Microparticles

• US 7,309,500 B2
• Filed: 12/04/2003
• Issued: 12/18/2007
• Est. Priority Date: 12/04/2003
• Status: Active Grant

• Current Assignee: Board of Trustees of The University of Illinois
• Original Assignee: Board of Trustees of The University of Illinois
• Inventors: Kim, Kyekyoon, Choi, Hyungsoo, Choy, Young Bin
• Primary Examiner(s): Richter; Johann R.
• Assistant Examiner(s): George; Konata M.
• Application Number:
  US10/728,190
• Publication Number:
  US 20050123614A1
• Time in Patent Office: 1,475 Days
• Field of Search: 424/489, 424/490, 424/491, 424/492, 424/494, 424/495, 424/497
• US Class Current: 424/489
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/1682 Processes

Abstract

A method of forming particles, comprises accelerating a first stream comprising a first liquid, applying a charging voltage of at most 1.5 kV to the first stream, and vibrating the first stream, to form particles.

Claims

1. A method of forming particles, comprising:

accelerating a first stream comprising a first liquid;

applying a charging voltage of at most 1.5 kV to the first stream; and

vibrating the first stream, to form particles;

wherein the first liquid comprises a hydrophilic polymer.

2. The method of claim 1, further comprising solidifying the particles.

3. The method of claim 1, wherein the first liquid comprises one or more polymers selected from the group consisting of chitosan, gelatin, alginate, carboxy methyl cellulose, dextran, hydroxypropyl cellulose, poly(acrylamide), poly(acrylic acid), poly(allylamine) hydrochloride, poly(diallyldimethylammonium chloride), poly(N,N-dimethyl acrylamide), poly(ethylene glycol), poly(ethylene oxide), poly(maltotriose), poly(methacrylic acid), poly(N-isopropyl acrylamide), poly(propylene glycol), poly(styrene carboxylic acid), poly(styrene sulphonic acid), poly(styrene sulphonate), poly(vinyl acetate), poly(vinyl alcohol), poly(vinyl butyral), poly(2-vinyl-N-methyl pyridinium iodide), poly(4-vinyl-N-methyl pyridiniuim), poly(2-vinyl pyridine), poly(2-vinyl pyridinium bromide), poly(vinyl pyrrolidone), poly(methyl vinyl ether), hydroxyalkyl starch, alkylcellulose, hydroxyalkylcellulose, hydroxyarylcellulose, and copolymers thereof.

4. The method of claim 1, wherein the particles comprise a pharmaceutical composition.

5. The method of claim 1, wherein the particles comprise a core and a shell.

6. The method of claim 5, wherein the particles comprise a plurality of shells.

7. The method of claim 6, wherein the core comprises a pharmaceutical composition.

8. The method of claim 1, wherein the accelerating comprises contacting the first stream with a second stream, and

the second stream comprises a second liquid.

9. The method of claim 8, wherein the second stream surrounds the first stream.

10. The method of claim 1, further comprising forming the first stream by passing the first liquid through a nozzle.

11. The method of claim 10, wherein the nozzle has a diameter greater than ½

of the average diameter of the particles.

12. The method of claim 10, wherein the nozzle has a diameter at least equal to the average diameter of the particles.

13. The method of claim 1, wherein the particles have an average diameter of at least 10 nm to at most 100 μ

m.

14. The method of claim 1, wherein the particles have an average diameter of at least 50 μ

m to at most 100 μ

m, and 90% of the particles have a diameter that is within 2% of an average diameter of the particles.

15. The method of claim 1, wherein the particles have an average diameter of at least 1 μ

m to at most 50 μ

m , and 90% of the particles have a diameter that is within 1 μ

m of an average diameter of the particles.

16. The method of claim 1, wherein

the accelerating is a step for accelerating the first stream, and

the vibrating is a step for vibrating the first stream.

17. The method of claim 1, wherein solidifying comprises:

heating the particles to a temperature of at least 90°

C. and of at most 170°

C.

18. The method of claim 2, wherein the solidifying comprises:

heating the particles to a temperature of at least 125°

C. and of at most 135°

C.

19. The method of claim 2, wherein the solidifying comprises:

maintaining the particles at a pressure of at least 0.1 mm Hg and of at most 760 mm Hg, while heating the particles to a temperature within ±

50°

C. of the boiling point of water at the pressure.

20. The method of claim 2, wherein solidifying comprises:

cooling the particles to a temperature of −

10°

C. to 25°

C.

21. The method of claim 2, wherein solidifying comprises:

cooling the particles to a temperature of −

2°

C. to 6°

C.

22. The method of claim 1, further comprising:

treating the particles with a crosslinking agent.

23. The method of claim 22, wherein the crosslinking agent is selected from the group consisting of formaldehyde, glyceraldehyde, glutaraldehyde, dextran dialdehyde, ethylene glycol, di(ethylene glycol), polyethylene glycol, propylene glycol, di(propylene) glycol, polypropylene glycol, ethylene glycol dimethacrylate, di(ethylene glycol) dimethacrylate, poly(ethylene glycol) dimethacrylate, poly(lauryl methacrylate-co-ethylene glycol dimethacrylate), propylene glycol dimethacrylate, di(propylene glycol) dimethacrylate, poly(propylene glycol) dimethacrylate, malonic dihydrazide, ethylmalonic dihydrazide, succinic dihydrazide, glutaric dihydrazide, adipic dihydrazide, isophthalic dihydrazide, oxalyl dihydrazide, pimelic dihydrazide, 3,3′

-sulfonyldibenzenesulfonic dihydrazide, m-xylylene isocyanate, 4-methyl-m-phenylene diisocyanate, 2-methyl-m-phenylene diisocyanate, 3,3′

-dimethoxy-4,4′

-biphenylene diisocyanate, 4-Br-6-methyl-1,3-phenylene diisocyanate, 4-Cl-6-methyl-1,3-phenylene diisocyanate, toluene 2,4-diisocyanate, 1,3-phenylene diisocyanate, 1,4-phenylene diisocyanate, 2,4,6-trimethyl-1,3-phenylene diisocyanate, 1,4-diisocyanatebutane, 1,6-diisocyanatehexane, 1,8-diisocyanateoctane, isophorone diisocyanate;

N,N-(3-dimethylaminopropyl)-N-ethyl carbodiimide, CaCl₂, divinylsulfone, sulfonylurea, hydrolysable polyrotaxane, L-lysine methyl ester, and genipin.

40. The method of claim 1, further comprising chopping the particles.

24. A method of forming chitosan or alginate particles, comprising:

accelerating a first stream comprising a solution of chitosan or alginate,

applying a charging voltage of at most 1.5 kV to the first stream;

vibrating the first stream, to form particles; and

maintaining the particles at a pressure of at least 0.1 mm Hg and of at most 760 mm Hg, while heating the particles to a temperature within ±

50°

C. of the boiling point of water at the pressure;

wherein the accelerating comprises contacting the first stream with a second stream, and the second stream comprises a hydrophobic liquid.

25. The method of claim 24, further comprising solidifying the particles.

26. The method of claim 24, wherein the particles comprise a pharmaceutical composition.

27. The method of claim 24, wherein the accelerating comprises contacting the first stream with a second stream, and

the second stream comprises a second liquid.

28. The method of claim 24, further comprising forming the first stream by passing the first liquid through a nozzle.

29. The method of claim 28, wherein the nozzle has a diameter greater than ½

of the average diameter of the particles.

30. The method of claim 25 wherein the particles have an average diameter of at least 10 nm to at most 100 μ

m.

31. Particles comprising chitosan or alginate having an average diameter of at least 1 μ

m to at most 100 μ

m , wherein 90% of the particles have a diameter that is within 1 μ

m of an average diameter of the particles.

32. The particles of claim 31, wherein the particles comprise a pharmaceutical composition.

33. The particles of claim 31, wherein the particles comprise a core and a shell.

34. The particles of claim 33, wherein the core comprises a pharmaceutical composition.

35. The particles of claim 31, wherein the particles comprise a plurality of shells.

36. A method of forming gelatin particles, comprising:

accelerating a first stream comprising an aqueous solution of gelatin,

applying a charging voltage of at most 1.5 kV to the first stream;

vibrating the first stream, to form particles; and

subjecting the particles to a temperature at most 10°

C. above the gelling temperature of the solution of gelatin;

wherein the accelerating comprises contacting the first stream with a second stream, and the second stream comprises a hydrophobic liquid.

37. The method of claim 36, further comprising:

collecting the particles in a collection bath comprising a surfactant.

38. The method of claim 36, further comprising:

treating the particles with a crosslinking agent.

39. The method of claim 38, wherein the crosslinking agent is selected from the group consisting of formaldehyde, glyceraldehyde, glutaraldehyde, dextran dialdehyde, ethylene glycol, di(ethylene glycol), polyethylene glycol, propylene glycol, di(propylene) glycol, polypropylene glycol, ethylene glycol dimethacrylate, di(ethylene glycol) dimethacrylate, poly(ethylene glycol) dimethacrylate, poly(lauryl methacrylate-co-ethylene glycol dimethacrylate), propylene glycol dimethacrylate, di(propylene glycol) dimethacrylate, poly(propylene glycol) dimethacrylate, malonic dihydrazide, ethylmalonic dihydrazide, succinic dihydrazide, glutaric dihydrazide, adipic dihydrazide, isophthalic dihydrazide, oxalyl dihydrazide, pimelic dihydrazide, 3,3′

-sulfonyldibenzenesulfonic dihydrazide, m-xylylene isocyanate, 4-methyl-in-phenylene diisocyanate, 2-methyl-m-phenylene diisocyanate, 3,3′

-dimethoxy-4,4′

-biphenylene diisocyanate, 4-Br-6-methyl-1,3-phenylene diisocyanate, 4-Cl-6-methyl-1,3-phenylene diisocyanate, toluene 2,4-diisocyanate, 1,3-phenylene diisocyanate, 1,4-phenylene diisocyanate, 2,4,6-trimethyl-1,3-phenylene diisocyanate, 1,4-diisocyanatebutane, 1,6-diisocyanatehexane, 1,8-diisocyanateoctane, isophorone diisocyanate;

N,N-(3-dimethylaminopropyl)-N-ethyl carbodiimide, CaCl₂, divinylsulfone, sulfonylurea, hydrolysable polyrotaxane, L-lysine methyl ester, and genipin.