Biofunctional hydroxyapatite coatings and microspheres for in-situ drug encapsulation

• US 20020155144A1
• Filed: 04/20/2001
• Published: 10/24/2002
• Est. Priority Date: 04/20/2001
• Status: Active Grant

• Current Assignee: University of British Columbia
• Original Assignee: University of British Columbia
• Inventors: Liu, Dean-Mo, Yang, Quanzu, Troczynski, Tomasz
• Granted Patent: US 6,730,324 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• 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: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/32 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C01B 25/32 Phosphates of magnesium, calcium, strontium, or barium
• CPC Class Codes: C04B 2111/00836 for medical or dental applications
• CPC Class Codes: C04B 28/34 containing cold phosphate binders
• CPC Class Codes: C04B 40/00 Processes, in general, for influencing or modifying the properties of mortars, concrete or artificial stone compositions, e.g. their setting or hardening ability active ingredients C04B22/00 - C04B24/00; hardening of a well-defined composition C04B26/00 - C04B28/00; making porous, cellular or lightening C04B38/00; mechanical aspects B28, e.g. conditioning the materials prior to shaping B28B17/02
• CPC Class Codes: C04B 41/009 characterised by the material treated
• CPC Class Codes: C04B 41/455 the coating or impregnating process including a chemical conversion or reaction
• CPC Class Codes: C04B 41/5092 Phosphate cements
• CPC Class Codes: C04B 41/67 Phosphates
• CPC Class Codes: C23C 30/00 Coating with metallic material characterised only by the composition of the metallic material, i.e. not characterised by the coating process C23C26/00, C23C28/00 take precedence

Abstract

This invention relates to novel room-temperature process for obtaining calcium phosphate, in particular hydroxyapatite, coatings and microspheres that encapsulate drugs, proteins, genes, DNA for therapeutical use. The coatings and microspheres are designed to perform a defined biological function related to drug delivery, such as gene therapy through gene delivery. A novel method for encapsulation, and subsequent controlled release of therapeutically active agents from such biofunctional coatings and microspheres is disclosed. Such coatings and microspheres are useful for side-effects free, long-term, targeted, controlled release and delivery of drugs, proteins, DNA, and other therapeutic agents.

Claims

1. A process for preparing a calcium phosphate phase which comprises:

(a) dispersing a homogenization of monocalcium phosphate Ca(H₂PO₄)₂ and calcium hydroxide Ca(OH)₂ precursors in a substantially water-free medium to form a paste or viscous slurry of precursors;

(b) drying the precursors slurry;

(c) admixing a water-based solution of phosphate ions in the slurry to produce a mixture; and

(d) incubating the resulting mixture in a humid environment at a temperature of 20-50°

C. to dissolve the precursors and precipitate a calcium phosphate phase.

2. A process as claimed in claim 1 wherein the calcium phosphate phase is hydroxyapatite.

3. A process as claimed in claim 1 wherein the Ca/P atomic ratio in the precursors mixture is in the range of 1.2-1.67 and the mixture has a solids concentration of 30-70 vol %.

4. A process as claimed in claim 1 wherein the substantially water-free medium is an alcohol.

5. A process as claimed in claim 4 wherein the alcohol is ethyl alcohol, methyl alcohol or propyl alcohol

6. A process as claimed in claim 1 wherein the water-based solution of phosphate ions is sodium phosphate and the humid environment is 50% to 100% Relative Humidity.

7. A process as claimed in claim 1 wherein the precursors slurry is dried in a prescribed shape.

8. A process as claimed in claim 7 wherein the shape is a pellet, a coating, a microsphere, or a dental cavity or bone cavity fill.

9. A process as claimed in claim 1 wherein a crystalline hydroxyapatite powder is added to the precursors slurry to promote crystallization of hydroxyapatite calcium phosphate phase during the incubation period.

10. A process as claimed in claim 1 wherein a therapeutically active material is added to the precursors slurry for encapsulation during crystallization of the hydroxyapatite calcium phosphate phase during the incubation period.

11. A process as claimed in claim 10 wherein the therapeutically active material is a drug, a protein, a gene or DNA.

12. A process as claimed in claim 1 wherein the slurry of precursors is deposited and dried on the surface of a calcium phosphate substrate.

13. A process as claimed in claim 12 wherein the calcium phosphate substrate is a thin film of hydroxyapatite coating deposited on a metallic substrate using sol-gel process

14. A process as claimed in claim 1 wherein the precipitated calcium phosphate phase is exposed to a solution supersaturated with Ca²⁺ and PO₄³⁻

ions to provide a coating of biomimetic hydroxyapatite film on the precipitated calcium phosphate phase.

15. A process as claimed in claim 10 wherein the precipitated calcium phosphate phase is exposed to a solution supersaturated with Ca²⁺ and PO₄³⁻

ions to provide a coating of biomimetic hydroxyapatite film on the precipitated calcium phosphate phase.

16. A process as claimed in claim 1 wherein the slurry of precursors is atomized and spray-dried to obtain microspheres of the precursors.

17. A process as claimed in claim 10 wherein the slurry of precursors is atomized and spray-dried to obtain microspheres of the precursors.

18. A process as claimed in claim 16 wherein the microspheres of the precursors are exposed to a water-based solution of phosphate ions and incubated in a humid environment at a temperature of 20-50°

C. to promote dissolution of the precursors and precipitation of calcium phosphate phase.

19. A process as claimed in claim 17 wherein the microspheres of the precursors are exposed to a water-based solution of phosphate ions and incubated in a humid environment at a temperature of 20-50°

C. to promote dissolution of the precursors and precipitation of calcium phosphate phase.

20. A process as claimed in claims 16 wherein the microsphere containing the precipitated calcium phosphate phase is exposed to a solution supersaturated with Ca²⁺ and PO₄³⁻

ions to provide a coating of biomimetic hydroxyapatite film on the precipitated calcium phosphate phase.

21. A process as claimed in claims 18 wherein the microsphere containing the precipitated calcium phosphate phase is exposed to a solution supersaturated with Ca²⁺ and PO₄³⁻

ions to provide a coating of biomimetic hydroxyapatite film on the precipitated calcium phosphate phase.

22. A process as claimed in claim 1 wherein the precipitated calcium phosphate phase is exposed to a solution polymer to form a polymer film on the microsphere surface.

23. A process as claimed in claim 10 wherein the precipitated calcium phosphate phase is exposed to a solution polymer to form a polymer film on the microsphere surface.

24. A process as claimed in claim 16 wherein the precipitated calcium phosphate phase is exposed to a solution polymer to form a polymer film on the microsphere surface.

25. A process as claimed in claim 18 wherein the precipitated calcium phosphate phase is exposed to a solution polymer to form a polymer film on the microsphere surface.

26. A process as claimed in claim 22 wherein the polymer is a biodegradable polymer

27. A process as claimed in claim 22 wherein the polymer is polyvinyl alcohol.

28. A calcium phosphate phase prepared according to the process of claim 1.

29. A calcium phosphate phase-substrate prepared according to claim 13.

30. A microsphere prepared according to the process of claim 16.