Aggregating microparticles for medical therapy

Abstract

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.

We claim: 
     
         1 . Surface-modified solid aggregating microparticles comprising at least one biodegradable polymer that:
 (i) have a solid core;   (ii) include a therapeutic agent;   (iii) have a modified surface which has been treated under mild conditions at a temperature less than about 18° C. to remove surface surfactant or both surface surfactant and surface polymer;   (iv) are sufficiently small to be injected in vivo;   (v) aggregate in vivo to form at least one pellet of at least 500 μm in vivo which provides sustained drug delivery in vivo for at least one month.   
     
     
         2 . The surface modified solid aggregating microparticles of  claim 1  suitable for injection. 
     
     
         3 . The surface modified solid aggregating microparticles of  claim 1  suitable for a delivery route selected from the group consisting of intravitreal, intrastromal, intracameral, subtenon, sub-retinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleral, circumcorneal, and tear duct inj ections. 
     
     
         4 . The surface modified solid aggregating microparticles of  claim 1  suitable for non-ocular delivery. 
     
     
         5 . The surface-modified solid aggregating microparticles of  claim 1 , wherein at least one pellet is capable of sustained drug delivery for at least two months. 
     
     
         6 . The surface-modified solid aggregating microparticles of  claim 1 , wherein at least one pellet is capable of sustained drug delivery for at least three months. 
     
     
         7 . The surface-modified solid aggregating microparticles of  claim 1 , wherein at least one pellet is capable of sustained drug delivery for at least four months. 
     
     
         8 . The surface-modified solid aggregating microparticles of  claim 1 , wherein at least one pellet is capable of sustained drug delivery for at least five months. 
     
     
         9 . The surface-modified solid aggregating microparticles of  claim 1 , wherein at least one pellet is capable of sustained drug delivery for at least six months. 
     
     
         10 . The surface-modified solid aggregating microparticles of  claim 1 , wherein the resulting aggregated pellet provides sustained drug delivery for at least seven months. 
     
     
         11 . The surface-modified solid aggregating microparticles of  claim 1 , wherein the surface modification is carried out at a pH between about 14 and about 12. 
     
     
         12 . The surface-modified solid aggregating microparticles of  claim 1 , wherein the surface modification is carried out at a pH between about 12 and about 10. 
     
     
         13 . The surface-modified solid aggregating microparticles of  claim 1 , wherein the surface modification is carried out at a pH between about 10 and about 8. 
     
     
         14 . The surface-modified solid aggregating microparticles of  claim 1 , wherein the surface modification is carried out at a pH between about 6 and about 8. 
     
     
         15 . The surface-modified solid aggregating microparticles of  claim 1 , wherein the surface modification is carried out at a pH between about 6.5 and about 7.5. 
     
     
         16 . The surface-modified solid aggregating microparticles of  claim 1 , wherein the surface modification is carried out at a pH between about 1 and about 6. 
     
     
         17 . The surface-modified solid aggregating microparticles of  claim 1 , wherein the surface modification is carried out at a temperature of less than 16° C. 
     
     
         18 . The surface-modified solid aggregating microparticles of  claim 1 , wherein the surface modification is carried out at a temperature of less than 10° C. 
     
     
         19 . The surface-modified solid aggregating microparticles of  claim 1 , wherein the surface modification is carried out at a temperature of less than 8° C. 
     
     
         20 . The surface-modified solid aggregating microparticles of  claim 1 , wherein the surface modification is carried out at a temperature of less than 5° C.