Surgery: splint – brace – or bandage – Bandage structure – Skin laceration or wound cover
Reexamination Certificate
2000-05-26
2003-04-15
Lewis, Kim M. (Department: 3761)
Surgery: splint, brace, or bandage
Bandage structure
Skin laceration or wound cover
C514S012200, C514S021800, C530S381000, C530S389600
Reexamination Certificate
active
06548729
ABSTRACT:
The present invention relates to a fibrin sponge having a defined residual moisture, methods of its preparation, its use for hemostasis, tissue adhesion and supporting wound healing as well as a kit for its application.
In the prior art, the most varying hemostatic wound cover materials, also based on fibrin, e.g. fibrin sponges, fibrin membranes or fibrin gels, have been described and partially also used.
So far the opinion has prevailed that for hemostasis, a combination of fibrinogen and thrombin or corresponding prothrombin activators is necessary. Thus, e.g., fleece-like flat materials based on collagen comprising fibrinogen and thrombin (TachoComb®), flat materials comprising fibrinogen and activated factor X (AT 0 359 653, IMMUNO AG) or flat materials comprising fibrinogen and thrombin as a dry preparation (EP 0 748 633, IMMUNO AG) have been known from the prior art. Whereas the fleece-like flat materials based on fibrinogen and activated factor X are already soft and pliable, other flat materials require absolutely dry storage so as to preclude a premature reaction of the fibrinogen contained therein with the thrombin or with other blood clotting activators.
Bering E. A. jr. (J. Clin. Invest. Vol. 23, 1944, p. 586) discusses general developments in the field of fibrin foams and their use as hemostatic agents.
A survey of various materials based on fibrin, e.g. fibrin powders, fibrin films and fibrin foams, is e.g. given in Gerendas M. “Fibrin Products as aids in hemostasis and wound healing”, pp. 277, in K. Laki (ed.) Fibrinogen, M. Dekker, New York, 1968.
Furthermore, fibrin foils or fibrin membranes, respectively, have been known from the prior art (cf. e.g. EP 0 485 210-A2). Such materials are extremely thin, non-absorbent and thus usable for hemostasis to a limited extent only. In contrast to fibrin sponges, these materials are compressed on purpose during their preparation, e.g. by the application of weights. Therefore, these materials are primarily characterized by their high density, as compared to foams.
The present invention has as its object to provide a means for hemostasis, tissue adhesion and the aiding of wound healing based on fibrin which, compared to conventional means, has a good, in particular an improved, efficacy, is simple to handle with a simultanous simple composition that allows for an inexpensive preparation, and which also has a broad field of application. Therebeyond, it should be possible to readily supply the fibrin material with other active and auxiliary substances.
According to the invention, this object is achieved in that a fibrin sponge having a residual moisture of at least 3%, preferably in the range of from 3 to 35%, in particular 10 to 20%, is provided which is storage stable. The water content or the residual moisture, respectively, preferably is adjusted such that the fibrin sponge has a soft and smooth consistency, thereby substantially improving its handling and efficacy.
From the prior art it has been known that dry preparations containing fibrin, which have a hard, brittle consistency, will become soft and smooth (pliable) by increasing their residual moisture. However, there has been a general prejudice as regards the stability of such protein preparations having an increased residual moisture, particularly if they contain a sensitive enzyme, such as thrombin, or another activator or proactivator of blood clotting.
It is not without reason that such sensitive protein preparations commonly are made stable by lyophilisation, a residual moisture of less than 3%, in most instances even of less than 1%, being attained.
Therefore, it has been suprising that a fibrin sponge preferably having a content of thrombin and an increased residual moisture or an increased water content nevertheless is storage stable.
By storage-stable according to the present invention, a fibrin sponge is understood which even after a storage of 6 months, generally, however, even after a storage of 2 or more years at room temperature is still extremely suitable for application, and the optionally present thrombin activity or blood clotting activator or proactivator activity remains substantially preserved. Preferably, more than 70% of the activity remain over a period of at least 6 months, preferably 2 or more years, at room temperature. Even at a temperature of 370° C. the fibrin sponge according to the invention having a residual moisture of 15% has been shown to be stable for at least 3 months, preferably more than 6 months, its thrombin activity being fully retained.
The preparation according to the invention particularly meets the manifold requirements made on a means for hemostasis, tissue adhesion and aiding wound healing, with the preparation according to the invention, properties such as
a good and lasting efficacy, i.e. rapid hemostasis or adhesive effect, no secondary bleedings or late detachment of glued tissue parts,
a good tolerance even with multiple applications (no sensitisation)
complete resorption during the wound healing process,
smooth and undisturbed wound healing,
the greatest possible safety as regards the transmission of viral or other pathogens (such as, e.g., prions, the pathogens of bovine spongiform encephalitis, BSE),
simple use as well as the already mentioned
storage stability of the ready-to-use product can, e.g., be ensured.
Preferably, the fibrin sponge according to the invention is a fibrin fleece-like flat material or a fibrin foam having a low density and a high absorptive capacity.
According to the invention, by fibrin fleece-like flat material a fibrin sponge is to be understood which has a porous, in particular fine porous structure substantially not interspersed by air bubbles, as it might be obtained by lyophilising non-foamed fibrin clots according to the invention. By fibrin foam, on the other hand, a material is to be understood which is obtained by foaming a fibrinogen solution, admixing with a thrombin solution and lyophilising the thus obtained foamed fibrin clot. Foaming may also occur immediately after the addition of the thrombin.
The fibrin sponge according to the invention may also be used as such. It may essentially consist of fibrin and the thrombin required for producing the fibrin from fibrinogen, and surprisingly even this simple embodiment exhibits an excellent hemostatic and adhesive effect.
It may, however, be impregnated with further additives, preferably a blood clotting activator or proactivator. Such additives are preferably homogenously distributed in the preparation according to the invention.
The blood clotting activator or proactivator preferably is selected from the group consisting of thrombin, prothrombin, activated factor X, prothrombin complex, activated prothrombin complex, FEIBA, calcium ions and mixtures thereof.
In particular, additional thrombin may be incorporated into the preparation according to the present invention, preferably in an amount of between 1 and 300 U/cm
3
, more preferably between 5 and 100 U/cm
3
, most preferably between 10 and 50 U/cm
3
.
Surprisingly, it has been found that the preparations according to the invention based on solid fibrin also with an additional content of thrombin are still stable over long periods of storage at refrigerator or room temperature and even at 37° C. (in an accelerated stability test). In particular, the thrombin activity contained is substantially maintained over long periods of time. The contained thrombin activity may, e.g. after extraction with 1 M NaCl solution, be determined according to methods known per se, e.g. with a chromogenic substrate (Th-1, Pentapharm).
In addition to substances, such as blood clotting activators or proactivators, the fibrin sponge according to the invention may also contain stabilizers, preservatives, antibiotics, therapeutic agents, antifibrinolytic agents, growth factors, further plasma proteins, enzymes, inhibitors or mixtures of such agents.
As stabilizers, preferably thrombin stabilizers, in particular polyoles, polysaccharides, polyalkylene glycols, amino acids or mixtures thereof, or s
Delmotte Yves Alain
Odar Johann
Scheel Edgar
Seelich Thomas
Baxter Aktiengesellschaft
Foley Hoag & Eliot LLP
Lewis Kim M.
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