Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-05-29
2004-03-16
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
Reexamination Certificate
active
06706684
ABSTRACT:
The present invention relates to a process for preparing a collagenic material making it possible to control the rate of in vivo biodegredation of this material.
It relates more particularly to a process for treating a collagenic component making it possible to obtain materials whose stability and mechanical properties can be varied depending on the conditions of said treatment, said materials being suitable for diverse biomedical applications of collagen.
Collagen-based biomaterials are currently used in many applications, having the major advantage of being resorbable. However, depending on their applications, it is necessary to control their biological degradation. This is because the mechanical properties of the implanted collagenic material have to deteriorate progressively and said material must finally be entirely digested over a defined period.
Depending on the applications of these collagen-based biomaterials, the degradation of the latter must in general take place over a time ranging from a few days to a few weeks.
To achieve these objectives, the collagen properties may be modified in several possible ways. Thus, it is known in the art to carry out treatments resulting in the formation of ionic bonds, hydrogen bonds or covalent bonds (Chvapil et al., in
International Review of Connective Tissue Research
, Vol. 6, ed. D. A. Hall and D. S. Jackson, Academic Press, UK, 1973, 1-61).
The creation of intermolecular links increases the biodegradation time of the collagenic material and the mechanical strength of the collagen fibers, while reducing the water absorptivity, the solubility and the rate of enzymatic degradation of these fibers (Pachence et al.,
Medical Device
&
Diagnostic Industry,
1987, 9, 46-55).
Thus, processes have been proposed in the art which allow the collagen to be crosslinked either by physical methods or by chemical methods.
The chemical methods use crosslinking agents such as aldehyde compounds, among which may be mentioned, in particular, formaldehyde, glutaraldehyde, succinaldehyde, glyoxal and acrolein, or else carbodiimides, diisocyanates and azide derivatives (Pachence et al.,
Medical Device
&
Diagnostic Industry,
1987, 9, 46-55; Weadock et al.,
Biomat. Med. Dev. Art. Org.,
1983-84, 11, 293-318; BIOETICA and INSERM, FR 2 617 855).
Aldehyde compounds are, to be sure, the most widely used crosslinking agents but they generate potentially cytotoxic biomaterials.
It is desirable to introduce as few chemicals as possible into an implantable biomaterial, since these additives cause complications and regulatory constraints of increasing severity in order to demonstrate the lack of toxicity of such chemicals.
Moreover, a process is known in the prior art for modifying the collagen by forming aldehyde functions within the collagen itself, by oxidative scission using periodic acid or one of its salts, this treatment crosslinking the collagen at neutral or basic pH (M. Tardy and J. L. Tayot, U.S. Pat. No. 4,931,546).
Finally, it has also been proposed in the prior art to modify the properties of the collagen by functionalizing the amino and carboxyl groups of the amino acids that it contains. According to this approach, charge and polarity modifications may thus slow down or accelerate the degradation of collagen (Green et al.,
Biochem. J.,
1953, 154, 181-7; Gustavson,
Ark. Kemi.,
1961, 55, 541-6).
As regards the physical methods, these include dehydration, aging, heating in the absence of moisture, and irradiation by ultraviolet rays or by beta or gamma rays.
Of these, irradiation treatment with beta or gamma rays is used to sterilize dehydrated collagenic materials, but, in the light of the existing literature, results in materials whose strength cannot easily be predicted.
The various parameters that can influence this type of treatment are not sufficiently well known to allow the quality of the resulting collagenic biomaterials to be controlled, particularly from the point of view of their mechanical strength and their rate of biodegradation (Sintzel et al.,
Drug Dev. Ind. Pharm.,
1997, 23, 857-878).
U.S. Pat. No. 5,035,715 describes irradiation by gamma rays of a substantially moisture-free mixture of collagen and a mineral material, thereby obtaining a certain amount of crosslinking.
Patent EP 0 351 296 describes gamma irradiation of collagen beads, making it possible to increase their density.
Application WO 95/34332 describes the sterilization of a valvular prosthesis made from porcine tissue, and therefore containing collagen, by an electron beam or by X-ray or gamma irradiation. Beta-type electron irradiation of the prosthesis, slightly crosslinked beforehand by a chemical agent, results in less degradation than gamma irradiation. This document does not teach that it is possible to increase the crosslinking and the degradation resistance of such a valve by beta radiation. On the contrary, it teaches that beta radiation has hardly any influence on the crosslinking.
U.S. Pat. No. 5,674,290 describes the sterilization by gamma irradiation of collagenic implants having a high water content, in a sealed envelope transparent to gamma radiation. When this teaching is applied to collagen, the collagen is precrosslinked by a chemical agent. This documents states that, unlike sterilization of a dry collagenic material by gamma irradiation, sterilization of wet collagenic material by gamma radiation only modifies the enzymatic degradability of the material very slightly. The document suggests, erroneously, that sterilization of such a material by an electron beam would be equivalent to sterilization by irradiation by gamma sterilization.
It may therefore be stated that the various known treatments in the prior art allowing certain properties of collagenic materials to be varied either generate undesirable or potential toxicities in the envisioned applications, or are difficult or expensive to implement, or do not allow effective control of the properties of the final material obtained.
It is an objective of the present invention to provide a treatment making it possible to obtain collagenic materials whose rate of degradation in vivo and whose mechanical properties can be varied according to the potential applications of said materials.
It is another objective of the invention to provide a treatment process resulting in a ready-to-use biomaterial by simultaneously carrying out crosslinking and sterilization of the collagenic material.
For this purpose, the subject of the present invention is a process for preparing a crosslinked collagenic material which is biocompatible and nontoxic and has a controlled in vivo rate of biodegradation, characterized in that it comprises subjecting a collagenic component in the wet state to irradiation by beta rays, the collagenic material obtained being sterile and biodegradable over a few days to several weeks.
The subject of the invention is also the aforementioned process characterized in that the collagenic component in the wet state is combined, prior to its irradiation, with a network of collagen fibers, preferably of helical structure.
The invention also relates to materials obtained by the above process.
The invention also relates to a bicomposite which is biocompatible, nontoxic and sterile, has a controlled in vivo rate of biodegradation and is able to be applied by sutures or staples, characterized in that it comprises only, or mainly, two layers intimately associated and crosslinked with interpenetration of the crosslinked networks, one of said layers being formed from a film based on a crosslinked collagenic component and the other from a compacted compress formed from crosslinked collagen fibers rendered insoluble, especially collagen fibers having a helical structure, prepared from collagen dissolved or dispersed in an aqueous solution.
The inventors have discovered, most surprisingly and unpredictably, that the properties of collagenic materials depend on the mode of irradiation—beta or gamma radiation.
In particular, they have discovered that the degree of hydration of the irradiated mat
Bayon Yves
Gravagna Philippe
Tayot Jean-Louis
Carlson Karen Cochrane
Imedex Biomateriaux
Larson & Taylor PLC
Snedden Sheridan K
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