METHODS FOR FINE PARTICLE MANUFACTURE

• US 20150050345A1
• Filed: 08/13/2014
• Published: 02/19/2015
• Est. Priority Date: 08/14/2013
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Smyth, Hugh D.C., Herpin, Matt
• Granted Patent: US 9,370,514 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/145 with organic compounds

Abstract

Processes for preparing micronized particles comprising a poorly water soluble bioactive agent are provided. The processes utilize a superheated aqueous phase which can serve as the continuous phase of an emulsion. The superheated aqueous phase can be used to melt poorly water soluble bioactive agents and/or matrix materials which them form molten droplets dispersed within the superheated aqueous phase. The size and size distribution of the molten droplets can be controlled using a variety of suitable methods. The molten droplets can then be cooled to form micronized particles comprising the poorly water soluble bioactive agent. If desired, the cooling rate can be selected to control the crystalline morphology of the resulting micronized particles.

Claims

1. A process for preparing micronized particles comprising a poorly water soluble bioactive agent, the process comprising

(a) heating an aqueous suspension comprising the poorly water soluble bioactive agent to a temperature of from about 100°

C. to about 280°

C. at a pressure of from greater than standard pressure to about 1,000 psi to form a superheated continuous phase comprising molten droplets of the poorly water soluble bioactive agent dispersed in superheated water; and

(b) cooling the molten droplets to form micronized particles comprising the poorly water soluble bioactive agent.

2. The process of claim 1, further comprising reducing the size of the molten droplets while maintaining the superheated continuous phase at a temperature of from about 100°

C. to about 280°

C. and a pressure of from greater than standard pressure to about 1,000 psi.

3. The process of claim 2, wherein reducing the size of the molten droplets comprises a low energy process.

4. The process of claim 3, wherein reducing the size of the molten droplets comprises low shear mixing.

5. The process of claim 1, further comprising drying the micronized particles.

6. The process of claim 1, further comprising stabilizing the micronized particles.

7. The process of claim 1, wherein cooling the molten droplets comprises cooling the molten droplets at a rate effective to form micronized particles comprising a particular crystalline form of the poorly water soluble bioactive agent.

8. The process of claim 1, wherein the micronized particles have an average particle size ranging from about 1 micron to about 5 microns.

9. The process of claim 1, wherein the poorly water soluble bioactive agent has a solubility in water of about 5 mg/mL or less at 25°

C.

10. The process of claim 1, wherein the poorly water soluble bioactive agent has a melting point of from about 100°

C. to about 280°

C., and

wherein step (a) comprises heating the aqueous suspension to a temperature ranging from the melting point of the poorly water soluble bioactive agent to about 10°

C. higher than the melting point of the poorly water soluble bioactive agent.

11. The process of claim 1, further comprising adding a second poorly water soluble bioactive agent to the aqueous suspension, to the superheated continuous phase, or combinations thereof.

12. The process of claim 11, wherein step (b) comprises a superheated aqueous phase heated to a temperature ranging from the melting point of the first poorly water soluble bioactive agent to less than the melting point of the second poorly water soluble bioactive agent.

13. A process for preparing micronized particles comprising a poorly water soluble bioactive agent, the process comprising

(a) melting the poorly water soluble bioactive agent;

(b) introducing the melted poorly water soluble bioactive agent into a superheated aqueous phase heated to a temperature of from about 100°

C. to about 280°

C. at a pressure of from greater than standard pressure to about 1,000 psi to form a superheated continuous phase comprising molten droplets of the poorly water soluble bioactive agent dispersed in superheated water, and

(c) cooling the molten droplets to form micronized particles comprising the poorly water soluble bioactive agent.

14. The process of claim 13, wherein introducing the melted poorly water soluble bioactive agent into the superheated aqueous phase comprises injecting droplets of the melted poorly water soluble bioactive agent into the superheated aqueous phase.

15. The process of claim 14, wherein injecting droplets of the melted poorly water soluble bioactive agent into the superheated aqueous phase comprises spraying the melted poorly water soluble bioactive agent into the superheated aqueous phase.

16. The process of claim 14, wherein injecting droplets of the melted poorly water soluble bioactive agent into the superheated aqueous phase comprises extruding the melted poorly water soluble bioactive agent into the superheated aqueous phase through a microporous membrane.

17. The process of claim 16, wherein injecting droplets of the melted poorly water soluble bioactive agent into the superheated aqueous phase comprises cross-flow membrane emulsification.

18. A process for preparing micronized particles comprising a poorly water soluble bioactive agent, the process comprising

(a) heating an aqueous suspension comprising a matrix material and the poorly water soluble bioactive agent to a temperature of from about 100°

C. to about 280°

C. at a pressure of from greater than standard pressure to about 1,000 psi to form a superheated continuous phase comprising molten droplets of the matrix material dispersed in superheated water, and

(b) cooling the molten droplets to form micronized particles comprising the matrix material and the poorly water soluble bioactive agent.

19. The process of claim 18, wherein the poorly water soluble bioactive agent has a higher melting point than the matrix material, and wherein step (a) comprises heating the aqueous suspension to a temperature ranging from the melting point of the matrix material to less than the melting point of the poorly water soluble bioactive agent.

20. The process of claim 18, wherein the matrix material has a melting point of from about 100°

C. to about 280°

C., and wherein step (a) comprises heating the aqueous suspension to a temperature ranging from the melting point of the matrix material to about 10°

C. higher than the melting point of the matrix material.