Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2001-01-02
2004-02-03
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S487000, C424S488000, C424S423000
Reexamination Certificate
active
06685963
ABSTRACT:
The present invention has for its principal object diphasic injectable compositions, in particular useful in reparative and plastic surgery. It has more precisely for object:
biocompatible diphasic compositions comprising a dispersed phase in suspension in a continuous phase;
a method for preparing said compositions;
a filling material useful in reparative surgery and in plastic surgery, based on said diphasic compositions.
The present invention proposes in particular a satisfactory solution to the technical problem of durable filling of the defects of volume of the skin, such as wrinkles or scars, particularly on the face.
With reference to this technical problem, different approaches and in particular different diphasic injection compositions have already been proposed according to the prior art.
As from 1970, Jaime Planas had the idea to make particles of silicone, in order to inject them under the skin.
More precisely, it has been described:
in EP-A-0 406 375: an alloplastic implant based on a histocompatible solid: said pulverulent solid being constituted by solid particles of diameter included on average between 10 &mgr;m and 200 &mgr;m, and which present a smooth surface having no angle nor edge. A product which corresponds to this Patent Application is found at present on the market. Said product, marketed under the Trademark Artecoll®, consists of microspheres of polymethacrylate (PMMA) in suspension in a collagen solution;
in EP-A-0 466 300: a viscoelastic gel comprising a gelatinous phase (having undergone a low-rate cross-linking) dispersed in a liquid phase (not having undergone cross-linking); said two phases advantageously having been prepared from fibers of Hylan (natural hyaluronic acid chemically modified in situ for the purpose of facilitating extraction thereof from the tissues);
in U.S. Pat. No. 5,137,875: injectable solutions or dispersions of collagen, containing hyaluronic acid in solution;
in WO-A-96 33751: diphasic compositions capable of containing in their continuous and dispersed phases hyaluronic acid or one of its salts; said acid or salt intervening, “relatively” cross-linked in the form of fragments, in order to constitute the dispersed phase, and in aqueous solution, not or very little cross-linked, in order to constitute the continuous phase. It is provided to employ in said continuous phase, in combination or in place of said hyaluronic acid or one of its salts, another biocompatible polymer selected from proteins, polysaccharides and derivatives thereof.
Furthermore, a product, of the diphasic composition type, would be evaluated in the United States. It is principally constituted by silicone balls, dispersed in a solution of polyvinylpyrrolidone.
Incidentally, it will be noted here that documents EP-A-826 381, FR-A-2 568 127, U.S. Pat. No. 4,657,553 and U.S. Pat. No. 4,563,490 do not describe diphasic compositions.
There are therefore numerous variants of diphasic compositions, useful in reparative and plastic surgery and it does not appear obvious to develop one of them, optimalized with reference to the numerous parameters consisting of:
the exact nature and form of the continuous phase;
the nature, form, surface state . . . of the dispersed phase.
In such a context, Applicants propose a novel type of diphasic composition which shows particularly high-performance.
The biocompatible diphasic composition of the type of the invention therefore includes a dispersed phase suspended in a continuous phase and, characteristically, said dispersed phase consists of particles of at least one hydrogel of a (co)polymer obtained by polymerizing and cross-linking acrylic acid and/or methacrylic acid and/or at least one derivative of said acids.
The diphasic compositions of the invention are injectable compositions. They have been formulated with this in view. It is particularly for that purpose that they contain a continuous phase; said phase serving as injection vehicle for the particles of the dispersed phase.
The term injectable used in the present text means manually injectable by means of syringes provided with conventional needles. The diphasic compositions of the invention are particularly interesting in that they can be formulated to be injectable by means of very fine needles (with a diameter included between 0.3 and 0.5 mm). The person skilled in the art understands that the determining parameter is that of the largest dimension of the particles in suspension. Within the framework of the present invention, it is in particular possible to formulate compositions injectable through hypodermic needles of 30 G ½, 27 G ½, 26 G ½, 25 G. Said compositions constitute the most advantageous variant of the compositions of the invention.
The injectable diphasic compositions of the invention are more particularly intended for dermic injection (superficial, mean or deep) for an implantation in the dermis. To that end, for the purpose of eliminating any unpleasant feeling or any pain during their injection and during their implantation, they are advantageously buffered at a pH included between 6.5 and 7.5, preferably included between 7 and 7.4, and preferably still, between 7.2 and 7.3.
In this way, the two continuous and dispersed phases of said diphasic compositions are advantageously buffered at that pH.
A phosphate buffer is generally employed.
The diphasic compositions of the invention therefore comprise an original dispersed phase as specified hereinabove, suspended in an adequate continuous phase.
Said continuous phase must, in effect, be capable of performing several functions, and in particular:
a) it must maintain the dispersed phase in suspension, in stable manner,
b) it must constitute a high-performance injection vehicle,
c) after injection and implantation of the diphasic composition, it must advantageously protect said dispersed phase (in particular prevent it from migrating and promote the formation of fibroblasts around its particles, which slows down degradation thereof).
With reference to points a and b, it will be understood that a compromise must be adopted. Said continuous phase must be sufficiently fluid to be able to be easily injected, and sufficiently viscous to avoid decantation of the dispersed phase.
The compromise mentioned hereinbefore may be obtained with different types of continuous phase. Within the framework of the invention, certain types, specified hereinafter, are largely preferred.
We now propose to give precisions on each of the phases—continuous phase, dispersed phase—of the diphasic compositions of the invention.
By way of continuous phase, an aqueous solution of at least one polymer selected from proteins, polysaccharides and their derivatives, cross-linked or not, is advantageously employed. Said polymer, depending on its nature, in order to perform the above-recalled functions, is capable of intervening not cross-linked, slightly cross-linked or strongly cross-linked. Collagen, albumin, elastin . . . may in particular be employed as protein; as polysaccharide or derivative of polysaccharide:hyaluronic acid, its salts, sulphates of chondroitine, keratane, heparin, alginic acid, starch, carboxymethylcellulose, chitosane.
The possible cross-linking of this type of polymer does not raise particular difficulties for the person skilled in the art.
It is more particularly recommended to employ “an aqueous solution” of a polymer selected from hyaluronic acid, its salts and mixtures of its salts; said polymer advantageously being cross-linked. In fact, according to a preferred variant, said continuous phase of the diphasic compositions of the invention is a hydrogel of a cross-linked polymer selected from hyaluronic acid, its salts and mixtures of its salts; said cross-linked polymer advantageously consisting of a sodium hyaluronate.
The term hyaluronic acid is used in the following text as generic name to designate both hyaluronic acid per se and its salts or mixtures of salts and in particular salts of hyaluronate. The diphasic compositions of the invention advantageously contain sodium hyaluronate
Piron Estelle
Taupin Valérie
Tholin Raymonde
Villain Franck
Corneal Industrie
Klauber & Jackson
Naff David M.
Ware Deborah K.
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