Injectable microdispersions for medical applications

• US 20030236310A1
• Filed: 06/25/2002
• Published: 12/25/2003
• Est. Priority Date: 06/25/2002
• Status: Active Grant

• Current Assignee: Ethicon Incorporated (Johnson & Johnson)
• Original Assignee: Ethicon Incorporated (Johnson & Johnson)
• Inventors: Nathan, Aruna, Rosenblatt, Joel, Arnold, Steven C.
• Granted Patent: US 7,026,374 B2
• Time in Patent Office: Days
• US Class Current: 514/772.4
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention is directed to microdispersions and pharmaceutical compositions containing a synthetic, bioabsorbable, biocompatible liquid polymer that is the reaction product of a polybasic acid or derivative thereof, a polyol and a fatty acid, the liquid polymer having a melting point less than about 40° C., as determined by differential scanning calorimetry, and a synthetic, bioabsorbable, biocompatible polymeric wax comprising the reaction product of a polybasic acid or derivative thereof, a fatty acid and a polyol, the polymeric wax having a melting point less than about 70° C., as determined by differential scanning calorimetry.

Claims

1. A composition, comprising:

a microdispersion, said microdispersion comprising a synthetic, bioabsorbable, biocompatible liquid polymer having a melting point less than about 40°

C., as determined by differential scanning calorimetry; and

a synthetic, bioabsorbable, biocompatible polymeric wax having a melting point less than about 70°

C., as determined by differential scanning calorimetry, wherein said liquid polymer and said polymeric wax comprise the reaction product of a polybasic acid or derivative thereof, a fatty acid, and a polyol.

2. The composition of claim 1 wherein said polymeric wax comprises the reaction product of said polybasic acid or derivative thereof and a monoglyceride, said monoglyceride comprising the reaction product of said fatty acid and said polyol.

3. The composition of claim 2 wherein said polybasic acid or derivative thereof is selected from the group consisting of succinic acid, succinic anhydride, malic acid, tartaric acid, citric acid, diglycolic acid, diglycolic anhydride, glutaric acid, glutaric anhydride, adipic acid, pimelic acid, suberic acid, sebacic acid, fumaric acid, maleic acid, maleic anhydride, mixed anhydrides, esters, activated esters and acid halides.

4. The composition of claim 2 wherein said monoglyceride is selected from the group consisting of monostearoyl glycerol, monopalmitoyl glycerol, monomyrisitoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinoleoyl glycerol and monooleoyl glycerol.

5. The composition of claim 4 wherein said polybasic acid derivative is succinic anhydride.

6. The composition of claim 4 wherein said polybasic acid is succinic acid.

7. The composition of claim 1 wherein said polymeric wax comprises a copolymer.

8. The composition of claim 7 wherein said polymeric wax copolymer comprises the reaction product of said fatty acid, said polyol, and at least two of said polybasic acids or derivatives thereof selected from the group consisting of succinic acid, succinic anhydride, malic acid, tartaric acid, citric acid, diglycolic acid and diglycolic anhydride.

9. The composition of claim 7 wherein said polymeric wax copolymer comprises the reaction product of said polybasic acid or derivative thereof, and at least two monoglycerides selected from the group consisting of monostearoyl glycerol, monopalmitoyl glycerol, monomyrisitoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinoleoyl glycerol and monooleoyl glycerol.

10. The composition of claim 7 wherein said polymeric wax copolymer comprises the reaction product of said polybasic acid or derivative thereof, a monoglyceride selected from the group consisting of monostearoyl glycerol, monopalmitoyl glycerol, monomyrisitoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinoleoyl glycerol and monooleoyl glycerol, and at least one additional polyol selected from the group consisting of ethylene glycol, 1,2-propylene glycol, 1,3-propanediol, bis-2-hydroxyethyl ether, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol, other diols, linear poly(ethylene glycol), branched poly(ethylene glycol), linear poly(propylene glycol), branched poly(propylene glycol), linear poly(ethylene-co-propylene glycol)s and branched poly(ethylene-co-propylene glycol)s.

11. The composition of claim 1 further comprising end capping-moieties selected from the group consisting of alkyls, alkenyls, alkynyls, acrylates, methacrylates, amines, isocyanates and isothiocyanates.

12. The composition of claim 1, further comprising an effective amount of a bioactive agent.

13. The composition of claim 12 wherein said polymeric wax comprises the reaction product of said polybasic acid or derivative thereof and a monoglyceride, said monoglyceride comprising the reaction product of said fatty acid and said polyol.

14. The composition of claim 12 wherein said polybasic acid or derivative thereof is selected from the group consisting of succinic acid, succinic anhydride, malic acid, tartaric acid, citric acid, diglycolic acid, diglycolic anhydride, glutaric acid, glutaric anhydride, adipic acid, pimelic acid, suberic acid, sebacic acid and derivatives thereof.

15. The composition of claim 13 wherein said monoglyceride is selected from the group consisting of mono stearoyl glycerol, monopalmitoyl glycerol, monomyrisitoyl glycerol, monocaproyl glycerol, monodecanoyl, monolauroyl glycerol, monolinoleoyl glycerol and monooleoyl glycerol.

16. The composition of claim 15 wherein said polybasic acid derivative is succinic anhydride.

17. The composition of claim 15 wherein said polybasic acid is succinic acid.

18. The composition of claim 12 wherein said polymeric wax comprises a copolymer.

19. The composition of claim 12 wherein said bioactive agent is selected from the group consisting of antiinfectives, analgesics, anorexics, antihelmintics, antiarthritics, antiasthmatics, anticonvulsants, antidepressants, antidiuretics, antidiarrheals, antihistamines, antiinflammatory agents, antimigraine preparations, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, anticholinergics, sympathomimetics, xanthine derivatives, calcium channel blockers, beta-blockers, antiarrhythmics, antihypertensives, diuretics, vasodilators, central nervous system stimulants, decongestants, hormones, steroids, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, psychostimulants, sedatives, tranquilizers, naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins, oligonucleotides, antibodies, antigens, cholinergics, chemotherapeutics, hemostatics, clot dissolving agents, radioactive agents and cystostatics.

20. The composition of claim 12 wherein said bioactive agent is risperidone.

21. The composition of claim 12 wherein said bioactive agent is erythropoietin.

22. The composition of claim 12 wherein said bioactive agent is rapamycin.

23. A medical device, comprising:

a microdispersion, said microdispersion comprising a synthetic, bioabsorbable, biocompatible liquid polymer having a melting point less than about 40°

C., as determined by differential scanning calorimetry; and

a synthetic, bioabsorbable, biocompatible polymeric wax having a melting point less than about 70°

C., as determined by differential scanning calorimetry, wherein said liquid polymer and said polymeric wax comprise the reaction product of a polybasic acid or derivative thereof, a fatty acid, and a polyol, said liquid polymer.

24. The medical device of claim 23 comprising a soft tissue repair material comprising said microdispersion.

25. The medical device of claim 23 comprising a soft tissue augmentation material comprising said microdispersion.

26. The medical device of claim 23 comprising a coating of said microdispersion.

27. The medical device of claim 26 wherein the surgical article is selected from the group consisting of sutures, stents, needles, vascular grafts, stent-graft combinations, meshes, tissue engineering scaffolds, pins, clips, staples, films, sheets, foams, anchors, screws and plates.

28. The medical device of claim 23 comprising a bone replacement material comprising said microdispersion.

29. The medical device of claim 28 further comprising a therapeutically effective amount of a bioactive agent.

30. The medical device of claim 29 wherein said bioactive agent is a growth factor.

31. The medical device of claim 30 wherein said growth factor is selected from the group consisting of cell attachment mediators, biologically active ligands, integrin binding sequence, bone morphogenic proteins, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, IGF-I, IGF-II, TGF- . I-III, growth differentiation factor, parathyroid hormone, vascular endothelial growth factor, hyaluronic acid, glycoprotein, lipoprotein, bFGF, TGF superfamily factors, BMP-2, BMP-4, BMP-6, BMP-12, sonic hedgehog, GDF5, GDF6, GDF8, PDGF, tenascin-C, fibronectin, thromboelastin, and thrombin-derived peptides.

32. The medical device of claim 28 further comprising a biologically derived substance selected from the group consisting of demineralized bone, platelet rich plasma, bone marrow aspirate and bone fragments.

33. The medical device of claim 28 further comprising an inorganic filler.

34. The medical device of claim 33 wherein said inorganic filler is selected from the group consisting of alpha-tricalcium phosphate, beta-tricalcium phosphate, calcium carbonate, barium carbonate, calcium sulfate, barium sulfate and hydroxyapatite.

35. The medical device of claim 33 wherein said inorganic filler is hydroxyapatite.