Diphasic injection composition containing dispersed and continuous phases useful for reparative and plastic surgery

• US 6,685,963 B1
• Filed: 01/02/2001
• Issued: 02/03/2004
• Est. Priority Date: 07/01/1998
• Status: Expired due to Fees

• Current Assignee: Corneal Industrie, Dermatech
• Original Assignee: Corneal Industrie, Dermatech
• Inventors: Piron, Estelle, Taupin, Valérie, Villain, Franck, Tholin, Raymonde
• Primary Examiner(s): Naff, David M.
• Assistant Examiner(s): Ware, Deborah K.
• Application Number:
  US09/720,936
• Time in Patent Office: 1,127 Days
• Field of Search: 435/174, 435/177, 424/502, 424/488, 424/487, 514/1
• US Class Current: 424/486
• CPC Class Codes: A61F 2002/30107 using materials or accessories for preventing galvanic or electrolytic corrosion
• CPC Class Codes: A61F 2210/0009 using materials or accessories for preventing galvanic or electrolytic corrosion
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/14 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: C08L 33/00 Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

Biocompatible diphasic compositions are prepared comprising a dispersed phase suspended in a continuous phase, more particularly suitable for use as a filling material in reparative and plastic surgery. The dispersed phase consists of particles of at least one hydrogel of a (co)polymer obtained by polymerizing and cross-linking acrylic acid, methacrylic acid and/or at least one derivative of said acids. The continuous phase is an aqueous solution or hydrogel of a polymer selected from proteins, polysaccharides and their derivatives which have been cross-linked. The polysaccharide may be hyaluronic acid, its salts and a mixture of its salts, advantageously consisting of a sodium hyaluronate.

Claims

1. A biocompatible diphasic composition comprising a dispersed phase and a continuous phase, said dispersed phase residing in suspension in said continuous phase, wherein said dispersed phase consists of particles of at least one hydrogel of a polymer/copolymer obtained by polymerizing and cross-linking acrylic acid, methacrylic acid and/or at least one derivative of said acids;

and wherein said continuous phase is an aqueous solution or hydrogel of at least one polymer selected from proteins, polysaccharides and their derivatives, which has been cross-linked.

2. The composition according to claim 1, wherein said continuous phase is a hydrogel of a cross-linked polysaccharide selected from hyaluronic acid, its salts and mixtures of its salts.

3. The composition according to claim 1, wherein said continuous phase is a hydrogel of cross-linked polysaccharide which is sodium hyaluronate.

4. The composition according to claim 2, wherein the hydrogel constituting said continuous phase is obtained from said polysaccharide whose molecular mass is greater than or equal to 1 million Daltons, which was cross-linked, via its hydroxy functions, by means of a cross-linking agent, at a cross-linking rate defined by the ratio:

total number of reactive functions of said cross-linking agent/total number of disaccharide repeating units of the molecules of said polysaccharide, wherein said ratio is between 0.25 and 0.50.

5. The composition according to claim 4, wherein said polysaccharide has molecular mass ranging between 2 and 4 million Daltons.

6. The composition according to claim 2, wherein the hydrogel constituting said continuous phase contains said cross-linked polymer at a concentration ranging between 10 and 25 mg/g.

7. The composition according to claim 2, wherein the hydrogel constituting said continuous phase contains said cross-linked polymer at a concentration ranging between 15 and 25 mg/g.

8. The composition according to claim 2, wherein said polymer of said hydrogel is produced by bacteria.

9. The composition according to claim 1, wherein said particles of said dispersed phase have a largest dimension ranging between 10 and 120 μ

m.

10. The composition according to claim 1, wherein said particles of said dispersed phase have a largest dimension ranging between 20 and 80 μ

m .

11. The composition according to claim 1, wherein said particles of said dispersed phase are fragments having a rough surface obtained by crushing a mass of hydrogel.

12. The composition according to claim 1, wherein said particles of said dispersed phase have a water content, at equilibrium, ranging between 10 and 40% by weight.

13. The composition according to claim 1, wherein said particles of said dispersed phase have a water content, at equilibrium, of about 25% by weight.

14. The composition according to claim 1, wherein said dispersed phase consists of hydrogel particles of a cross-linked copolymer of hydroxyethyl methacrylate (HEMA) and of ethyl methacrylate (EMA).

15. The composition according to claim 14, wherein said cross-linked copolymer contains the repeating HEMA and EMA units in a ratio $R=\frac{\mathrm{HEMA}}{\mathrm{EMA}};$

said ratio R being included between 3.0 and 6.1.

16. The composition according to claim 15, wherein said ratio R is included between 3.5 and 5.

17. The composition according to claim 15, wherein said ratio is 4.1.

18. The composition according to claim 14, wherein said cross-linked copolymer is obtained by reaction, for 100 parts by weight of monomers:

HEMA+EMA, of;

77.5 to 87.5 parts by weight of HEMA, and

12.5 to 22.5 parts by weight of EMA;

in the presence of an efficient quantity of at least one cross-linking agent.

19. The composition according to claim 14, wherein said cross-linked copolymer is obtained by reaction, for 100 parts by weight of monomers:

HEMA+EMA, of;

80 to 85 parts by weight of HEMA, and

15 to 20 parts by weight of EMA;

in the presence of an efficient quantity of at least one cross-linking agent.

20. The composition according to claim 1, wherein it contains from 10 to 30% by mass of said particles in suspension in said continuous phase.

21. The composition according to claim 1, wherein it contains from 15 to 25% by mass of said particles in suspension in said continuous phase.

22. A method for preparing a composition according to claim 1, comprising:

a. cross-linking an aqueous solution of at least one polymer selected from proteins, polysaccharides and their derivatives to obtain the continuous phase;

b. obtaining particles of at least one hydrogel resulting from the polymerization and cross-linking of acrylic acid, methacrylic acid and/or one derivative of said acids;

c. optionally drying the said particles; and

d. incorporating and mixing the said particles in said continuous phase.

23. The method according to claim 22, wherein the said particles are obtained by mechanically crushing a mass of the hydrogel.

24. A method of reparative surgery or plastic surgery, comprising using the biocompatible diphasic composition according to claim 1 as a filling material.