Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Reexamination Certificate
2002-01-14
2004-09-14
Russel, Jeffrey Edwin (Department: 1654)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
C128SDIG008, C514S021800, C525S054100, C530S356000, C602S050000, C604S289000
Reexamination Certificate
active
06790438
ABSTRACT:
The domain of the invention is that of biocompatible, bioresorbable medical or surgical biomaterials which can be used in the prevention of post-operative adhesions, more particularly after intraperitoneal and pelvic surgical interventions.
The invention relates to a means, more especially, but not in a limiting way, a film, a gel or a liquid (applicable e.g. by pulverization), for preventing these post-surgical adhesions, consisting of a chemically modified specific collagenic peptide which is crosslinked in situ or used in the crosslinked state.
The invention also relates to a process for producing, inter alia, the abovementioned means.
One of the major problems encountered in surgery, in particular digestive, abdominal and gynecological surgery, is related to the formation of post-surgical adhesions (abnormal association between two surfaces or segments of tissues which are normally separated) which are the result of an inflammatory and/or cicatricial activity automatically generated subsequent to a tissue trauma engendered by the invention. Such delocalized adhesions can have unfortunate repercussions. Thus, in abdominal surgery, these adhesions may lead to obstructions. In gynecological surgery, post-operative pelvic lesions are one of the recognized causes of the lack of effectiveness of surgical treatment for sterility.
In order to attempt to remedy this problem, chemical and/or therapeutic approaches have been proposed.
The chemical approach consists in applying to surgical wounds chemical treatment agents capable of curbing the physiological phenomena of inflammation and cicatrization which cause the adhesions. These treatment agents are enzymes such as fibrinolysin and papase, or products such as phenylbutazone, prednisolone, polyvinylpyrrolidone or dextrans.
The physical approach consists in isolating the surgical wound from the neighboring tissue by intercalating a physical barrier, which may be a film or a dressing which is nonfibrous or fibrous, woven or nonwoven, or in the form of a gel. This physical barrier prevents adhesion during the cicatrization. However, as soon as the latter is no longer taking place and, therefore, the risks of adhesion are nonexistent, this physical barrier represents nothing other than a useless, or even bothersome, not to say dangerous in certain cases, foreign body.
Hence, it ensues that the known anti-adhesive means made of polymer materials of the polytetrafluoroethylene or silicon type which, although being tried and trusted in terms of anti-adhesion, nonetheless remain nonbiodegradable and must therefore be removed during a second surgical operation. This practice which is doubly traumatizing for the patient has the other drawback of shifting the problem of post-surgical adhesion from one tissue region to another which is lesioned during the second operation (laparotomy).
Thus, in order to move on from this, attempts have been made to develop means for preventing post-operative surgical adhesions, consisting of materials which are biodegradable (or bioresorbable) at the end of the cicatrization, as soon as their function as a barrier has been fulfilled and that no risk of adhesion remains. Some researches, in the knowledge of the presumed biodegradability and biocompatibility properties of natural polymers and of derivatives thereof, have proposed using collagenic peptides (collagen, gelatin), polysaccharides (cellulose-starch and derivatives) and mucopolysaccharides, inter alia, as a constituent material of implants or of surgical prostheses, and in particular of post-surgical anti-adhesion barriers.
The company Johnson & Johnson Products Inc, has developed a bioresorbable material based on oxidized regenerated cellulose, which can be used as a post-operative anti-adhesion barrier and is in the form of cloth with a density of 8 to 15 Mg/cm
2
and a porosity of 10 to 20% (EP-A-0 213 563). JOHNSON & JOHNSON has also developed a process for preparing neutralized oxidized cellulose, the integrity and tensile strength of which are preserved, with a view to uses, in particular as a means for preventing post-surgical adhesions (EP-A-0 437 095). As an extension to that, this company has also developed a multilayer film made of oxidized cellulose and cellulose, which can be used as an anti-adhesion barrier or as a dressing (EP-A-0 815 881).
In patents U.S. Pat. No. 5,017,229 and U.S. Pat. No. 5,527,893, the inventors, BURNS et al. of the company GENZYME CORPORATION, describe a barrier for preventing post-surgical adhesions, consisting of a polyanionic polysaccharide, namely carboxynethylcellulose, combined with hyaluronic acid so as to form a gel.
In general, uses for collagenic materials as surgical films have been known for a long time. Thus, British patent GB-A-1 095 552 from 1964 describes a collagen film made from multiple nonwoven filaments.
French patent FR-A-2 628 634 describes a visceral surgery patch prepared using a biomaterial made from two superposed and tightly associated layers of collagen, namely an adhesive porous layer of fibrous collagen and a film of collagen and/or of gelatin. The aim of this patch is to allow good cicatrization of the viscera. It is a dressing intended to temporarily replace the visceral wall to be reconstituted. It is presented as being entirely biodegradable and as being capable of producing an excellent effect of containment and of hemostasis. It does not, in this case, specifically involve use for preventing post-surgical adhesions.
PCT patent application WO 96/08277 relates to the use of collagenic membranes as a prosthesis for peritoneal regeneration. The collagenic material under consideration is a gel of optionally crosslinked collagen, which is transparent and biocompatible, which can be sutured or stapled, and which is bioresorbable. The collagen used is a collagen with or without telopeptides, optionally associated with a glycosaminoglycan. It should be noted that the crosslinking agent optionally used is a reactive chemical compound (glutaraldehyde, diphenylphosphoryl azide, carbodiimide) which is not neutral in terms of toxicity.
In patent FR-A-2 628 634, the patch is formed by two superposed and tightly associated layers of collagen. The first layer is made from fibrous collagen which confers a porous and adhesive nature on it. The second layer is obtained by adhering a film of collagen or of gelatin onto the first layer of fibrous collagen. According to the inventors of PCT patent WO 96/08277, this patch has a relatively low mechanical resistance. Document FR-A-2 628 634 makes no mention of the prevention of post-surgical adhesions.
European patent application EP-A-0 686 402 discloses a collagenic membrane for preventing post-surgical adhesions, comprising a collagen-based support covered with a layer of gelatin which is not mixed with the support. This membrane is preferably provided in lyophilized form. The collagen used may be crosslinked using diphenylphosphoryl azide (DPPA). Once again, this type of crosslinked collagen is not a sound choice because of the problems of toxicity of which it is the underlying cause.
French patent application FR-A-2 759 083 describes a collagenic material which can be used in particular for preventing post-surgical adhesions. According to the inventors, this collagenic material is biocompatible, nontoxic, potentially adhesive and biodegradable in less than a week. This collagenic material comprises collagen which is modified by oxidative cleavage and heating above 37° C. and which is crosslinked in the presence of at least one macromolecular hydrophilic additive which is chemically nonreactive with respect to collagen. The hydrophilic agent is, for example, polyethylene glycol or a polysaccharide such as starch, dextran or cellulose.
It emerges from this review of the prior art that none of the biodegradable materials, in particular the cellulose or collagenic materials, used to date in the prevention of post-surgical adhesions are satisfactory, in particular for the reasons stated hereinafter.
Some may have residual toxicity, given their method of
Constancis Alain
Meyrueix Remi
Flamel Technologies
Russel Jeffrey Edwin
LandOfFree
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