Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-04-06
2001-12-11
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S362000, C530S363000
Reexamination Certificate
active
06329337
ABSTRACT:
BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION
The present invention relates to an adhesive for biological tissue. More particularly, the present invention relates to an adhesive for biological tissue containing a glue agent and a cross-linking agent, such that the glue agent contains a recombinant human plasma protein as a main component, and that the cross-linking agent contains a bifunctional or multifunctional aldehyde an a main component, the adhesive providing excellent hemostatic and adhesion properties and being biologically absorbable and highly safe. 2. Description of the Related Art
Conventionally, various adhesives have been proposed as adhesives for biological tissue. Among others, cyanoacrylate type adhesives (e.g., Aronalpha A from ToaGosei Industry Co., Ltd. and Biobond from Yoshitomi Pharmaceutical Industries, Ltd.), fibrin glues (e.g., Tisseel from Nippon Zoki K.K., Beriplast from Hoechst, and Bolheal from The Chemo-Sero-Therapeutic Research Institute), and gelatin-resorcin-(bifunctional or multifunctional) aldehyde type adhesives (e.g., Cardial GRP Glue from Cardial (France)) are used in actual clinical applications. (See for example, Journal of Biomedical Materials Research, vol. 31, 157-166 (1996).)
The features of conventional tissue adhesives which are used for clinical purposes will now be summarized. First, cyanoacrylate type adhesives provide good adhesion speed and adhesion strength. However, this type of adhesives have significant problems in that flexibility is lost from the adhesion surface obtained by using this type of adhesives, and substances which may pose safety hazards might be produced through in vivo-degradation. Fibrin glues are considered free from safety concerns associated with in vivo-degradation products since they are of biological origin. However, fibrin glues have problems in that they provide somewhat lower adhesion strength. Also, the possibilities of viral infection associated with the use of fibrin glues are non-negligible. Gelatin-resorcin-aldehyde type adhesives provide good adhesion strength. However, this type of adhesive also has problems in that some products employ highly-toxic formaldehyde as an aldehyde, and that gelatin is not entirely free from prion infection possibilities.
Adhesives containing a plasma protein obtained from blood, e.g., serum albumin, and a bifunctional or multifunctional aldehyde have been proposed and are known to provide good adhesion strength (See, for example, PCT Publication WO04/01508; this publication is incorporated herein by reference). Some of these adhesives are used for clinical purposes in Europe. However, this type of adhesives are not entirely free from safety concerns because there are possibilities of infection with viruses from human or animal blood products or derivatives. Therefore, those who are engaged in clinical practice are awaiting the development of an adhesive for biological tissue which provides good adhesion strength and yet is highly safe.
SUMMARY OF THE INVENTION
An adhesive for biological tissue according to the present invention includes: a glue agent and a cross-linking agent, wherein the glue agent contains a recombinant human plasma protein as a main component, and wherein the cross-linking agent contains a bifunctional or multifunctional aldehyde an a main component.
In one embodiment of the invention, the recombinant human plasma protein is human serum albumin.
In another embodiment of the invention, the glue agent is substantially free of components derived from a host cell from which the recombinant human serum albumin was produced or any other contaminants, and the coloration of the glue agent is at a minimum level.
In still another embodiment of the invention, the bifunctional or multifunctional aldehyde is selected from a group including glyoxal, succinaldehyde, glutaraldehyde, and malealdehyde.
In still another embodiment of the invention, the glue agent contains a further component for enhancing the cross-linking rate and/or for adjusting the viscosity of the glue agent.
In still another embodiment of the invention, the further component includes a chitosan which is used for medical purposes.
An adhesive kit for biological tissue according to the present invention includes: a first container containing recombinant human serum albumin as a main component; and a second container containing an aldehyde as a main component.
Thus,the present invention provides an adhesive for biological tissue containing a glue agent and a cross-linking agent, wherein the glue agent contains a recombinant human plasma protein as a main component, and wherein the cross-linking agent contains a bifunctional or multifunctional aldehyde as a main component.
The recombinant human plasma protein may preferably be human serum albumin, and may more preferably be high-purity human serum albumin. Human serum globulin may also used. The human serum albumin may be high-purity human serum albumin which is purified by a method described in, for example, U.S. Pat. No. 5,440,018 and 5,521,287 (the entire disclosure thereof is incorporated herein by reference for this disclosure), which is substantially free of components derived from a host call from which the recombinant human serum albumin was produced or any other contaminants, and whose coloration is sufficiently controlled. In such cases, the purity of the high-purity human serum albumin is preferably 99.999999%, and more preferably 99.9999999%. The degree of coloration may be in the range of 0.01 to 0.05 for A
350
/A
280
ratio, for example.
The bifunctional or multifunctional aldehyde may be a dialdehyde selected from a group including glyoxal, succinaldehyde, glutaraldehyde, and malealdehyde.
The present invention also provides an adhesive kit for biological tissue including a first container containing a glue agent which contains a recombinant human plasma protein as a main component, and a second container containing a cross-linking agent which contains a bifunctional or multifunctional aldehyde as a main component, and optionally an explanation manual for the kit.
In accordance with the adhesive for biological tissue according to the present invention, a plasma protein which is obtained through gene recombinant techniques, preferably human serum albumin, and more preferably high-purity human serum albumin, is used as a main component of a glue agent. As a result, not only can infection with viruses of from human or animal blood products or derivatives be prevented, but it is also possible to provide an adhesive for biological tissue having stable quality. The adhesive for biological tissue according to the present invention also permits stable mass production without depending on supplies of animal or human blood. As the bifunctional or multifunctional aldehyde, it is preferable to use glutaraldehyde and/or glyoxal, which have conventionally been used in cardiovascular surgery and the like, instead of highly-toxic formaldehyde.
The recombinant human serum albumin which is used as a main component of the glue agent of the present invention may be produced by a known method using a known human serum albumin sequence. It will be readily understood by those skilled in the art that a serum albumin sequence having at least one of substitution, deletion, and/or addition of one or more (preferably not all) amino acids may also be used to produce the human serum albumin which is used as the glue agent of the adhesive according to the present Invention.
For example, a host for producing human serum albumin may be prepared by a known method, and the host is cultured by a known culture method (See, for example, U.S. Pat. No. 5,440,018 and 5,521,287, the entire disclosure of which is incorporated herein by reference for this disclosure). Examples of host cells include, without limitation, bacterial cells (e.g.,
E. coli
), yeast cells (e.g.,
Pichia pastoris
, and
Saccharomyces cerevisiae
), and mammalian cells. After the recombinant human serum albumin of interest is obtained, the human serum albumin is subjected to adequate puri
Morita Yasunobu
Murayama Ken
Carlson Karen Cochrane
Leydig , Voit & Mayer, Ltd.
Toyo Boseki Kabushiki Kaisha
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