Bone substitute composition

• US 8,420,127 B2
• Filed: 03/05/2004
• Issued: 04/16/2013
• Est. Priority Date: 03/05/2003
• Status: Expired due to Fees

• Current Assignee: BONE Support NYA AB
• Original Assignee: Bone Support AB (BONESUPPORT HOLDING AB)
• Inventors: Lidgren, Lars, Nilsson, Malin
• Primary Examiner(s): Kemmerer, Elizabeth C
• Assistant Examiner(s): Deberry, Regina M
• Application Number:
  US10/547,671
• Publication Number:
  US 20070041906A1
• Time in Patent Office: 3,329 Days
• Field of Search: None
• US Class Current: 424/602
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 33/06 Aluminium, calcium or magnesium; Compounds thereof , e.g. clay
• CPC Class Codes: A61K 33/42 Phosphorus; Compounds thereof
• CPC Class Codes: A61K 49/0409 Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
• 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 24/001 Use of materials characterised by their function or physical properties
• CPC Class Codes: A61L 24/0063 Phosphorus containing materials, e.g. apatite
• CPC Class Codes: A61L 24/02 containing inorganic materials
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/425 of phosphorus containing material, e.g. apatite
• 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

Abstract

An injectable bone mineral substitute material composition with the capability of being hardened in a body fluid in vivo, which comprises at least one calcium phosphate component and at least one calcium sulfate component as a dry mixture mixed with an aqueous liquid, and at least one accelerator, the at least one calcium sulfate component being particulate hardened calcium sulfate, which has a specified particle size that is in order to confer injectability to the composition. The invention also concerns the bone mineral substitute material produced from the composition as well as methods and uses thereof.

Claims

1. A composition comprising:

a) at least one calcium phosphate component in the form of a powder capable of being hardened into a cement when contacted with an aqueous liquid;

b) at least one hardened particulate calcium sulfate dihydrate component containing

a prophylactic or therapeutic amount of at least one water soluble bioactive agent, wherein said at least one hardened particulate calcium sulfate dihydrate component is present in an amount ranging from 10 wt % to 60 wt % of said composition and has a particle diameter of less than 100 μ

m; and

c) at least one accelerator chosen from disodium hydrogen phosphate (Na₂HPO₄), calcium phosphate cement, precipitated hydroxyapatite (PHA), and calcium deficient hydroxyapatite (CDHA), or a mixture thereof, and

wherein the at least one hardened particulate calcium sulfate dihydrate component is prepared according to a process comprising reacting calcium sulfate hemihydrate, the at least one water soluble bioactive agent, and water.

2. The composition of claim 1, wherein said at least one hardened particulate calcium sulfate dihydrate component is present in an amount ranging from 10 wt % to 40 wt % of said composition.

3. The composition of claim 1, wherein said at least one hardened particulate calcium sulfate dihydrate component has a particle diameter between 1 μ

m and 50 μ

m.

4. The composition of claim 1, wherein said at least one hardened particulate calcium sulfate dihydrate component has a particle diameter between 1 μ

m and 10 μ

m.

5. The composition of claim 1, wherein said at least one calcium phosphate component is present in an amount ranging from 40 wt % to 90 wt % of said composition.

6. The composition of claim 1, wherein said at least one calcium phosphate component is present in an amount ranging from 60 wt % to 90 wt % of said composition.

7. The composition of claim 1, wherein said at least one calcium phosphate component is chosen from tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), dicalcium phosphate dihydrate (DCPD), anhydrous dicalcium phosphate (DCPA), dicalcium phosphate (OCP), tricalcium phosphate (TCP), and octocalcium phosphate (OCP).

8. The composition of claim 7, wherein said at least one calcium phosphate component is tricalcium phosphate (TCP).

9. The composition of claim 1, wherein said at least one water soluble bioactive agent is chosen from an endogenously produced bioactive molecule;

an antioxidant;

a vitamin chosen from calciferons, calcitrols, other D vitamins and derivatives thereof;

a cytostatic agent;

a protein;

an analgesic, an antiviral, an antifungal or tuberculostatic/tuberculocidal compound;

an antiparasite compound;

a natural antibiotic;

a semisynthetic or synthetic antibacterial;

a bacteriostatic compound;

an antiinfectious substance;

a natural or synthetically produced prostaglandin;

a precursor or metabolite to prostaglandin;

a prostaglandin analogue or compound that induces or inhibits endogenous prostaglandin production or induces or inhibits prostaglandin metabolism;

a compound that affects the production of precursors or further metabolism of active prostaglandin metabolites;

a growth factor which is optionally endogenously produced;

an enamel matrix protein;

biophosphonates;

osteocalcin;

osteonectin or derivatives thereof;

an osteoinductive compound;

a hormone which is optionally autologous;

a growth factor or a derivative thereof; and

a statin.

10. The composition of claim 1, wherein said at least one water soluble bioactive agent is an antibiotic.

11. The composition of claim 10, wherein said antibiotic is gentamycin.

12. The composition of claim 1, wherein said at least one accelerator is hydroxyapatite (HA).

13. The composition of claim 1, wherein said calcium phosphate cement accelerator is present in an amount between 0.1 wt % and 10 wt % of said at least one calcium phosphate component.

14. The composition of claim 1, wherein said calcium phosphate cement accelerator has a Ca/P ratio between 1.5 and 2.

15. The composition of claim 1, wherein said calcium phosphate cement accelerator has a particle diameter of less than 20 μ

m.

16. The composition of claim 1, wherein said composition further comprises a pH reducing component.

17. A method of substituting bone comprising

(a) injecting a composition comprising a composition according to claim 1 and an aqueous liquid

into a gap in the bone, a bone void, and/or a pre-existing bone cavity;

and

(b) allowing said composition to harden.

18. A method of substituting bone comprising

placing a cement composition prepared from the hardening reaction of a composition according to claim 1

and

an aqueous liquid, into a gap in the bone, a bone void, and/or a pre-existing bone cavity.

19. A method of preparing an injectable composition comprising contacting

at least one calcium phosphate component;

at least one hardened particulate calcium sulfate dihydrate component containing a prophylactic or therapeutic amount of at least one water soluble bioactive agent, wherein said at least one hardened particulate calcium sulfate dihydrate component is present in an amount ranging from 10 wt % to 60 wt % of the total weight of the components other than the aqueous liquid before said combination and has a particle diameter of less than 100 μ

m; and

at least one accelerator chosen from disodium hydrogen phosphate (Na₂HPO₄), calcium phosphate cement, precipitated hydroxyapatite (PHA), and calcium deficient hydroxyapatite (CDHA), or a mixture thereof,

with an aqueous liquid, wherein the resulting composition is in the form of an injectable composition, and

wherein the at least one hardened particulate calcium sulfate dihydrate component is prepared according to a process comprising reacting calcium sulfate hemihydrate, the at least one water soluble bioactive agent, and water.

20. The method of claim 19, wherein the aqueous liquid comprises an accelerator.

21. The method of claim 20, wherein said aqueous liquid comprises a water soluble non-ionic X-ray contrast agent.

22. The method of claim 21, wherein said water soluble non-ionic X-ray contrast agent is iohexol.

23. A system comprising:

(a) a first unit comprising at least one calcium phosphate component, at least one hardened particulate calcium sulfate dihydrate component containing at least one water soluble bioactive agent, and at least one accelerator chosen from disodium hydrogen phosphate (Na₂HPO₄), calcium phosphate cement, precipitated hydroxyapatite (PHA), and calcium deficient hydroxyapatite (CDHA), or a mixture thereof,

wherein said at least one hardened particulate calcium sulfate dihydrate component is present in an amount ranging from 10 wt % to 60 wt % of said composition of said first unit and has a particle diameter of less than 100 μ

m; and

wherein the at least one hardened particulate calcium sulfate dihydrate component is prepared according to a process comprising reacting calcium sulfate hemihydrate, the at least one water soluble bioactive agent, and water; and

(b) a second unit comprising an aqueous liquid,

wherein the composition of said first unit and the liquid of said second unit are not in contact.

24. The system of claim 23, wherein the aqueous liquid comprises an accelerator.

25. The system of claim 23, wherein said at least one hardened particulate calcium sulfate dihydrate component is present in an amount ranging from 10 wt % to 40 wt % of said composition of said first unit.

26. The system of claim 23, wherein said at least one hardened particulate calcium sulfate dihydrate component has a particle diameter between 1 μ

m and 50 μ

m.

27. The system of claim 23, wherein said at least one hardened particulate calcium sulfate dihydrate component has a particle diameter between 1 μ

m and 10 μ

m.

28. The system of claim 23, wherein said at least one calcium phosphate component is present in an amount ranging from 40 wt % to 90 wt % of said composition of said first unit.

29. The system of claim 23, wherein said at least one calcium phosphate component is present in an amount ranging from 60 wt % to 90 wt % of said composition of said first unit.

30. The system of claim 23, wherein said at least one calcium phosphate component is chosen from tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), dicalcium phosphate dihydrate (DCPD), anhydrous dicalcium phosphate (DCPA), dicalcium phosphate (OCP), tricalcium phosphate (TCP), and octocalcium phosphate (OCP).

31. The system of claim 30, wherein said at least one calcium phosphate component is tricalcium phosphate (TCP).

32. The system of claim 23, wherein said at least one water soluble bioactive agent is chosen from an endogenously produced bioactive molecule;

an antioxidant;

a vitamin chosen from calciferons, calcitriols, other D vitamins and derivatives thereof;

a cytostatic agent;

a protein;

an analgesic, an antiviral, an antifungal or tuberculostatic/tuberculocidal compound;

an antiparasite compound;

a natural antibiotic;

a semisynthetic or synthetic antibacterial;

a bacteriostatic compound;

an antiinfectious substance;

a natural or synthetically produced prostaglandin;

a precursor or metabolite to prostaglandin;

a prostaglandin analogue or compound that induces or inhibits endogenous prostaglandin production or induces or inhibits prostaglandin metabolism;

a compound that affects the production of precursors or further metabolism of active prostaglandin metabolites;

a growth factor which is optionally endogenously produced;

an enamel matrix protein;

biophosphonates;

osteocalcin;

osteonectin or derivatives thereof;

an osteoinductive compound;

a hormone which is optionally autologous;

a growth factor or a derivative thereof; and

a statin.

33. The system of claim 23, wherein said at least one water soluble bioactive agent is an antibiotic.

34. The system of claim 33, wherein said antibiotic is gentamycin.

35. The system of claim 23, wherein said system further comprises an accelerator.

36. The system of claim 35, wherein said accelerator is chosen from disodium hydrogen phosphate (Na₂HPO₄), calcium phosphate cement, precipitated hydroxyapatite (PHA), calcium deficient hydroxyapatite (CDHA), or a mixture thereof.