires only a short time for crosslinking, in other words, requires only a short time for gelation. Collagen is used by dissolving in a non-toxic solvent with respect to the living body, examples of which include water, physiological saline, a buffer such as borate buffer, or an aqueous solution containing a salt such as sodium chloride, sodium bromide and potassium bromide, or protein, sugar or lipid, etc.
The polyanion used in the present invention is a polymer that is water-soluble and has numerous carboxyl groups as functional groups. It may be polymer originated from living body or synthetic polymer provided it has a low level of toxicity with respect to the living body. Specific examples include hyaluronic acid, alginic acid, gum arabic, polyglutamic acid, polyacrylic acid, polyaspartic acid, polymalic acid, carboxymethylcellulose and carboxylated starch. Since the molecular weight of these polyanions has an effect on the adhesiveness of the gel during collagen gel formation or on the hardness after curing and so forth, it is arbitrarily decided as desired. These polyanions are used by dissolving in an aqueous solvent having low toxicity with respect to the living body similar to that used to dissolve the collagen. In addition, the concentration of polyanion aqueous solution is suitably determined according to the viscosity of the aqueous solution or the number of carboxyl groups possessed by one polymer molecule, etc.
Examples of water-soluble carbodiimides preferably used in
Shimizu Yasuhiko
Takimoto Yukinobu
Corless Peter F.
Edwards & Angell LLP
Fubara Blessing
O'Day Christine C.
Page Thurman K.
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