Three-layered microcapsules as a long-term sustained release injection preparation.

Three-layered milli-capsules (3LMC), diameter of 1.85+/-0.07 and 0.15+/-0.09 mm thickness, were designed for the long-term subcutaneous (sc) administration of drugs. 3LMCs composed of (1) surface membrane (release rate control membrane), (2) drug-carrying layer and (3) base membrane were prepared by dispensing each solution in series. As surface membrane, poly-(epsilon-caprolactone) having MW of 70 kDa (PCL70) was used in combination with plasticizer, polysorbate 60 (Tween60). Base membrane was prepared with PCL70. Fluorescein isothiocyanate labeled dextrans (FD-4, MW=4 kDa and FD-20, MW=20 kDa) were used as model drug and in vitro release experiment was performed with PCL70 surface membrane containing Tween60 with 0.3, 1.0 and 3.0% (w/w). As the amount of Tween60 increased, release rate of FD-4 was increased. PCL70+0.3% Tween60 membrane showed a good sustained release property for 5 weeks; 50.3+/-6.0% of FD-4 was released during 5 weeks. When FD-20 was encapsulated, long-term sustained release was not obtained, 10.7+/-3.6% was released during 5 weeks. However, when lower MW drug, leuprolide acetate, was encapsulated, 3LMC composed of PCL70+0.3% Tween60 showed a good sustained release property, 63.0+/-5.9% released for 5 weeks. Leuprolide acetate encapsulated 3LMC was evaluated in rat experiment. After sc administration to rats, 0.5 and 1.0 mg, plasma leuprolide concentration showed its maximum concentration at day 1, thereafter gradually decreased and maintained the effective concentration for 14 weeks. Plasma leuprolide concentration vs. time curve showed a good dose-dependency. When surface membrane prepared by blending PCL70 and poly(lactic acid) (PLA) in the molar ratio of 5:1 was used, long-term sustained release property was not obtained. Instead, lower MW PCL, PCL40, was blended with PLA (5:1) to prepare surface membrane, sustained release of leuprolide was observed for 5 weeks. Through those studies, 3LMC has been shown to be a long-term sustained release preparation by properly selecting the surface membrane.