INJECTABLE FILLERS FOR AESTHETIC MEDICAL ENHANCEMENT AND FOR THERAPEUTIC APPLICATIONS

• US 20130060230A1
• Filed: 08/17/2012
• Published: 03/07/2013
• Est. Priority Date: 08/19/2011
• Status: Active Grant

• Current Assignee: Xtant Medical Holdings, Inc. (OrbiMed Advisors LLC (China))
• Original Assignee: Pioneer Surgical Technology Incorporated (Surgalign Holdings, Inc.)
• Inventors: Ahn, Edward S., Capistron, Stephen M.
• Granted Patent: US 9,561,961 B2
• Time in Patent Office: Days
• US Class Current: 604/506
• CPC Class Codes: A61K 2800/594 Mixtures of polymers
• CPC Class Codes: A61K 2800/91 Injection
• CPC Class Codes: A61K 8/0279 Porous; Hollow
• CPC Class Codes: A61K 8/042 Gels
• CPC Class Codes: A61K 8/24 Phosphorous; Compounds thereof
• CPC Class Codes: A61K 8/73 Polysaccharides
• CPC Class Codes: A61K 8/90 Block copolymers A61K8/89 takes precedence
• CPC Class Codes: A61Q 19/08 Anti-ageing preparations
• CPC Class Codes: C01B 25/32 Phosphates of magnesium, calcium, strontium, or barium
• CPC Class Codes: C01B 25/327 After-treatment increasing the phosphate content of ores C01B25/32
• CPC Class Codes: C01P 2004/61 Micrometer sized, i.e. from 1-100 micrometer
• CPC Class Codes: C01P 2006/12 Surface area

Abstract

The present invention relates to a biocompatible injectable filler composition comprising calcium phosphate particles having a porosity of about 10% to about 90%, a BET surface area of about 1 m²/g to about 100 m²/g, and a mean particle size of about 1 micron to about 30 microns, a thermoreversible hydrophilic gelling agent, a carrier comprising water and an optional persistence enhancer and/or volumizing agent, and methods of its use to restore tissue volume and/or to smooth out tissue defects as in soft tissue or deep tissue augmentation.

Claims

1. An injectable tissue filler composition comprising

(a) about 10% to about 75% calcium phosphate particles, based on the weight of the filler composition, wherein the calcium phosphate particles have a porosity of about 10% to about 90%, a surface area of about 1 m²/g to about 100 m²/g, and a mean particle size of about 1 micron to about 30 microns,

(b) about 0.5% to about 50% thermoreversible gelling agent, based on the weight of the filler composition, wherein the gelling agent is a hydrogel that is in the form of a liquid a 25°

C. and in the form of a gel having a viscosity of about 2000 cP or more at 35°

C., and

(c) aqueous carrier,

wherein the filler composition has a pH of about 6.5 to about 7.5.

2. The filler composition of claim 1, wherein the calcium phosphate particles are selected from the group consisting of hydroxyapatite, tricalcium phosphate, octacalcium phosphate, and combinations thereof.

3. The filler composition of claim 1, wherein the calcium phosphate particles comprise hydroxyapatite.

4. The filler composition of claim 1, wherein the calcium phosphate particles have an average crystal size of about 300 nm or less.

5. The filler composition of claim 1, wherein the gelling agent comprises a poloxamer containing a block copolymer having a middle block of poly(propylene oxide) with a molecular weight of from about 1450 g/mol to about 6000 g/mol, and end blocks of poly(ethylene oxide) that comprise about 50% to about 90% by weight of the copolymer.

6. The filler composition of claim 5, wherein the gelling agent comprises a poloxamer with a polyoxypropylene molecular mass of 4,000 g/mol and a 70% polyoxyethylene content.

7. The filler composition of claim 1, wherein the composition further comprises a persistence enhancer.

8. The filler composition of claim 1, wherein the persistence enhancer is a dextran having an average molecular weight of about 500,000 g/mol or greater.

9. The filler composition of claim 1, wherein the composition comprises about 0.1% to about 25% persistence enhancer, by weight of the filler composition.

10. The filler composition of claim 1, wherein the calcium phosphate particles have a rounded morphology.

11. The filler composition of claim 1, wherein the calcium phosphate particles are acid etched.

12. The filler composition of claim 1, wherein the filler composition can be injected through a needle of 18 gauge or smaller.

13. The filler composition of claim 1, wherein the filler composition has a viscosity of about 100,000 cP to about 200,000 cP.

14. The filler composition of claim 1, wherein the calcium phosphate particles comprise about 95% or more hydroxyapatite, wherein the thermoreversible gelling agent is poloxamer 407, and wherein the composition further comprises a persistence enhancer that is dextran having an average molecular weight of about 500,000 g/mol or greater, glycerol, and a phosphate buffer.

15. The filler composition of claim 14, wherein the amount of calcium phosphate particles is about 30% to about 50%, the amount of poloxamer 407 is about 5% to about 15%, the amount of dextran is about 2% to about 8%, the amount of glycerol is about 2% to about 6%, and the amount of aqueous carrier is about 40% to about 50%, based on the weight of the filler composition.

16. A method of tissue augmentation comprising:

(i) obtaining an injectable filler composition comprising;

(a) about 10% to about 75% calcium phosphate particles, based on the weight of the filler composition, wherein the calcium phosphate particles have a porosity of about 10% to about 90%, a surface area of about 1 m²/g to about 100 m²/g, and a mean particle size of about 1 micron to about 30 microns,

(b) about 0.5% to about 50% thermoreversible gelling agent, based on the weight of the filler composition, wherein the gelling agent is a hydrogel that is in the form of a liquid a 25°

C. and in the form of a gel having a viscosity of about 2000 cP or more at 35°

C., and

(c) aqueous carrier,

wherein the filler composition has a pH of about 6.5 to about 7.5;

(ii) injecting or implanting the filler composition into or underneath tissue to form a bleb,

wherein the formation of the bleb increases tissue volume in the region surrounding the site of injection or implantation.

17. The method of claim 16, wherein the injecting or implanting step is not accompanied by acute inflammation of the tissue surrounding the site of injection or implantation.

18. The method of claim 16, wherein the method results in a reduction in the severity of lines, wrinkles, grooves, creases or other imperfections in the tissue surrounding the site of injection or implantation.

19. A method of producing a calcium phosphate particles having a rounded morphology comprising:

(i) providing calcium phosphate particles having a particle size of 30 micron or less and a surface area of 20 m²/g or less, and

(ii) contacting the calcium phosphate particles with an acid selected from the group consisting of nitric acid, hydrochloric acid, sulfuric acid, and phosphoric acid, in water.

20. The method of claim 19, wherein the calcium phosphate particles are hydroxyapatite particles.

21. A method of producing an injectable tissue filler composition comprising:

(i) partially sintering calcium phosphate particles having a particle size of 30 micron or less and a surface area of 20 m²/g or less, and

(ii) contacting the partially sintered calcium phosphate particles with an acid selected from the group consisting of nitric acid, hydrochloric acid, sulfuric acid, and phosphoric acid, in water to form calcium phosphate particles have a rounded morphology, a porosity of about 10% to about 90%, a surface area of about 1 m²/g to about 100 m²/g, and a mean particle size of about 1 micron to about 30 microns, and

(iii) compounding the calcium phosphate particles with a thermoreversible gelling agent that is a hydrogel that is in the form of a liquid a 25°

C. and in the form of a gel having a viscosity of about 2000 cP or more at 35°

C., and an aqueous carrier.

22. The method of claim 21, wherein the calcium phosphate particles are hydroxyapatite particles.