Bone substitute composition comprising hydroxyapatite and a method of production therefor

• US 6,201,039 B1
• Filed: 06/24/1996
• Issued: 03/13/2001
• Est. Priority Date: 09/21/1993
• Status: Expired due to Term

• Current Assignee: Penn State Research Foundation (Pennsylvania State University)
• Original Assignee: Penn State Research Foundation (Pennsylvania State University)
• Inventors: Brown, Paul W., Martin, Roger I., Huisen, Kevor S. Ten
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US08/617,809
• Time in Patent Office: 1,723 Days
• Field of Search: 424/423, 523/115, 523/116
• US Class Current: 523/115
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2/30756 Cartilage endoprostheses A61F2/3603 takes precedence
• CPC Class Codes: A61F 2310/00293 containing a phosphorus-containing compound, e.g. apatite
• CPC Class Codes: A61F 2310/00365 Proteins; Polypeptides; Degradation products thereof
• 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 27/24 Collagen
• CPC Class Codes: A61L 27/46 with phosphorus-containing inorganic fillers
• CPC Class Codes: C08K 3/32 Phosphorus-containing compounds
• CPC Class Codes: C08L 89/06 derived from leather or skin , e.g. gelatin

Abstract

The present invention is directed to polymineralic particles which are precursors of hydroxyapatite and a method for their production. The present invention is also directed to a synthetic bone-like composition comprising said hydroxyapatite polymineralic precursor particles of hydroxyapatite and optionally, a polymeric material capable of promoting mineralization of hydroxyapatite, which are useful for fixing prosthetic devices, useful as bone substitutes to directly fill bone defects, to provide substrates for cartilage, and to repair teeth, and methods of making such preparations. The present invention is also directed to a method of treating collagen to provide a micro-structure close to that of native bone.

Claims

1. A synthetic bone-like substitute kit comprising:

(a) a container of polymineralic precursor particles produced by reacting a calcium source, with an acidic phosphate source having at least two protons attached to one phosphate, in a non-aqueous liquid for a time sufficient to produce polymineralic precursor particles capable of forming hydroxyapatite without additional sources of calcium or phosphate said polymineralic precursor particles having a Ca/P ratio of 1.5 to 1.67, capable of forming hydroxyapatite in the absence of additional sources of calcium and phosphate.

2. The kit according to claim 1 further comprising a container of a polymeric material capable of promoting mineralization of hydroxyapatite.

3. The kit according to claim 1 wherein said polymineralic material is treated insoluble collagen having a pore size of from 2 to 100 μ

m.

4. The invention according to claim 1 wherein said calcium source is calcium oxide, calcium carbonate, calcium hydroxide, calcium hydroxide-calcium carbonate double salts, or a basic calcium phosphate having a Ca/P ratio greater than 1.67 or mixtures thereof.

5. A method of treating insoluble collagen for use in a synthetic bone-like composition which comprises the steps of:

(a) suspending insoluble collagen in an acidic solution to form a suspension;

(b) subjecting said suspension to a mechanical action;

(c) freezing said suspension;

(d) thawing said frozen suspension; and

(e) collecting said treated collagen.

6. The method according to claim 5 wherein said treated collagen has a pore size from 2 μ

m to 100 μ

m.

7. The method according to claim 5 further comprising repeating steps (c) and (d), prior to step (e).

8. The method according to claim 5, wherein said collecting step (e) is freeze-drying.

9. Insoluble collagen produced by the process according to claims 5 or 6.

19. The method according to claim 8 wherein said calcium source is calcium oxide, calcium carbonate, calcium hydroxide, calcium hydroxide-calcium carbonate double salts, or a basic calcium phosphate having a Ca/P ratio greater than 1.67 or mixtures thereof.

20. The method according to claim 19 wherein said basic calcium phosphate is Ca₄(PO₄)₂O.

21. The method according to claim 8 wherein said basic calcium phosphate is Ca₄(PO₄)₂O and the non aqueous liquid is an aliphatic hydrocarbon.

10. A method of producing polymineralic precursor particles capable of forming hydroxyapatite in the absence of additional sources of calcium and phosphate, which comprises the steps of:

(a) reacting at least one calcium source, with at least one acid phosphate source having at least 2 protons attached to one phosphate, in a non-aqueous liquid for a time sufficient to form said polymineralic precursors particles and having a Ca/P ratio of 1.5 to 1.67; and

(b) collecting said polymineralic precursor particles.

11. The method according to claim 10 wherein said calcium source has an average particle size of from 1 μ

m to 5 μ

m.

12. The method according to claim 10 wherein said non-aqueous liquid is selected from the group consisting of substituted or unsubstituted liquid aliphatic hydrocarbons and liquid aromatic hydrocarbons.

13. The method according to claim 10 wherein said calcium source is selected from the group consisting of calcium oxide, calcium carbonate, calcium hydroxide, calcium hydroxide-calcium carbonate double salts, or a basic calcium phosphate having a Ca/P ratio of greater than 1.67 or mixtures thereof.

14. The method according to claim 10 wherein said acidic phosphate source having at least two protons attached to one phosphate is selected form the group consisting of phosphoric acid, H₃PO₄, H₃PO₄.½

H₂O, Ca(H₂PO₄)₂, Ca(H₂PO₄)₂.H₂O and NH₄H₂(PO₄)₂.nH₂O, or mixtures thereof.

15. The method according to claim 10 wherein said collecting step (b) comprises evaporating off said non-aqueous liquid.

16. Polymineralic precursor particles produced by the process according to claim 10.

17. A hydroxyapatite composition comprising the polymineralic precursor particles according to claim 16.

18. The composition according to claim 17, which completely reacts to form phase pure hydroxyapatite within 2 hours.

22. The method according to claim 10, wherein said non-aqueous liquid is heptane.