Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-07-14
2004-09-14
Horlick, Kenneth R. (Department: 1637)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000, C424S424000, C424S425000, C623S015120, C530S356000
Reexamination Certificate
active
06790454
ABSTRACT:
SUBJECT OF THE INVENTION
This invention relates to a composite product as a collagen support comprising at least one porous collagen layer covered on at least one side with an essentially compact collagen membrane consisting either of a collagen film prepared by trying a collagen gel, preferably in air or a gaseous fluid, or of a very highly compressed collagen sponge. This composite product may be used for the manufacture of artificial skin.
TECHNOLOGICAL BACKGROUND
For many years collagen has proved to be an irreplaceable substrate for the production of artificial tissues containing living cells.
The biomaterials obtained are increasingly used in the field of pharmaceutics and they appear to have a very promising future for the preparation of injured connective tissues or for gene therapy by allowing the introduction and survival of modified cells in a living organism.
Furthermore, for “in vitro” tests, the cosmetic and dermopharmaceutical industries are increasingly using reconstructed skin, especially since animal tests are used less and less in these disciplines.
It is for this reason that several research teams throughout the world have been endeavoring to develop collagen-based supports for the production of living artificial tissues such as skin, cartilage, bone, tendon or reconstructed cornea, so these novel biomaterials have numerous fields of application.
It should be noted that the principal studies carried out in the field covered by the invention are attributable mainly to the following teams: Yannas I., Collombel C., Tinois E., Boyce S., Eisenberg H., Bell E., Kuroyanagi Y., Maruguchi T., Hanthamrongwit M., Auger F. A. and Osborne C. S.; cf. U.S. Pat. No. 5,273,900, for example.
All these researchers use either collagen gels or collagen sponges, the latter being obtained by lyophilization.
The main difficulties to be overcome in the production of supports for the production of living artificial tissues are as follows: good mechanical strength, low sensitivity to temperatures around 37° C., biological properties favorable to cell development and metabolism, low susceptibility to enzymatic degradation and, finally, for certain applications and particularly reconstructed skin, preferably the presence of a bilayer structure in which one of the layers is as compact as possible the other is porous.
The researches carried out hitherto have not provided collagen supports which satisfactorily comply with all the constraints listed above.
PURPOSES OF THE INVENTION
The object of the present invention is to solve these problems which have remained shelved from both the technical and industrial points of view.
The present invention makes it possible to solve all these technical problems in a particularly simple, inexpensive manner applicable to the industrial scale, particularly in cosmetics, dermopharmaceutics or pharmaceutics.
SUMMARY OF THE INVENTION
According to a first feature, the present invention provides a novel composite product forming a collagen support comprising at least one porous collagen layer covered on at least one side with an essentially compact collagen membrane consisting either of a collagen film prepared by drying a collagen gel, preferably in air or a gaseous fluid, or of a very highly compressed collagen sponge.
According to yet another advantageous characteristic of the composite product of the invention, the collagen sponge is compressed at a pressure of at least about 50 bar, equivalent to about 50.10
5
Pascals (Pa), and preferably of between 50 bar (50.10
5
Pa) and 200 bar (200.10
5
Pa), this compression optionally taking place at a temperature of between 20 and 80° C. and preferably of between 40° C. and 60° C.
According to one advantageous characteristic of this composite product, the collagen product is selected from collagen and a mixture of collagen with a polysaccharide, particularly a glycosaminoglycan, chitosan or a derivative thereof, cellulose or a derivative thereof, dextran or a derivative thereof, an alginate or a derivative thereof, or a carrageenan.
According to another advantageous characteristic of this composite product, at least one of the two layers of the latter, i.e. the porous layer and the essentially compact membrane, comprises normal, genetically modified or malignant living cells originating particularly from young or elderly subjects.
In one advantageous variant, the living cells are selected from the group consisting of fibroblasts, keratinocytes, melanocytes, Langerhans' cells originating from the blood, endothelial cells originating from the blood, blood cells, particularly macrophages or lymphocytes, adipocytes, sebocytes, chondrocytes, osteocytes, osteoblasts and Merkel's cells originating from the blood, said cells being normal, genetically modified or malignant.
According to yet another advantageous characteristic, the composite product contains normal, genetically modified or malignant fibroblasts in the porous layer and normal, genetically modified or malignant living cells on the surface of the compact membrane, said cells being selected particularly from keratinocytes, melanocytes, Merkel's cells originating from the blood, Langerhans' cells originating from the blood, sebocytes, cells originating from the blood, and nerve cells.
In yet another advantageous embodiment of the invention, it can be of particular value to prepare either “young” reconstructed skin using cells taken substantially exclusively from young subjects, or “aged” reconstructed skin obtained from cells taken substantially exclusively from elderly subjects. These models will make it possible to improve our knowledge of the skin ageing process and study the influence of active agents on this process.
In yet another advantageous embodiment of the invention, the essentially compact membrane is prepared prior to combination with the porous layer, preferably comprising a collagen sponge, in particular by preparing the membrane and depositing it on a collagen gel before the whole is frozen and lyophilized to give said composite product.
In yet another embodiment of the composite product according to the invention, the collagen sponge and/or the collagen film and/or the collagen membrane of said product comprise collagen of mammalian origin, particularly of bovine origin.
In yet another advantageous embodiment of the composite product according to the invention, at least one of the two layers of said product is produced from a collagen gel containing a mixture of soluble collagen and insoluble collagen, for example in the form of fibers.
In the case of the composite product according to the invention, the collagen can be type I and/or type III collagen.
According to a second feature, the present invention also covers a process for the manufacture of a composite product comprising at least one porous collagen layer covered on at least one side with an essentially compact collagen membrane,
wherein:
a) first of all the essentially compact collagen membrane is prepared either by drying a first collagen gel, preferably in air or with the aid of a gaseous fluid, or by compressing a collagen sponge obtained by the freezing-lyophilization of a collagen gel;
b) a second collagen gel is prepared separately;
c) either the essentially compact membrane is deposited on the second collagen gel, or the second collagen gel is poured onto the essentially compact membrane; and finally
d) the whole is frozen-lyophilized to give said composite product.
In one advantageous variant of this process, the collagen sponge used to prepare the compact membrane is compressed at a pressure of at least 50 bar (about 50.10
5
Pa) and preferably of between 50 bar (50.10
5
Pa) and 200 bar (200.10
5
Pa).
The compression step advantageously takes place at a temperature of between 20 and 80° C. and preferably of between 40° C. and 60° C.
In another advantageous embodiment of this process, the collagen sponge and/or the collagen film and/or the collagen membrane are prepared using either collagen or a mixture of collagen with a polysaccharide, particularly
Abdul Malak Nabil
Andre Valerie
Huc Alain
Coletica
Horlick Kenneth R.
Merchant & Gould P.C.
Strzelecka Teresa
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