Coated particles for sustained-release pharmaceutical administration

• US 9,492,388 B2
• Filed: 12/22/2003
• Issued: 11/15/2016
• Est. Priority Date: 12/20/2002
• Status: Active Grant

• Current Assignee: Auritec Pharmaceuticals
• Original Assignee: St. James Associates LLC
• Inventors: Smith, Thomas J.
• Primary Examiner(s): YOUNG, MICAH PAUL
• Application Number:
  US10/538,589
• Publication Number:
  US 20070003619A1
• Time in Patent Office: 4,712 Days
• Field of Search: 424/407, 424/408, 424464-482, 424489-496
• US Class Current: 1/1
• 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 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Abstract

Coated microparticles for sustained-release of an active pharmaceutical ingredient after parenteral administration, and methods of producing such coated microparticles, are provided. The coated microparticles comprise core particles of an active pharmaceutical ingredient and a first polymeric coating on the core particles. The first polymeric coating is permeable to the active pharmaceutical ingredient forms a saturated solution within the coated microparticle, resulting in pseudo-zero-sustained release period. A second polymeric coating can be employed to add mechanical support or as a rate-controlling element.

Claims

1. A pharmaceutical preparation for sustained-release of an active pharmaceutical ingredient after parenteral administration comprising:

a multiplicity of coated microparticles, said coated microparticles having a mean dimension of less than 1 mm and each coated microparticle comprising

(a) a core particle consisting of said active pharmaceutical ingredient; and

(b) a first polymeric coating enveloping said core particle;

wherein said first polymeric coating is crystalline and is permeable to water and said active pharmaceutical ingredient while maintaining structure integrity during a sustained-release period from administration of said microparticles.

2. The pharmaceutical preparation of claim 1, wherein diffusion of said active pharmaceutical ingredient across said first polymeric coating exhibits pseudo-zero-order kinetics during said sustained-release period.

3. The pharmaceutical preparation of claim 1, wherein said first polymeric coating is substantially degraded after said sustained-release period.

4. The pharmaceutical preparation of claim 1, wherein said microparticles are administrable via parenteral injection.

5. The pharmaceutical preparation of claim 4, wherein said microparticles have a maximum dimension between 20 μ

m and 800 μ

m.

6. The pharmaceutical preparation of claim 4, wherein said microparticles have a maximum dimension between 40 μ

m and 400 μ

m.

7. The pharmaceutical preparation of claim 4, wherein said microparticles have a maximum dimension between 100 μ

m and 250 μ

m.

8. The pharmaceutical preparation of claim 1, wherein the first polymeric coating is formed by coating the core particle of said active pharmaceutical ingredient in a first polymer-forming solution, and wherein the core particle is substantially insoluble in said first polymer-forming solution.

9. The pharmaceutical preparation of claim 8, wherein said active pharmaceutical ingredient is hydrophobic and said first polymer-forming solution is hydrophilic.

10. The pharmaceutical preparation of claim 8, wherein said active pharmaceutical ingredient is hydrophilic and said first polymer-forming solution is hydrophobic.

11. The pharmaceutical preparation of claim 1, further comprising:

(c) a second polymeric coating on said first polymeric coating;

wherein said second polymeric coating is permeable to said active pharmaceutical ingredient during said sustained-release period.

12. The pharmaceutical preparation of claim 1, further comprising:

(c) a porous second polymeric coating on said first polymeric coating;

wherein said second polymeric coating defines pore regions which permit fluid communication between a pore portion of said first polymeric coating and an external environment, thereby allowing diffusion of said active pharmaceutical ingredient across said first polymeric coating in said pore regions; and

wherein said second polymeric coating defines non-pore regions which prevent fluid communication between a non-pore portion of said first polymeric coating and an external environment, thereby inhibiting diffusion of said active pharmaceutical ingredient across said first polymeric coating in said non-pore regions.

13. The pharmaceutical preparation of claim 12, wherein said second polymeric coating is substantially impermeable to said active pharmaceutical ingredient in said non-pore regions.

14. The pharmaceutical preparation of claim 12, wherein said second polymer-forming solution comprises pore-forming agents which dissolve to produce said pore regions after formation of said second polymeric coating.

15. The pharmaceutical preparation of claim 1, wherein said first polymeric coating comprises a polymer or co-polymer including at least one monomer selected from the group consisting of sugar phosphates, alkylcellulose, hydroxyalkylcelluloses, lactic acid, glycolic acid, β

-propiolactone, β

-butyrolactone, γ

-butyrolactone, pivalolactone, α

-hydroxy butyric acid, α

-hydroxyethyl butyric acid, α

-hydroxy isovaleric acid, α

-hydroxy-β

-methyl valeric acid, α

-hydroxy caproic acid, α

-hydroxy isocaproic acid, α

-hydroxy heptanic acid, α

-hydroxy octanic acid, α

-hydroxy decanoic acid, α

-hydroxy myristic acid, α

-hydroxy stearic acid, α

-hydroxy lignoceric acid, β

-phenol lactic acid and polyvinyl alcohol.

16. The pharmaceutical preparation of claim 11 or 12, wherein said second polymeric coating comprises a polymer or co-polymer including at least one monomer selected from the group consisting of sugar phosphates, alkylcellulose, hydroxyalkylcelluloses, lactic acid, glycolic acid, β

-propiolactone, β

-butyrolactone, γ

-butyrolactone, pivalolactone, α

-hydroxy butyric acid, α

-hydroxyethyl butyric acid, α

-hydroxy isovaleric acid, α

-hydroxy-β

-methyl valeric acid, α

-hydroxy caproic acid, α

-hydroxy isocaproic acid, α

-hydroxy heptanic acid, α

-hydroxy octanic acid, α

-hydroxy decanoic acid, α

-hydroxy myristic acid, α

-hydroxy stearic acid, α

-hydroxy lignoceric acid, β

-phenol lactic acid and polyvinyl alcohol.

17. The pharmaceutical preparation of claim 1, wherein said first polymeric coating is applied to said core particles by an air suspension technique.

18. The pharmaceutical preparation of claim 1, wherein said first polymeric coating is applied to said core particles by a dip coating technique.

19. The pharmaceutical preparation of claim 1, wherein the weight of said first polymeric coating is between 0.1% and 200% of the weight of said core particle.

20. The pharmaceutical preparation of claim 1, wherein the weight of said first polymeric coating is between 2% and 60% of the weight of said core particle.

21. The pharmaceutical preparation of claim 1, wherein the volume of said first polymeric coating is between 0.1% and 200% of the volume of said core particle.

22. The pharmaceutical preparation of claim 1, wherein the volume of said first polymeric coating is between 2% and 60% of the volume of said core particle.

23. A method of sustained-release administration of an active pharmaceutical ingredient comprising administering parenterally a pharmaceutical preparation of claim 1 in the form of a suspension of said coated microparticles in a pharmaceutically acceptable carrier.

24. The method of claim 23, wherein said parenteral administration is selected from the group consisting of subcutaneous, intravenous, intramuscular and intraocular injection.

28. A pharmaceutical preparation of claim 1 wherein the active pharmaceutical ingredient is in the form of single crystal, a multiplicity of crystals, macrocrystal, or pressure-fused particle.

25. A pharmaceutical preparation for sustained-release of an active pharmaceutical ingredient after parenteral administration comprising:

a multiplicity of coated microparticles, said coated microparticles having a mean dimension of less than 1 mm and each coated microparticle comprising

(a) a core particle consisting of said active pharmaceutical ingredient; and

(b) a first polymeric coating enveloping said core particle;

wherein said active pharmaceutical ingredient forms a saturated solution within said coated microparticles after said administration;

wherein said first polymeric coating is crystalline and is permeable to said active pharmaceutical ingredient during a sustained-release period from administration of said microparticles until the concentration of said active pharmaceutical ingredient contained within said microparticles is unsaturated; and

wherein the weight of the first polymeric coating is between 2% and 60% of the weight of the core particle.

26. A pharmaceutical preparation for sustained-release of an active pharmaceutical ingredient after parenteral administration comprising:

a multiplicity of coated microparticles, said coated microparticles having a mean dimension of less than 1 mm and each coated microparticle comprising

(a) a core particle consisting of said active pharmaceutical ingredient; and

(b) a first polymeric coating enveloping said core particle;

wherein said active pharmaceutical ingredient forms a saturated solution within said coated microparticles after said administration;

wherein said first polymeric coating is crystalline and is permeable to said active pharmaceutical ingredient during a sustained-release period from administration of said microparticles until the concentration of said active pharmaceutical ingredient contained within said microparticles is unsaturated; and

wherein the volume of the first polymeric coating is between 2% to 60% of the volume of the core particle.

27. A pharmaceutical preparation for sustained-release of an active pharmaceutical ingredient after parenteral administration comprising:

a multiplicity of coated microparticles, said coated microparticles having a mean dimension of less than 1 mm and each coated microparticle comprising

(a) a core particle consisting of said active pharmaceutical ingredient; and

(b) a first polymeric coating enveloping said core particle;

wherein said active pharmaceutical ingredient forms a saturated solution within said coated microparticles after said administration;

wherein said first polymeric coating is crystalline and is permeable to said active pharmaceutical ingredient during a sustained-release period from administration of said microparticles until the concentration of said active pharmaceutical ingredient contained within said microparticles is unsaturated; and

wherein the sustained-release period is at least five days.