SITU SELF-SETTING MINERAL-POLYMER HYBRID MATERIALS, COMPOSITION AND USE THEREOF

• US 20100029549A1
• Filed: 10/08/2009
• Published: 02/04/2010
• Est. Priority Date: 12/09/1999
• Status: Active Grant

• Current Assignee: Smith & Nephew Orthopaedics Ag (Smith & Nephew PLC)
• Original Assignee: Biosyntech Canada Inc.
• Inventors: Rodrigues El Zein, Anabelle, Chaput, Cyril
• Granted Patent: US 8,389,467 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 24/0063 Phosphorus containing materials, e.g. apatite
• CPC Class Codes: A61L 24/0084 containing fillers of phosphorus-containing inorganic compounds, e.g. apatite
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/24 Collagen
• CPC Class Codes: A61L 27/32 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/425 of phosphorus containing material, e.g. apatite
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

The present invention relates to self-setting compositions consisting in admixed liquid and solid components enable the formation of hardened bio-materials having a broad range of properties and performances. The present invention proposes a) a thermo-sensitive self-gelling liquid component, being water-based, comprising at least a polycationic and a phosphate source, wherein the liquid component is a thermo-gelling solution at a pH ranging from 6.5 to 7.4; b) a powder component consisting in at least two calcium phosphate sources. The preferred calcium phosphate source includes apatites, tricalcium phosphates, tetracalcium phosphates and dicalcium phosphates. Both solid and liquid components are admixed to form a flowable slurry that sets in situ into a hardened calcium phosphate based bio-material.

Claims

1. An injectable self-setting composition comprising:

a) a water-based liquid component comprising at least one cationic polymer and one mono-phosphate salt;

said liquid component having a pH ranging from 6. 5 to 7.4, said liquid component having an endothermally gelling character and being free of insoluble particles; and

b) a powder component comprising at least two calcium phosphate sources selected from apatites and apatitic calcium phosphates, octacalcium phosphates, amorphous calcium phosphates, tetracalcium phosphates, tricalcium phosphates, dicalcium phosphates and monocalcium phosphates,

wherein when said components of step a) and b) are intimately and uniformly mixed together, said components of step a) and b) form an injectable thermo-setting slurry, said slurry when heated turns into a solid material.

2. The composition of claim 1, wherein said cationic polymer is a polysaccharide, a polypeptide or a synthetic polymer.

3. The composition of claim 1, wherein said cationic polymer has a concentration in said liquid component between 0.1 and 5.0% wt.

4. The composition of claim 1, wherein said cationic polymer is chitosan or collagen, or a mixture of chitosan and collagen.

5. The composition of claim 1, wherein said cationic polymer is a partially-deacetylated chitin or chitosan with a degree of deacetylation between 30 and 99%.

6. The composition of claim 1, wherein said cationic polymer is a polylysine.

7. The composition of claim 1, wherein said monophosphate salt has a basic character.

8. The composition of claim 1, wherein said liquid component comprises a first phosphate source selected from the group consisting of Na₂PO₄C₃H₅(OH)₂, Fe₂PO₄C₃H₅(OH)₂, K₂PO₄C₃H₅(OH)₂, MgPO₄C₃H₅(OH)₂, MnPO₄C₃H₅(OH)₂, Ca₂PO₄C₃H₅(OH)₂, Na₂PO₇C₃H₇, Na₂PO₇C₄H₇, K₂PO₇C₄H₇, NaPO₇C₄H₈, K₂PO₇C₄H₈, Na₂PO₈C₅H₉, K₂PO₈C₅H₉, NaPO₈C₅H₁₀, KPO₈C₅H₁₀, Na₂PO₉C₆H₁₁, NaPO₉C₆H₁₂, K₂PO₉C₆H₁₁, KPO₉C₆H₁₂, Na₂PO₈C₆H₁₃, K₂PO₈C₆H₁₃, NaPO₈C₆H₁₄, KPO₈C₆H₁₄, Na₂PO₉C₆H₁₂, K₂PO₉C₆H₁₂, NaPO₉C₆H₁₃, KPO₉C₆H₁₃, Na₂PO₈C₁₀H₁₁, K₂PO₈C₁₀H₁₁, NaPO₈C₁₀H₁₂, KPO₈C₁₀H₁₂ and the like, or a derivative thereof.

9. The composition of claim 1, wherein said monophosphate salt is a sodium, magnesium, potassium, ferric and/or calcium alpha- or beta-glycerophosphate salt, or a mixture thereof.

10. The composition of claim 1, wherein said monophosphate salt is glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate or fructose-6-phosphate salt, or a mixture thereof.

11. The composition of claim 1, wherein said liquid component has a pH between 6.8 and 7.2.

12. The composition of claim 1, wherein said liquid component has a viscosity superior to 200 mPa·

s.

13. The composition of claim 1, wherein said liquid component further comprises at least one other water-soluble polymer selected from the group consisting of polypeptides, cellulosics and synthetic polymers, including methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl propylcellulose, hydroxymethyl propylcellulose, poly(ethylene oxide), poly(propylene oxide), poly(ethylene glycol), poly(vinylpyrrolidone), poly(vinyl alcohol), and derivatives thereof.

14. The composition of claim 1, wherein said liquid component further comprises at least one organic polyol, including sugar-polyol, saccharide-polyol and glycol, selected from the group consisting of glycerol, mannitol, sorbitol, ethylene glycol oligomers, propylene glycol oligomers, saccharose, fructose, glucose, maltose, and the like.

15. The composition of claim 1, wherein said liquid component further comprises at least one water-soluble amino acid having a basic character and a pKa between 6.5 and 8.5.

16. The composition of claim 1, wherein said liquid component further comprises a water-soluble sulfonate or carboxylate salt having a basic character and a pKa between 6.5 and 8.5.

17. The composition of claim 1, wherein the liquid component and the powder component have a ratio liquid/powder component from 0.05 to 1.50 mL/g.

18. The composition of claim 1, wherein the composition has a final molar ratio of calcium/phosphorus between 1.20 and 1.80.

19. The composition of claim 1, wherein said powder component comprises at least one phosphate selected from the group consisting of alpha-tricalcium phosphate, an apatitic calcium phosphate, dicalcium phosphate, monocalcium phosphate, an amorphous calcium phosphate, and tetracalcium phosphate.

20. The composition of claim 1, wherein said powder component comprises less than 40% wt. of an apatitic calcium phosphate.

21. The composition of claim 1, wherein said powder component further comprises at least one fluoride selected from the group consisting of NaF, Na₂Si₆F, KF, KSi₆F, CaF₂, MgF₂, ZnF₂, and sodium fluorophosphates, and the like, or derivatives thereof.

22. The composition of claim 1, wherein said powder component further comprises at least one carbonate selected from the group consisting of Na₂CO₃, CaCO₃, K₂CO₃, MgCO₃, ZnCO₃, Ca₉K(PO₄)₅(CO₃)₂, Ca_8.5Na_1.5(PO₄)_4.5(CO₃)_2.5, Ca₉(PO₄)_4.5(CO₃)_1.5, and the like.

23. The composition of claim 1, wherein said powder component comprises a strontium salt including strontium carbonate.

24. The composition of claim 1, wherein said powder component comprises at least one calcium phosphate selected from the group consisting of fluoride, strontium, carbonate, magnesium, zinc, and barium containing calcium phosphates.

25. The composition of claim 1, wherein said powder component comprises at least one inorganic salt including sodium phosphates and disodium glycerophosphate, or the like.

26. The composition of claim 1, wherein said powder component comprises at least one organic salt including oxalate, citrate, malate, gluconate, lactate, lactobionate, or the like.

27. The composition of claim 1, wherein said powder component comprises at least one organic salt including oxalic, citric, malic, gluconic, lactic, lactobionic acids, or the like.

28. The composition of claim 1, wherein said powder component is a powder having a size ranging from 0.1 to 100 micrometers.

29. The composition of claim 1, further comprising a bioactive ingredient such as a drug, a protein, a peptide, a synthetic molecule or an inorganic molecule.

30. The composition of claim 1, which further comprises at least one osteoinductive agent selected from the group consisting of hormones, bone proteins and mixtures of osteoinductive proteins, demineralized bone matrix (DBM) or powder (DBP), bone morphogenic proteins (BMP), sialoproteins, osteonectin, osteopontin, osteocalcin, calcitonin.

31. The composition of claim 1, which further comprises at least one growth factor selected from the group consisting of IGF, EGF, a-FGF, b-FGF, PDGF-A, PDGF-B and TGF-beta.

32. The composition of claim 1, which further comprises an antiresorptive, antibiotic, antiviral, antitumor, or an immunosupressive agent.

33. An injectable self-setting composition comprising:

a) a liquid component, free of insoluble material, comprising, an organic and/or inorganic acid, a partially N-deacetylated chitosan and/or a collagen, and a glycerophosphate;

said liquid component having a pH ranging from 6.5 to 7.4, said liquid component having an endothermally gelling character, said partially N-deacetylated chitosan having a final concentration ranging between 0.5 to 3.0% w/v, and said glycerophosphate salt having a final concentration ranging between 1.0 to 10.0% w/v, and

b) a powder component comprising a dry mixture of a tricalcium phosphate with a calcium deficient apatite or an octacalcium phosphate, and with at least one of an inorganic salt, an organic salt, an organic acid source and an organic compound,

wherein when said components of step a) and b) are intimately and uniformly mixed together, said components of step a) and b) form an injectable thermo-setting slurry, said slurry when heated turns into a solid material.

35. A composition as described in claim 33 or 34, wherein said inorganic salt is selected from carbonate, phosphate, strontium, fluoride salts, and the like.

36. A composition as described in claim 33 or 34, wherein said organic salt is selected from citrate, malate, lactate, gluconate salts, and the like.

37. A composition as described in claim 33 or 34, wherein said organic acid is selected from citric acid, malic acid, lactic acid, gluconic acid, and the like.

38. A composition as described in claim 33 or 34, wherein said organic compound is selected from the group consisting of biological fluids and components, water-soluble or miscible organic polyols, drugs, aminoacids, proteins, and the like.

39. A composition as described in claim 33 or 34, which further comprises a water-soluble or miscible organic polyol, including sugar-polyol, saccharide-polyol and glycol, selected from the group consisting of glycerol, mannitol, sorbitol, ethylene glycol oligomers, propylene glycol oligomers, saccharose, fructose, glucose, maltose, and the like.

40. A composition as described in claim 33 or 34, which further comprises glucosamine and/or histidine.

41. A composition as described in claim 33 or 34, which further comprises a strontium containing compound.

42. A composition as described in claim 33 or 34, which further comprises a carbonate containing compound.

43. A composition as described in claim 33 or 34, which further comprises a fluoride containing compound.

34. An injectable self-setting composition comprising:

a) a liquid component, free of insoluble particle, comprising an organic and/or inorganic acid, a partially N-deacetylated chitosan and/or a collagen, and a glycerophosphate;

said liquid component having a pH ranging from 6.5 to 7.4, said liquid component having an endothermally gelling character, said partially N-deacetylated chitosan has a concentration ranging between 0.5 to 3.0% w/v, and said glycerophosphate salt has a concentration ranging between 1.0 to 10.0% w/v, and

b) a powder component comprising a dry mixture of a tetracalcium phosphate with a calcium deficient apatite or an octacalcium phosphate, and with at least one of an inorganic salt, an organic salt, an organic acid source and an organic compound,

wherein when said components of step a) and b) are intimately and uniformly mixed together, said components of step a) and b) form an injectable thermo-setting slurry, said slurry once heated setting into a solid material.

44. A method of preparation of an injectable self-setting composition, said method comprising the step of admixing a water-based liquid component comprising at least one cationic polymer and one monophosphate salt with a powder component comprising at least two calcium phosphate sources selected from apatites and apatitic calcium phosphates, octacalcium phosphates, amorphous calcium phosphates, tetracalcium phosphates, tricalcium phosphates, dicalcium phosphates and monocalcium phosphates, wherein said liquid component comprising at least one cationic polymer and one mono-phosphate salt;

said liquid component having a pH ranging from 6.5 to 7.4, said liquid component having an endothermally gelling character and being free of insoluble particles, said admixing thus forming an injectable thermo-setting slurry, said slurry when heated turns into a solid material.

45. A method of preparation of an injectable self-setting composition, said method comprising admixing a liquid component, free of insoluble material, comprising, an organic and/or inorganic acid, a partially N-deacetylated chitosan and/or a collagen, and a glycerophosphate, with a powder component comprising a dry mixture of a tricalcium phosphate with a calcium deficient apatite or an octacalcium phosphate, and with at least one of an inorganic salt, an organic salt, an organic acid source and an organic compound, said liquid component having a pH ranging from 6.5 to 7.4, said liquid component having an endothermally gelling character, said partially N-deacetylated chitosan having a final concentration ranging between 0.5 to 3.0% w/v, and said glycerophosphate salt having a final concentration ranging between 1.0 to 10.0% w/v, said admixing thus forming an injectable thermo-setting slurry, said slurry when heated turns into a solid material.

46. A method of preparation of an injectable self-setting composition, said method comprising admixing a liquid component, free of insoluble particle, comprising an organic and/or inorganic acid, a partially N-deacetylated chitosan and/or a collagen, and a glycerophosphate with a powder component comprising a dry mixture of a tetracalcium phosphate with a calcium deficient apatite or an octacalcium phosphate, and with at least one of an inorganic salt, an organic salt, an organic acid source and an organic compound, said liquid component having a pH ranging from 6.5 to 7.4, said liquid component having an endothermally gelling character, said partially N-deacetylated chitosan has a concentration ranging between 0.5 to 3.0% w/v, and said glycerophosphate salt has a concentration ranging between 1.0 to 10.0% w/v, said admixing thus forming an injectable thermo-setting slurry, said slurry when heated turns into a solid material.