Aggregating microparticles for medical therapy
The present invention is a surface treated drug-loaded solid (e.g., non-porous) microparticle that aggregates in vivo to form a consolidated larger particle for medical therapy. In one embodiment, the particles are used for ocular therapy. Processes for producing the surface treated microparticle and injectable formulations which include the surface treated microparticle are also provided. When used in the eye, long-term consistent intraocular delivery can be achieved without disrupting vision and minimizing undesirable inflammatory responses.
1. A method for the treatment of an ocular disorder with a therapeutic agent capable of treating the disorder, comprising administering to a host in need thereof surface-modified aggregating microparticles wherein the surface-modified aggregating microparticles are injected into the eye and aggregate in vivo to form at least one pellet of at least 500 μm to provide sustained drug delivery for at least one month and wherein the microparticles
(i) comprise poly(lactide-co-glycolide) covalently linked to polyethylene glycol, surfactant, and an effective amount of the therapeutic agent that is encapsulated in the biodegradable microparticle;
(ii) have a mean diameter between 10 μm and 60 μm; and
(iii) contain from about 0.001 percent to about 1 percent surfactant and have been surface-modified to contain less surfactant than a microparticle prior to the surface modification wherein the surface has been modified at a temperature less than about 18° C.
2. The method of claim 1 , wherein the ocular disorder is wet age-related macular degeneration.
3. The method of claim 1 , wherein the ocular disorder is dry age-related macular degeneration.
4. The method of claim 1 , wherein the ocular disorder is glaucoma.
5. The method of claim 1 , wherein the surface-modified aggregating microparticles do not cause substantial inflammation in the eye.
6. The method of claim 1 , wherein the surface-modified aggregating microparticles do not cause an immune response in the eye.
7. The method of claim 1 , wherein the therapeutic agent is a pharmaceutical drug.
8. The method of claim 7 , wherein the therapeutic agent is a tyrosine kinase inhibitor.
9. The method of claim 8 , wherein the therapeutic agent is sunitinib or a pharmaceutically acceptable salt.
10. The method of claim 9 , wherein the therapeutic agent is sunitinib malate.
11. The method of claim 1 , wherein the microparticles deliver a therapeutically effective amount of a therapeutic agent selected from dorzolamide, brinzolamide, brimonidine, and timolol.
12. The method of claim 11 , wherein the therapeutic agent is timolol.
13. The method of claim 1 , wherein the microparticles have a mean diameter between about 20 and 30 μm.
14. The method of claim 1 , wherein the microparticles have a mean diameter between about 25 and 35 μm.
15. The method of claim 1 , wherein the microparticles have a mean diameter between about 20 and 40 μm.
16. The method of claim 1 , wherein the microparticles have a mean diameter between about 20 and 50 μm.
17. The method of claim 1 , wherein the microparticles have a mean diameter between about 25 and 40 μm.
18. The method of claim 1 , wherein the microparticles also comprise free poly(lactide-co-glycolide).
19. The method of claim 1 , wherein the microparticles also comprise free poly(lactic acid).
20. The method of claim 1 , wherein the microparticles also comprise poly(lactic acid) covalently linked to polyethylene glycol.
21. The method of claim 1 , wherein the microparticles also comprise free poly(lactide-co-glycolide) and free poly(lactic acid).
22. The method of claim 1 wherein the surfactant comprises polyvinyl alcohol.
23. The method of claim 1 , wherein the surface-modified aggregating microparticles are injected into the host via intravitreal injection.
24. The method of claim 1 , wherein the surface-modified aggregating microparticles are injected into the host via suprachoroidal injection.
25. The method of claim 1 , wherein the surface modification is carried out at a temperature of less than 16° C.
26. The method of claim 1 , wherein the surface modification is carried out at a temperature of less than 10° C.
27. The method of claim 1 , wherein the surface modification is carried out at a temperature of less than 8° C.
28. The method of claim 1 , wherein the surface modification is carried out at a temperature of less than 5° C.
29. The method of claim 1 , wherein the surface-modified aggregating microparticles have a solid core with less than 10% porosity by ratio of void space to total volume.
30. The method of claim 1 , wherein the surface-modified aggregating microparticles have a solid core with less than 8% porosity by ratio of void space to total volume.
31. The method of claim 1 , wherein the surface-modified aggregating microparticles have a solid core with less than 5% porosity by ratio of void space to total volume.
32. The method of claim 1 , wherein the surface-modified aggregating microparticles have a solid core with less than 3% porosity by ratio of void space to total volume.
33. The method of claim 1 , wherein the host is a human.
34. The method of claim 1 , wherein the surface-modified aggregating microparticles are injected into the host via suprachoroidal injection.
35. The method of claim 19 , wherein the surface-modified aggregating microparticles are injected into the host via suprachoroidal injection.