Processes for preparation of microspheres

• US 4,166,800 A
• Filed: 07/31/1978
• Issued: 09/04/1979
• Est. Priority Date: 08/25/1977
• Status: Expired due to Term

• Current Assignee: Sandoz Inc. (Novartis Ag)
• Original Assignee: Sandoz Inc. (Novartis Ag)
• Inventors: Fong, Jones W.
• Primary Examiner(s): Silverberg, Sam
• Application Number:
  US05/929,517
• Time in Patent Office: 400 Days
• Field of Search: 252/316, 427/3, 427/212, 427/221
• US Class Current: 427/212
• CPC Class Codes: A01N 25/28 Microcapsules or nanocapsules
• CPC Class Codes: A61K 2800/412 Microsized, i.e. having sizes between 0.1 and 100 microns
• CPC Class Codes: A61K 2800/624 by macromolecular compounds
• CPC Class Codes: A61K 8/0241 Containing particulates characterized by their shape and/or structure see also A61K8/04, A61K8/11, and A61K8/14, further aspects are classified in A61K2800/40 and subcodes
• CPC Class Codes: A61K 8/85 Polyesters
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61Q 13/00 Formulations or additives for perfume preparations essential oils or perfumes per se C11B9/00
• CPC Class Codes: A61Q 15/00 Anti-perspirants or body deodorants deodorisation of air A61L9/00
• CPC Class Codes: B01J 13/08 Simple coacervation, i.e. addition of highly hydrophilic material combined with spraying B01J13/043; combined with mechanical division B01J13/04
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]

Abstract

Microspheres, prepared by the low-temperature e.g., -40° to -100° C., phase separation of a polymer and a core material.

Claims

1. In a process for the preparation of microspheres having a particulate core material encapsulated by a polymeric coating wherein the polymer is dissolved in a solvent in which the core material is not soluble and the polymer is precipated by phase separation to encapsulate the core material by the addition of phase separation agent to the polymer-core material-solvent system;

the improvement which comprises lowering the temperature of said system from about -40°

to -100°

C. and then adding the phase separation agent to the polymer-core material-solvent system to cause phase separation of the polymer.

2. The process according to claim 1 wherein the temperature is from about -40°

to -75°

C.

3. The process according to claim 2 wherein the temperature is from about -50°

to -70°

C.

4. The process according to claim 1 wherein the core material is a drug.

5. The process according to claim 4 wherein the polymer is selected from the group consisting of cellulosic polymers, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polyacrylates, polystyrene, polylactic acid, polyglycolic acid, polyhydroxybutyric acid and copolymers thereof.

6. The process according to claim 5 wherein the polymer is polylactic acid.

7. The process according to claim 6 wherein the core material is selected from the group consisting of thioridazine, bromocriptine, pindolol or dihydroergotamine, or acid addition salts thereof.

8. The process according to claim 6 wherein the solvent is selected from the group consisting of benzene, toluene, xylene, chloroform, methylene chloride, acetone, ethyl acetate, tetrahydrofuran, dioxane, hexafluoroisopropanol and mixtures thereof.

9. The process according to claim 8 wherein the phase separation agent is a nonsolvent selected from the group consisting of water, monohydric alcohols, dihydric alcohols, trihydric alcohols, ethers, polyhydric alcohol ethers, polyhydric alcohol esters, alkane hydrocarbons, fluorocarbons and mixtures thereof.

10. The process according to claim 9 wherein the nonsolvent is selected from the group consisting of isopropyl alcohol, isobutyl alcohol, propylene glycol, heptane, cyclohexane and mixtures thereof.

11. A process for the preparation of microspheres having a homogeneous mixture of a polymer and core material which comprises,

dissolving the polymer and core material in a solvent, lowering the temperature of the resultant solution to about -40°

to -100°

C., and adding a polymer-core material phase separation agent to the solution to precipate microspheres of a homogeneous mixture of the polymer and core material.

12. The process according to claim 11 wherein the temperature is from about -40°

to -75°

C.

13. The process according to claim 12 wherein the temperature is from about -50°

to -70°

C.

14. The process according to claim 11 wherein the core material is a drug.

15. The process according to claim 14 wherein the polymer is selected from the group consisting of cellulosic polymers, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polyacrylates, polystyrene, polylactic acid, polyglycolic acid, polyhydroxybutyric acid and copolymers thereof.

16. The process according to claim 15 wherein the polymer is polyacetic acid.

17. The process according to claim 16 wherein the core material is selected from the group consisting of thioridazine, bromocriptine, pindolol or dihydroergotamine, or an acid addition salt thereof.

18. The process according to claim 16 wherein the solvent is selected from the group consisting of benzene, toluene, xylene, chloroform, methylene chloride, acetone, ethyl acetate, tetrahydrofuran, dioxane, hexafluoroisopropanol and mixtures thereof.

19. The process according to claim 18 wherein the phase separation agent is a nonsolvent selected from the group consisting of water, monohydric alcohols, dihydric alcohols, trihydric alcohols, ethers, polyhydric alcohol ethers, polyhydric alcohol esters, alkane hydrocarbons, fluorocarbons and mixtures thereof.

20. The process according to claim 19 wherein the nonsolvent is selected from the group consisting of isopropyl alcohol, isobutyl alcohol, propylene glycol, heptane, cyclohexane and mixtures thereof.

21. In a process for the encapsulation of preformed microspheres having a particulate core material encapsulated by a polymeric coating wherein the polymer is dissolved in a solvent in which the microsphere is not soluble and the polymer is precipated by phase separation to encapsulate the microsphere by the addition of phase separation agent to the polymer-microsphere-solvent system;

the improvement which comprises lowering the temperature of said system from about -40°

to -100°

C. and then adding the phase separation agent to the polymer-microsphere-solvent system to cause phase separation of the polymer.

22. The process according to claim 21 wherein the temperature is from about -40°

to -75°

C.

23. The process according to claim 22 wherein the temperature is from about -50°

to -70°

C.

24. The process according to claim 21 wherein the microsphere is a preformed microcapsule wherein a drug is encapsulated by a polymeric coating.

25. The process according to claim 24 wherein the preformed microsphere polymer is polylactic acid and the microencapsulated drug is selected from the group consisting of thioridazine, bromocriptine, pindolol or dihydroergotamine, or an acid addition salt thereof.

26. The process according to claim 25 wherein the coating polymer is selected from the group consisting of cellulosic polymers, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polyacrylates, polystyrene, polylactic acid, polyglycolic acid, polyhydroxybutyric acid and copolymers thereof.

27. The process according to claim 26 wherein the coating polymer is polylactic acid.

28. The process according to claim 27 wherein the solvent is selected from the group consisting of benzene, toluene, xylene, chloroform, methylene chloride, acetone, ethyl acetate, tetrahydrofuran, dioxane, hexafluoroisopropanol and mixtures thereof.

29. The process according to claim 28 wherein the phase separation agent is a nonsolvent selected from the group consisting of water, monohydric alcohols, dihydric alcohols, trihydric alcohols, ethers, polyhydric alcohol ethers, polyhydric alcohol esters, alkane hydrocarbons, fluorocarbons and mixture thereof.

30. The process according to claim 29 wherein the nonsolvent is selected from the group consisting of isopropyl alcohol, isobutyl alcohol, propylene glycol, heptane, cyclohexane and mixtures thereof.

31. The process according to claim 21 wherein the microsphere is a preformed microprill wherein a core material is in homogeneous mixture with a polymer.

32. The process according to claim 31 wherein the temperature is from about -40°

to -75°

C.

33. The process according to claim 32 wherein the temperature is from about -50°

to -70°

C.

34. The process according to claim 31 wherein the microsphere is a preformed microprill wherein a drug is in homogeneous mixture with a polymer.

35. The process according to claim 34 wherein the preformed microprill polymer is polylactic acid and the drug is selected from the group consisting of thioridazine, bromocriptine, pindolol or dihydroergotamine, or an acid addition salt thereof.

36. The process according to claim 35 wherein the coating polymer is selected from the group consisting of cellulosic polymers, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polyacrylates, polystyrene, polylactic acid, polyglycolic acid, polyhydroxybutyric acid and copolymers thereof.

37. The process according to claim 36 wherein the coating polymer is polylactic acid.

38. The process according to claim 37 wherein the solvent is selected from the group consisting of benzene, toluene, xylene, chloroform, methylene chloride, acetone, ethyl acetate, tetrahydrofuran, dioxane, hexafluoroisopropanol and mixtures thereof.

39. The process according to claim 38 wherein the phase separation agent is a nonsolvent selected from the group consisting of water, monohydric alcohols, dihydric alcohols, trihydric alcohols, ethers, polyhydric alcohol ethers, polyhydric alcohol esters, alkane hydrocarbons, fluorocarbons and mixtures thereof.

40. The process according to claim 39 wherein the nonsolvent is selected from the group consisting of isopropyl alcohol, isobutyl alcohol, propylene glycol, heptane, cyclohexane and mixtures thereof.

41. A process for encapsulating a plurality of heterogeneous preformed microspheres consisting essentially of, dissolving a polymer in a solvent in which the preformed microspheres are not soluble, lowering the temperature to about -40°

to -100°

C., adding the preformed microspheres to the polymer-solvent solution;

adding a phase separation agent to the polymer-microsphere-solvent system to cause phase separation of the polymer, coating the microspheres.

42. A process for encapsulating a plurality of heterogeneous preformed microspheres consisting essentially of, dissolving a polymer and core material in a solvent in which the preformed microspheres are not soluble, lowering the temperature to about -40°

to -100°

C., adding the preformed microspheres to the polymer-core material-solvent solution;

adding a phase separation agent to the polymer-core material-microsphere-solvent system to cause phase separation of the polymer, coating the microspheres.

43. A process for encapsulating a plurality of heterogeneous preformed microspheres with a polymer coating having core material dispersed therein consisting essentially of, dissolving a polymer in a solvent in which the core material and the preformed microspheres are not soluble, lowering the temperature to about -40°

to -100°

C., adding the core material and the preformed microspheres to the polymer-solvent solution;

adding a phase separation agent to the polymer-core material-microsphere-solvent system to cause phase separation of the polymer, coating the microspheres.

44. A process for encapsulating preformed microspheres consisting essentially of, dissolving a polymer and core material in a solvent in which the preformed microspheres are not soluble, lowering the temperature to about -40°

to -100°

C., adding the preformed microspheres to the polymer-core material-solvent solution;

adding a phase separation agent to the polymer-core material-microsphere-solvent system to cause phase separation of the polymer, coating the microspheres.

45. A process for encapsulating preformed microspheres with a polymer coating having core material dispersed therein consisting essentially of, dissolving a polymer in a solvent in which the core material and the preformed microspheres are not soluble, lowering the temperature to about -40°

to -100°

C., adding the core material and the preformed microspheres to the polymer-solvent solution;

adding a phase separation agent to the polymer-core material-microsphere-solvent system to cause phase separation of the polymer, coating the microspheres.