Claims
- 1. A microsphere comprising:
(1) a macromolecule; (2) a water soluble polymer; (3) a polyanionic first complexing agent; and (4) a divalent metal cation second complexing agent selected from the group consisting of calcium and magnesium.
- 2. The microsphere of claim 1, wherein the macromolecule is a protein.
- 3. The microsphere of claim 2, wherein the protein is selected from the group consisting of: Albumins (preferably, human serum albumin), HAS; BSA, IgG, IgM, insulin, hGH, lysozyme, alpha-lactoglobulin, basic fibroblast growth factor, VEGF, chymotrypsin, trypsin, carbonic anhydrase, ovalbumin, phosphorylase b, alkaline phosphatase, beta-galactosidase, fibrinogen, poly-1-lysine, immunoglobulins (e.g., antibodies), casein, collagen, soy protein, gelatin, insulin, human growth hormone, GCSF, GMCSF, LHRH, VEGF, basic fibroblast growth factor (bFGF), asparaginase, tPA, urokinase, streptokinase, interferon, glucagon, ACTH, oxytocin, secretin, vasopressin, and levothyroxin.
- 4. The microsphere of claim 3, wherein the protein is an albumin.
- 5. The microsphere of claim 3, wherein the protein is an immunoglobulin.
- 6. The microsphere of any of claims 2-5, wherein the microsphere contains from 40 to less than 100% protein.
- 7. The microsphere of any of the preceding claims, wherein the water soluble polymer is selected from the group consisting of: carbohydrate-based polymers, such as methylcellulose, carboxymethyl cellulose-based polymers, dextran, polydextrose, derivatized chitins, chitosan, starch (including hetastarch) and derivatives thereof, polyaliphatic alcohols, such as polyethylene oxide and derivatives thereof including polyethylene glycol (PEG), PEG-acrylates, polyethylene imine, polyvinyl acetate, and derivatives thereof, poly(vinyl) polymers, such as poly(vinyl) alcohol, poly(vinyl)pyrrolidone, poly(vinyl)phosphate, poly(vinyl)phosphonic acid and derivatives thereof, polyacrylic acids and derivatives thereof, polyorganic acids, such as polymaleic acid, and derivatives thereof, polyamino acids, such as polylysine and polyimino acids, such as polyimino tyrosine and derivatives thereof, co-polymers and block co-polymers, such as poloxamer 407 or Pluronic L-101 TM polymer and derivatives thereof, tert-polymers and derivatives thereof, polyethers, such as poly(tetramethylene ether glycol) and derivatives thereof, naturally occurring polymers, such as zein and pullulan and derivatives thereof, polyimids, such as polyn-tris(hydroxymethyl)methylmethacrylate and derivatives thereof, surfactants, such as polyoxyethylene sorbitan and derivatives thereof, polyesters such as poly(ethylene glycol)(n)monomethyl ether mono(succinimidylsuccinate)ester and derivatives thereof, branched and cyclo-polymers, such as branched PEG and cyclodextrins and derivatives thereof, and polyaldehydes, such as poly(perfluoropropylene oxide-b-perfluoroformaldehyde) and derivatives thereof.
- 8. The microsphere of claim 7, wherein the water soluble polymer is a carbohydrate-based polymer.
- 9. The microsphere of claim 7, wherein the starch is a hydroxyethylstarch.
- 10. The microsphere of claim 7, wherein the starch is a hetastarch.
- 11. The microsphere of claim 1, wherein the polyanionic first complexing agent is a polyanionic polysaccharide.
- 12. The microsphere of claim 11, wherein the polyanionic polysaccharide is selected from the group consisting of: dextran sulfate, galacturonic acids, alginates, mannuronic acid, guluronic acid, hyaluronic acid, chondroitin sulfates, heparin, chitin, chitosan, glycosaminoglycans, and proteoglycans.
- 13. The microsphere of claim 12, wherein the polyanionic polysaccharide is dextran sulfate.
- 14. The microsphere of claim 1, wherein the divalent metal cation is calcium.
- 15. The microsphere of claim 1, wherein the divalent metal cation is magnesium.
- 16. The microsphere of claim 1, wherein the microsphere has a smooth surface that includes a plurality of channel openings, each of said channel openings having a diameter that is less than 1000 Angstroms.
- 17. The microsphere of claim 1, wherein the microsphere does not contain detectable oil or organic solvent.
- 18. The microsphere of claim 1, wherein the macromolecule is albumin, and the water soluble polymer is a carbohydrate-based polymer.
- 19. The microsphere of claim 18, wherein the albumin is human serum albumin, and wherein the carbohydrate based polymer is hetastarch.
- 20. The microsphere of claim 1, further comprising an active agent.
- 21. The microsphere of claim 20, wherein the active agent is a therapeutic agent.
- 22. The microsphere of claim 20, wherein the active agent is a diagnostic agent.
- 23. The microsphere of claim 20 wherein, the active agent is selected from the group consisting of: a hormone, an antibiotic, an antiinfective agent, a hematopoietic, a thrombopoietic agent, an antidementia agent, an antiviral agent, an antitumoral agent, an antipyretic, an analgesic, an antiinflammatory agent, an antiulcer agent, an antiallergic agent, an antidepressant, a psychotropic agent, a cardiotonic, an antiarrythmic agent, a vasodilator, an antihypertensive agent, an antidiabetic agent, an anticoagulant, a cholesterol lowering agent, a therapeutic agent for osteoporosis, an enzyme, a vaccine, an immunological agent, an adjuvant, a cytokine, a growth factor, a nucleotide, a nucleic acid, a carbohydrate, a polysaccharide, a virus, and a virus particle.
- 24. The method of claim 20, wherein the active agent is a luteinizing hormone releasing hormone or analog thereof.
- 25. The method of claim 20, wherein the active agent is leuprolide.
- 26. The microsphere of claim 20, wherein the first polyanionic complexing agent is dextran sulfate and the active agent is leuprolide acetate.
- 27. A syringe containing a single dose of the microspheres of any of the preceding claims, wherein the syringe preferably further includes a needle having a bore size that is from 14 to 30 gauge.
- 28. A microsphere comprising:
(1) a macromolecule; (2) a water soluble polymer; and (3) a polycationic complexing agent.
- 29. The microsphere of claim 28, wherein the macromolecule is a nucleic acid.
- 30. The microsphere of claim 29, wherein the nucleic acid is selected from the group consisting of: DNA, RNA, plasmid, viral vector, oligonucleotide, antisense nucleic acids, and missense nucleic acds.
- 31. The microsphere of any of claims 28-30, wherein the microsphere contains from 40 to less than 100% macromolecule.
- 32. The microsphere of any of claims 28-31, wherein the water soluble polymer is selected from the group consisting of: carbohydrate-based polymers, such as methylcellulose, carboxymethyl cellulose-based polymers, dextran, polydextrose, derivatized chitins, chitosan, and starch (including hetastarch) and derivatives thereof, polyaliphatic alcohols, such as polyethylene oxide and derivatives thereof including polyethylene glycol (PEG), PEG-acrylates, polyethylene imine, polyvinyl acetate and derivatives thereof, poly(vinyl) polymers, such as poly(vinyl) alcohol, poly(vinyl)pyrrolidone, poly(vinyl)phosphate, poly(vinyl)phosphonic acid and derivatives thereof, polyacrylic acids and derivatives thereof, polyorganic acids, such as polymaleic acid and derivatives thereof, polyamino acids, such as polylysine and polyimino acids, such as polyimino tyrosine and derivatives thereof, co-polymers and block co-polymers, such as poloxamer 407 or Pluronic L-101 TM polymer and derivatives thereof, tert-polymers and derivatives thereof, polyethers, such as poly(tetramethylene ether glycol) and derivatives thereof, naturally occurring polymers, such as zein and pullulan and derivatives thereof, polyimids, such as polyn-tris(hydroxymethyl)methylmethacrylate and derivatives thereof, surfactants, such as polyoxyethylene sorbitan and derivatives thereof, polyesters, such as poly(ethylene glycol)(n)monomethyl ether mono(succinimidylsuccinate)ester and derivatives thereof, branched and cyclo-polymers, such as branched PEG and cyclodextrins and derivatives thereof and polyaldehydes, such as poly(perfluoropropylene oxide-b-perfluoroformaldehyde) and derivatives thereof.
- 33. The microsphere of claim 32, wherein the water soluble polymer is a carbohydrate-based polymer.
- 34. The microsphere of claim 32, wherein the starch is a hydroxyethylstarch.
- 35. The microsphere of claim 32, wherein the starch is a hetastarch.
- 36. The microsphere of claims 28-35, wherein the polycationic complexing agent is selected from the group consisting of: poly-lysine, poly-arginine, poly-imino acids, poly-imino tyrosine, cholestyramine-resin, diethyl amino ethyl cellulose, poly-citrulline, and poly-ornithine.
- 37. The microsphere of claim 36, wherein the polycationic complexing agent is polylysine.
- 38. The microsphere of claims 28-37, wherein the microsphere has a smooth surface that includes a plurality of channel openings, each of said channel openings having a diameter that is less than 1000 Angstroms.
- 39. The microsphere of claims 28-38, wherein the microsphere does not contain detectable oil or organic solvent.
- 40. The microsphere of claim 28, further comprising an active agent.
- 41. The microsphere of claim 40, wherein the active agent is a therapeutic agent.
- 42. The microsphere of claim 40, wherein the active agent is a diagnostic agent.
- 43. The microsphere of claim 40 wherein, the active agent is selected from the group consisting of: a hormone, an antibiotic, an antiinfective agent, a hematopoietic, a thrombopoietic agent, an antidementia agent, an antiviral agent, an antitumoral agent, an antipyretic, an analgesic, an antiinflammatory agent, an antiulcer agent, an antiallergic agent, an antidepressant, a psychotropic agent, a cardiotonic, an antiarrythmic agent, a vasodilator, an antihypertensive agent, an antidiabetic agent, an anticoagulant, a cholesterol lowering agent, a therapeutic agent for osteoporosis, an enzyme, a vaccine, an immunological agent, an adjuvant, a cytokine, a growth factor, a nucleotide, a nucleic acid, a carbohydrate, a polysaccharide, a virus, and a virus particle.
- 44. The method of claim 40, wherein the active agent is a luteinizing hormone releasing hormone or analog thereof.
- 45. The method of claim 40, wherein the active agent is leuprolide.
- 46. A syringe containing a single dose of the microspheres of any of claims 28-45, wherein the syringe preferably further includes a needle having a bore size that is from 14 to 30 gauge.
- 47. A method for forming a microsphere comprising:
(1) forming an aqueous mixture containing:
(a) a macromolecule; (b) a water soluble polymer; and (c) a polycationic complexing agent; (2) allowing the microspheres to form in the aqueous mixture; and (3) stabilizing the microspheres, preferably by contacting the microspheres with a crosslinking agent and/or exposing the microspheres to an energy source, preferably heat, under conditions sufficient to stabilize the microspheres.
- 48. The method of claim 47, wherein forming the aqueous mixture is performed by combining the macromolecule, the water soluble polymer, and the polycationic complexing agent essentially simultaneously.
- 49. The method of claim 47, wherein the macromolecule is a nucleic acid.
- 50. The method of claim 49, wherein the nucleic acid is selected from the group consisting of: DNA, RNA, plasmid, viral vector, oligonucleotide, antisense nucleic acids, and missense nucleic acids.
- 51. The method of claim 47, further comprising the step of:
(4) contacting the microsphere with a solution of an active agent, to incorporate the active agent into the microsphere.
- 52. The method of claim 51, wherein the active agent is a therapeutic agent.
- 53. The method of claim 51, wherein the active agent is a diagnostic agent.
- 54. The method of claim 51, wherein the step of contacting the microsphere with the solution of active agent results in a yield of incorporation of at least 60% of the active agent.
- 55. The method of claim 51, wherein the active agent is selected from the group consisting of: a hormone, an antibiotic, an antiinfective agent, a hematopoietic, a thrombopoietic agent, an antidementia agent, an antiviral agent, an antitumoral agent, an antipyretic, an analgesic, an antiinflammatory agent, an antiulcer agent, an antiallergic agent, an antidepressant, a psychotropic agent, a cardiotonic, an antiarrythmic agent, a vasodilator, an antihypertensive agent, an antidiabetic agent, an anticoagulant, a cholesterol lowering agent, a therapeutic agent for osteoporosis, an enzyme, a vaccine, an immunological agent, an adjuvant, a cytokine, a growth factor, a nucleotide, a nucleic acid, a carbohydrate, a polysaccharide, a virus, and a virus particle.
- 56. The method of claim 51, wherein the active agent is a luteinizing hormone releasing hormone or analog thereof.
- 57. The method of claim 51, wherein the active agent is leuprolide.
- 58. The method of claim 51, wherein the step of contacting the microsphere with the solution of an active agent results in a yield of incorporation of at least 70% of the active agent.
- 59. The method of claim 51, wherein the step of contacting the microsphere with the solution of an active agent results in a yield of incorporation of at least 80% of the active agent.
- 60. The method of claim 51, wherein the step of contacting the microsphere with the solution of an active agent results in a yield of incorporation of at least 90% of the active agent.
- 61. The method of claim 51, wherein the step of contacting the microsphere with the solution of an active agent results in a yield of incorporation of at least 95% of the active agent.
- 62. The method of claim 51, wherein the step of contacting the microsphere with the solution of an active agent results in a yield of incorporation of at least 98% of the active agent.
- 63. The method of claim 47, wherein the step of stabilizing comprises exposing the microspheres to an energy source.
- 64. The method of claim 63, wherein the energy source is heat.
- 65. The method of claim 47, wherein the step of stabilizing comprises contacting the microspheres with a crosslinking agent.
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser. No. 09/420,361, filed on Oct. 18, 1999, now pending.
Continuations (1)
|
Number |
Date |
Country |
Parent |
09420361 |
Oct 1999 |
US |
Child |
10245776 |
Sep 2002 |
US |