Production of microspheres

• US 20040043077A1
• Filed: 10/10/2003
• Published: 03/04/2004
• Est. Priority Date: 10/27/2000
• Status: Active Grant

• Current Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Original Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Inventors: Brown, Larry R.
• Granted Patent: US 7,374,782 B2
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Abstract

Protein microspheres are produced by contacting an aqueous solution of a macromolecule and a polymer with a surface at a high surface area to volume ratio, and heating the solution. The microspheres are useful for preparing pharmaceuticals of defined dimensions which can be delivered to a patient by inhalation therapy.

Claims

1. A process for preparing microspheres comprising the steps of

combining a macromolecule and a polymer in an aqueous solution,

contacting a volume of the aqueous solution with a surface at a surface area to volume ratio of at least about 6.5 cm⁻

1, and

exposing the solution to an energy source for a sufficient period of time to form microspheres.

2. The process of claim 1 wherein the surface area to volume ratio is at least about 14 cm⁻

1.

3. The process of claim 1 wherein the surface is a hydrophobic surface

4. The process of claim 3 wherein the hydrophobic surface is formed from a material selected from metals, ceramics and glass.

5. The process of claim 4 wherein the metal is stainless steel.

6. The process of claim 3 wherein the hydrophobic surface is formed from a hydrophobic polymer.

7. The process of claim 6 wherein the hydrophobic polymer is selected from the group consisting of polypropylene, polystyrene, Teflon and silicone polymers

8. The process of claim 1 wherein the macromolecule is selected from the group consisting of proteins, peptides, nucleic acids, carbohydrates, protein conjugates, virus, virus particles, and mixtures thereof.

9. The process of claim 8 wherein the macromolecule is a peptide.

10. The process of claim 9 wherein the peptide is a polypeptide.

11. The process of claim 8 wherein the macromolecule is a carbohydrate.

12. The process of claim 11 wherein the carbohydrate is a polysaccharide.

13. The process of claim 8 wherein the macromolecule is a protein.

14. The process of claim 13 wherein the protein is a therapeutic protein.

15. The process of claim 14 wherein the protein is selected from the group consisting of insulin, human serum albumin, human growth hormone, parathyroid hormone and calcitonin.

16. The process of claim 1 wherein the microspheres have a mean diameter in the range of from about 0.1 microns to about 10.0 microns.

17. The process of claim 16 wherein the microspheres have a mean diameter in the range of from about 0.5 microns to about 5.0 microns.

18. The process of claim 17 wherein the microspheres have a mean diameter in the range of from about 1.0 microns to about 2.0 microns.

19. The process of claim 1 wherein the energy source is heat energy.

20. The process of claim 19 wherein the aqueous solution of macromolecule and polymer is heated to a temperature in the range of from about 37°

C. to about 95°

C. for a time period of about 1 minute to about 24 hours.

21. The process of claim 1 wherein the polymer is water soluble or soluble in a water miscible solvent.

22. The process of claim 21 wherein the polymer is selected from the group consisting of carbohydrate polymers, polyaliphatic alcohols, poly(vinyl) polymers, polyacrylic acids, polyorganic acids, polyamino acids, polyethers, naturally occurring polymers, polyimids, polyesters, polyaldehydes, co-polymers, block co-polymers, tertpolymers, surfactants, branched polymers, cyclo-polymers, and mixtures thereof.

23. The process of claim 22 wherein the polymer is selected from the group consisting of dextran, polyethylene glycol, polyvinyl pyrrolidone, co-polymers of polyethylene glycol and polyvinyl pyrrolidone, polyvinyl alcohol, co-polymers of polyoxyethylene and polyoxypropylene, and mixtures thereof.

24. The process of claim 23 wherein the polymer is a co-polymer of polyethylene glycol and polyvinyl pyrrolidone, and a co-polymer of polyoxyethylene and polyoxypropylene.

25. The process of claim 1 wherein the microspheres comprise greater than about 90% macromolecule by weight.

26. The process of claim 25 wherein the microspheres comprise greater than about 95% macromolecule by weight.

27. The process of claim 26 wherein the microspheres comprise greater than about 99% macromolecule by weight.

28. The process of claim 1 which is a batch process.

29. The process of claim 1 which is a continuous process.

35. A device for the pulmonary administration of a therapeutic agent to a patient comprising an inhaler containing a therapeutic dose of microspheres formed by the process of claim 1.

36. The inhaler of claim 35 which is a dry powder inhaler.

37. The inhaler of claim 35 which is a metered dose inhaler.

38. The inhaler of claim 35 which is a nebulizer.

39. The inhaler of claim 35 which is an electrostatic delivery device.

40. The device of claim 35 wherein the protein is selected from the group consisting of insulin, human growth hormone, calcitonin, parathyroid hormone,

41. The device of claim 35 which is used to treat a pulmonary condition.

42. A product prepared according to the process of claim 1.

30. A device for the production of microspheres comprising

a reactor having an internal surface area to volume ratio of 6.5 cm⁻

1,

an aqueous solution of a macromolecule and a polymer contacting the internal surfaces of the reactor, and

means for heating the aqueous solution.

31. The device of claim 30 which contains a bed of inert material providing surfaces for contacting the aqueous solution and is operated in a batch mode.

32. The device of claim 31 wherein surfaces are formed from a hydrophobic material.

33. The device of claim 30 wherein the reactor is a tube operated in a continuous mode.

34. The device of claim 33 wherein the reactor tube is formed from polypropylene.