Controlled release microparticles
View Patent ↗Formulations for controlled, sustained release of biologically active agents for the treatment of ocular disorders have been developed. These formulations are based on solid microparticles formed of the combination of biodegradable, synthetic polymers such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and copolymers thereof. The microparticles are characterized by low burst levels and efficient drug loading and sustained release.
1. A sustained release suspension composition for intravitreal administration consisting essentially of a plurality of microparticles suspended in a pharmaceutically acceptable liquid carrier comprising phosphate buffer saline (PBS) and a surfactant comprising sodium dodecyl sulfate (SDS), wherein the liquid carrier is suitable for intravitreal administration, wherein
said microparticles comprise: (a) a biologically active anti-VEGF aptamer; and (b) poly(lactic acid) (PLA) or poly(lactic acid-co-glycolic acid) (PLGA) polymer and have a smooth, non-pitted external morphology, wherein said polymer has a monomer ratio of lactide:glycolide in the range of about 40:60 to 100:0;
said suspension comprises 100-300 mg microparticles per mL of said liquid carrier;
said microparticles release said biologically active anti-VEGF aptamer over a period of at least 40 days;
said microparticles have a particle size distribution in the range of 10 μm to 45 μm in diameter;
said microparticles comprise a PLA or PLGA polymeric material incorporating a core load of at least 7 wt % of said anti-VEGF aptamer and;
said microparticles release said anti-VEGF aptamer at an initial burst of less than 15 wt % of said core load within 24 hours of administration.
2. The composition of claim 1 , wherein the microparticles release the anti-VEGF aptamer over a period of at least 3 months.
3. The composition of claim 1 , wherein the microparticles release the anti-VEGF aptamer over a period of about 3-6 months.
4. The composition of claim 1 , wherein the microparticles are syringable through a 29-gauge needle or narrower.
5. The composition of claim 1 , wherein the microparticles have a mean diameter of about 30 μm.
6. The composition of claim 1 , wherein the microparticles have a mean diameter of about 15 μm.
7. The composition of claim 1 , wherein the microparticles are syringable through a 27-gauge needle or narrower and have a diameter of less than or equal to 75% of the inner diameter of the needle.
8. The composition of claim 1 , wherein the microparticles are syringable through a 27-gauge needle or narrower and have a diameter of less than or equal to 50% of the inner diameter of the needle.
9. The composition of claim 1 , wherein the microparticles are syringable through a 27-gauge needle or narrower and have a diameter of less than or equal to 25% of the inner diameter of the needle.
10. The composition of claim 1 , wherein the microparticles have a core load of at least 10% by weight.
11. The composition of claim 1 , wherein the microparticles have a core load of at least 15% by weight.
12. The composition of claim 1 , wherein the microparticles have a core load of at least 20% by weight.
13. The composition of claim 1 , wherein the microparticles exhibit a 24 hour burst of less than 10 wt % of said core load.
14. The composition of claim 1 , wherein the microparticles exhibit a 24 hour burst of less than 5 wt % of said core load.
15. The composition of claim 1 , wherein the microparticles form a homogeneous or un-agglomerated suspension with the pharmaceutically acceptable carrier.
16. The composition of claim 1 , wherein the microparticles are microspheres.
17. The composition of claim 1 , wherein the internal morphology of the microparticles is homogeneous or monolithic.
18. The composition of claim 1 , wherein the anti-VEGF aptamer is a therapeutic agent suitable for the treatment of an ophthalmic disease or disorder.
19. The composition of claim 18 , wherein the anti-VEGF agent is conjugated to a non-toxic, long-chain, hydrophilic, hydrophobic or amphiphilic polymer.
20. The composition of claim 19 , wherein the anti-VEGF aptamer is conjugated to polyethylene glycol.
21. The composition of claim 20 , wherein the anti-VEGF aptamer is pegaptanib.
22. The composition of claim 21 wherein pegaptanib is released from the microparticles at a rate ranging from about 0.01 to about 10 micrograms (μg) per day.
23. The composition of claim 22 wherein pegaptanib is present in an amount sufficient to provide pegaptanib plasma concentrations of about 0.05-0.40 nM throughout an administration period of at least 3 weeks.
24. The composition of claim 21 wherein the microparticles are suspended in a pegaptanib solution.
25. The composition of claim 1 wherein the liquid carrier further comprises a surfactant selected from the group consisting of poly(vinyl alcohol), carboxymethyl cellulose, lecithin, gelatin, poly(vinyl pyrrolidone), polyoxyethylenesorbitan fatty acid esters and mannitol.
26. The composition of claim 25 wherein the surfactant is selected from polyoxyethylenesorbitan fatty acid esters and mannitol.
27. A sustained release suspension composition consisting essentially of a plurality of microparticles having a smooth, non-pitted external morphology suspended in a pharmaceutically acceptable liquid carrier comprising phosphate buffer saline (PBS) and a surfactant comprising sodium dodecyl sulfate (SDS), wherein the liquid carrier is suitable for intravitreal administration, wherein said microparticles form a homogeneous or un-agglomerated suspension with the pharmaceutically acceptable carrier, said suspension comprises 100-300 mg microparticles per mL of said liquid carrier; wherein said microparticles comprise a poly(lactic acid-co-glycolic acid) (PLGA) polymeric material having a monomer ratio of lactide:glycolide of 75:25 and incorporating a core load of at least 7 wt % of pegaptanib, wherein said microparticles have a particle size distribution in the range of 10 μm to 45 μm in diameter, wherein said microparticles release pegaptanib over a period of at least 40 days at an initial burst of less than 15 wt % of said core load within 24 hours of administration, wherein pegaptanib is released from the microparticles at a rate ranging from about 0.01 to about 10 micrograms (μg) per day, and wherein said microparticles are syringable through a 27-gauge needle or narrower.
28. The composition of claim 27 wherein pegaptanib is released from the microparticles at a rate ranging from about 0.1 to about 6 μg per day.
29. The composition of claim 27 wherein pegaptanib is released at a rate sufficient to achieve pegaptanib plasma concentrations of about 0.05-0.40 nM throughout an administration period of at least 3 weeks.
30. The composition of claim 27 wherein pegaptanib is released at a rate sufficient to achieve pegaptanib plasma concentrations of about 0.05-0.40 nM throughout an administration period of at least 6 weeks.
31. The composition of claim 27 , wherein the microparticles release pegaptanib over a period of at least 3 months.
32. The composition of claim 27 , wherein the microparticles have a core load of at least 10% by weight.
33. The composition of claim 27 , wherein the microparticles exhibit a 24 hour burst of less than 10 wt % of said core load.
34. The composition of claim 27 , wherein the microparticles exhibit a 24 hour in vitro burst of less than 5 wt % of said core load.
35. The composition of claim 27 , wherein the carrier further comprises a pharmaceutically acceptable surfactant or excipient.
36. The composition of claim 1 , wherein the microparticles release the anti-VEGF aptamer over a period of at least 180 days.
37. The composition of claim 1 , wherein the microparticles release the anti-VEGF aptamer over a period of at least 365 days.
38. The composition of claim 27 , wherein the microparticles release the anti-VEGF aptamer over a period of at least 180 days.
39. The composition of claim 27 , wherein the microparticles release the anti-VEGF aptamer over a period of at least 365 days.