Inorganic-polymer complexes for the controlled release of compounds including medicinals

• US 6,630,486 B1
• Filed: 03/21/2000
• Issued: 10/07/2003
• Est. Priority Date: 09/22/1997
• Status: Expired due to Fees

• Current Assignee: Royer Biomedical, Inc.
• Original Assignee: Royer Biomedical, Inc.
• Inventors: Royer, Garfield P.
• Primary Examiner(s): Barts, Samuel
• Assistant Examiner(s): Khare, Devesh
• Application Number:
  US09/509,016
• Time in Patent Office: 1,295 Days
• Field of Search: 514/303, 514/777, 514/947, 424/468, 424/499, 424/422, 424/423, 424/425, 424/426, 424/451, 424/457, 424/464, 424/484, 424/488, 424/489, 536/55.2
• US Class Current: 514/303
• 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 47/56 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623

Abstract

This invention relates generally to the production and use of inorganic-polymer complexes for the controlled release of compounds including medicinals. Advantageously, the inorganic used is calcium sulfate.

Claims

1. A method of producing sustained release of an active agent in a mammal comprising administering to said mammal a solid composition comprising an active agent which is dispersed throughout a solid matrix reaction product of an aqueous mixture comprised of:

a) active agent, b) calcium sulfate hemihydrate c) a matrix polymer, and/or d) a complexing agent, and wherein said composition is in the form of a bead, wafer, tablet, sphere, granule or cylinder.

2. A method as in claim 1, wherein said solid composition is a reaction product of an aqueous mixture comprised of:

a) active agent, b) calcium sulfate hemihydrate and c) a matrix polymer.

3. A method as in claim 2, wherein said matrix polymer is a biopolymer selected from the group consisting of hyaluronic acid, chondroitin sulfate, dextran, and protein.

4. A method as in claim 3, wherein said solid composition comprises an active agent, calcium sulfate and hyaluronic acid.

5. A method as in claim 2, wherein said solid composition comprises an active agent, calcium sulfate and a glycosaminoglycan.

6. A method as in claim 5, wherein said glycosaminoglycan is hyaluronic acid or chondroitin sulfate.

7. A method as in claim 1, wherein there is no matrix polymer and said complexing agent is selected from the group consisting of chondroitin sulfate, polyglutamic acid, polyaspartic acid, polynucleotides, a cationic polypeptide, cyclodextrin, polyoxyethylene alcohol, ester or ether, and defatted albumin.

8. A method as in claim 7, wherein said polyoxyethylene alcohol, ester or ether is a surfactant.

9. A method as in claim 7, wherein said complexing agent is a lipid or a liposome.

10. A method as in claim 9, wherein said lipid is a lipid of biological origin selected from the group consisting of cholesterol and lecithin.

11. A method as in claim 7, wherein said complexing agent is a polar.

12. A method as in claim 7, wherein said complexing agent is two or more complexing agents of more than one size.

13. A method as in claim 12, wherein said two or more completing agents are selected from the group consisting of procaine, benzathin, polymyxin, and a polymer of cationic amino acids.

14. A method as in claim 12, wherein said two or more complexing agents are condroitin sulfate fragments of more than one size.

15. A method as in claim 7, wherein said complexing agent is a complexing agent selected from the group consisting of a polyoxyethylene ester or ether, and a surfactant of either biological or non-biological origin.

16. A method as in claim 7, wherein said complexing agent is selected from the group consisting of polyacrylic acid, alginic acid, dextran sulfate, polyvinylpyridine, polyvinylamine, polyethyleneimine and a lipid.

17. A method as in claim 1, wherein said composition is in the form of a granule.

18. A method as in claim 1, wherein said active agent is a medicinal selected from the group consisting of antibiotics, antineoplastic agents, anesthetics, vaccines, hormones, anti-inflammatories, analgesics, tranquilizers, cytokines, colony stimulating factors, antidepressants, antiseptics, cardiovascular agents anti-addictives, and antihypertensives.

19. A method as in claim 18, wherein said medicinal is a salt.

20. A method as in claim 18, wherein said medicinal is at least two medicinals of varying a polar character.

21. A method as in claim 1, wherein said active agent is a drug precursor.

22. A method as in claim 1, wherein said active agent is a protein medicinal.

23. A method as in claim 22, wherein said protein medicinal is growth hormone.

24. A method as in claim 1, wherein said active agent is imipenem.

25. A method as in claim 1, wherein said active agent, is lidocaine.

26. A method as in claim 1, wherein said active agent is selected from the group consisting of G-CSF, GM-CSF, and M-CSF;

erythropoietin, IL-2, IL-4, IL-6;

interferon, tumor necrosis factor (TNF).

27. A method as in claim 1, wherein said active agent is selected from the group consisting of epidermal-GF, nerve-GF, ACTH;

angiotensin, atrial natriuretic peptide, bradykynin, dynorphin, endorphin, β

-lipotropin fragment, enkephalin, gastrin, glucacon, growth hormone, growth hormone releasing factor, luteinizing hormone, releasing hormone, melanocyte stimulating hormone, neurotensin, opiode peptide, oxytocin, vasopressin, vasotocin, somatostatin, substance P, Factor VIII, TPA, streptokinase, glucocerebrosidase, hexoseaminidase A, tetanus toxoid and diptheria toxoid.

28. A method as in claim 1, wherein said active agent is a nutrient.

29. A method as in claim 1, wherein said matrix polymer is selected from the group consisting of polyethyleneglycol, polyvinylpyrrolidone, polyvinylalcohol, starch, xanthan, and cellulose.

30. A method as in claim 28 or 29 further comprising amikacin.

31. A method as in claim 28 or 29 further comprising silver sulfadiazine.

32. A method as in claim 1 wherein said solid composition is porous.

33. A method as in claim 1 comprising an active agent, calcium sulfate and dextran sulfate.

34. A method as in claim 1 comprising an active agent, calcium sulfate and polyethyleneglycol.

35. A method as in claim 1, wherein said administration is by subcutaneous injection.

36. A method of producing a delivery system comprising:

(i) mixing (a) calcium sulfate hemihydrate, (b) an active agent and (c) a matrix biopolymer,

(ii) forming the mixture of step (i) into a bead, wafer, tablet, sphere, granule or cylinder.

37. A method as in claim 36, wherein said inorganic compound is calcium sulfate hemihydrate and said active agent are premixed and then added to said matrix biopolymer.

38. A method of producing a solid composition for the controlled release of an active agent comprising the steps of:

(a) forming a particulate mixture comprising (i) calcium sulfate hemihydrate, and (ii) a solid active agent; and

thereafter

(b) adding to the particulate mixture of step (a) an aqueous solution of a matrix polymer in an amount sufficient to hydrate the calcium sulfate hemihydrate to form a solid matrix containing the active agent, and to slow the release of said active agent therefrom, and

(c) forming the mixture of step (b) into a bead, wafer, tablet, sphere, granule or cylinder.

39. A method of producing a solid composition for controlled release of an active agent comprising the steps of:

(i) forming a mixture of (a) calcium sulfate hemihydrate, (b) an active agent (c) a matrix polymer in an amount sufficient to slow the release of said active agent, and (d) water in an amount sufficient to form a solid matrix due to the hydration of said calcium sulfate hemihydrate; and

(ii) prior to formation of the mixture of step (i) into a solid matrix, shaping the mixture of step (i) into a bead, wafer, tablet, sphere, granule or cylinder.