MINERAL-COATED MICROSPHERES

• US 20140161886A1
• Filed: 09/25/2009
• Published: 06/12/2014
• Est. Priority Date: 09/25/2008
• Status: Active Grant

• Current Assignee: TRS Holdings LLC
• Original Assignee: Tissue Regeneration Systems, Inc.
• Inventors: Murphy, William L., Jongpaiboonkit, Leenaporn
• Granted Patent: US 11,607,391 B2
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 35/02 from inanimate materials carbon A61K33/44
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 9/501 Inorganic compounds
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation

Abstract

Provided is a microsphere comprising a bead coated with a first calcium-containing mineral. Also provided is a method of producing a microsphere. Additionally, a method of administering a compound to a vertebrate is provided.

Claims

1. A microsphere comprising a bead coated with a first calcium-containing mineral.

2. The microsphere of claim 1, wherein the first calcium-containing mineral is at least one of apatite, hydroxyapatite, α

-tricalcium phosphate, β

-tricalcium phosphate, amorphous calcium phosphate, dicalcium phosphate, octacalcium phosphate, calcium carbonate, and a carbonated-substituted calcium-deficient hydroxyapatite.

5. The microsphere of claim 1, wherein the bead is negatively charged.

6. The microsphere of claim 5, wherein the negative charge is due to carboxylate groups.

7. The microsphere of claim 1, wherein the bead is a polymer.

8. The microsphere of claim 7, wherein the polymer is bioabsorbable.

9. The microsphere of claim 7, wherein the polymer is a synthetic polymer.

10. The microsphere of claim 7, wherein the polymer comprises polar oxygen groups.

11. The microsphere of claim 7, wherein the polymer is at least one of a poly(D,L-lactide-co-dlycolide) (PLG), a polycarboxylate, a polyanhydride, a poly(α

-hydroxy ester), a poly(ethylene terephthalate), poly(carbonate), a poly(amides), a poly(lactone), a poly(saccharide), a poly(acrylate), and about 85;

15 lactide;

glycolide.

14. The microsphere of claim 1, wherein the first calcium-containing mineral is a carbonated-substituted calcium-deficient hydroxyapatite and the bead is poly(D,L-lactide-co-glycolide) (PLG), wherein the PLG is about 85:

15 lactide;

glycolide.

15. The microsphere of claim 1, further comprising a component adhering to the first calcium-containing mineral, wherein the component introduces a functional group to the first calcium-containing mineral.

16. The microsphere of claim 15, wherein the functional group is a carboxylate, an amine, a carbonyl, a nitro, a hydroxyl, an aldehyde, or an ester.

17. The microsphere of claim 15, wherein the component comprises a poly(aspartic acid), a poly(glutamic acid), or a bisphosphonate.

18. The microsphere of claim 1, further comprising a first compound adhering to the first calcium-containing mineral.

19. The microsphere of claim 18, wherein the first calcium-containing mineral is a carbonated-substituted calcium-deficient hydroxyapatite and the bead is poly(D,L-lactide-co-glycolide) (PLG), wherein the PLG is about 85:

15 lactide;

glycolide.

20. The microsphere of claim 18, wherein the first compound is at least one of an organic compound less than 2000 MW, an oligopeptide, a polypeptide, and a nucleic acid.

21. The microsphere of claim 20, wherein the organic compound is an antibiotic, a corticosteroid or a statin.

22. The microsphere of claim 20, wherein the organic compound is cefazolin, cefuroxime, clindamycin, vancomycin or dexamethasone.

24. The microsphere of claim 20, wherein the oligopeptide or polypeptide is selected from the group consisting of (i) a cytokine, an enzyme, or a protein comprising an antibody binding site, (ii) an oligopeptide having the amino acid sequence GGRGDSP, GGIKVAV, GGYIGSR, GGDGEA, GGKIPKASSVPTELSAISTLYL, AAAAEPRREVAEL or AAAAγ

EPRRγ

EVAγ

EL, where γ

E is carboxyglutamate, and (iii) a bone morphogenetic protein-2, a bone morphogenetic protein-7, a vascular endothelial growth factor, a fibroblast growth factor-2, a platelet-derived growth factor, a transforming growth factor-beta, an interleukin, or a human growth hormone.

28. The microsphere of claim 20, wherein the nucleic acid is a microRNA, an antisense nucleic acid, or a vector.

29. The microsphere of claim 18, wherein the first compound noncovalently adheres to the microsphere.

30. The microsphere of claim 18, further comprising a component adhering to the first calcium-containing mineral and introducing a functional group to the microsphere, to which the first compound is covalently attached.

31. The microsphere of claim 18, wherein the first compound is at more than one level of the first calcium-containing mineral.

32. The microsphere of claim 18, wherein the first compound is modified to change the rate at which the first compound is released from the microsphere.

33. The microsphere of claim 32, wherein the first compound further comprises a moiety that increases the strength of binding of the first compound to the first calcium-containing mineral.

34. The microsphere of claim 33, wherein the moiety is a peptide comprising a poly(aspartic acid), a poly(glutamic acid), AAAAEPRREVAEL or AAAAγ

EPRRγ

EVAγ

EL, where γ

E is carboxyglutamate.

35. The microsphere of claim 15, further comprising a second compound adhering to the first calcium-containing mineral or the component.

36. The microsphere of claim 35, wherein the first compound and the second compound are on different levels of the first calcium-containing mineral.

37. The microsphere of claim 1, further comprising a living cell.

38. The microsphere of claim 37, wherein the first calcium-containing mineral is a carbonated-substituted calcium-deficient hydroxyapatite and the bead is poly(D,L-lactide-co-glycolide) (PLG), wherein the PLG is about 85:

15 lactide;

glycolide.

39. The microsphere of claim 37, wherein the living cell is a mammalian cell.

40. The microsphere of claim 37, wherein the microsphere comprises a first binding agent that binds to a second binding agent on the cell.

41. The microsphere of claim 40, wherein the first binding agent is a receptor, a first nucleic acid or a cell adhesion peptide and the second binding agent is a ligand of the receptor, a second nucleic acid complementary to the first nucleic acid, or a ligand of the cell adhesion peptide.

42. The microsphere of claim 40, wherein the first binding agent is the cell adhesion peptide GGRGDSP, GGIKVAV, GGYIGSR or GGDGEA.

43. The microsphere of claim 37, further comprising a cytokine that interacts with the cell.

44. The microsphere of claim 1, wherein the bead is further coated with a second calcium-containing mineral.

45. The microsphere of claim 1, having a diameter from about 0.5 μ

m to about 100 μ

m.

46. The microsphere of claim 1, having a diameter from about 2 μ

m to about 6 μ

m.

47. A plurality of the microsphere of claim 1, aggregated.

48. The plurality of the microsphere of claim 47, wherein the first calcium-containing mineral is a carbonated-substituted calcium-deficient hydroxyapatite and the bead is poly(D,L-lactide-co-glycolide) (PLG), wherein the PLG is about 85:

15 lactide;

glycolide.

49. The plurality of the microsphere of claim 48, further comprising a first compound adhering to the first calcium-containing mineral.

93. Use of the microsphere of at least one of claims 18-46 for the manufacture of a medicament for treating a vertebrate.

94. The use of claim 93, wherein the vertebrate is a human.

95. Use of the microsphere of at least one of claims 1-46 for the treatment of a vertebrate.

96. The use of claim 95, wherein the vertebrate is a human.

3-4. -4. (canceled)

12-13. -13. (canceled)

23. (canceled)

25-27. -27. (canceled)

50-92. -92. (canceled)