Desai Kashappa Goud H, Mallery Susan R, Schwendeman Steven P
Department of Pharmaceutical Sciences, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA.
Eur J Pharm Biopharm. 2008 Sep;70(1):187-98. doi: 10.1016/j.ejpb.2008.03.007. Epub 2008 Mar 20.
The objective of this study was to investigate the potential of various formulation strategies to achieve 1-month continuous (improved) release of the novel anti-cancer drug, 2-methoxyestradiol (2-ME), from injectable cylindrical poly(DL-lactide-co-glycolide) (PLGA) implants. PLGA implants were prepared by a solvent extrusion method. PLGA 50:50 (M(w)=51 kDa, end group=lauryl ester) (PLGA-lauryl ester) implants loaded with 3-30 wt% 2-ME exhibited a pronounced lag phase (i.e., corresponding to induction time to polymer mass loss) and triphasic release profile. Incorporation of 5 wt% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) (approximately 57% release after 28 days) or Pluronic F127 (approximately 42% release after 28 days) in PLGA-lauryl ester implants reduced the lag-phase and improved the drug release moderately over a period of 28 days. The formation and the incorporation of a 2-ME/polyethylene glycol (PEG) 8000 solid dispersion in PLGA-lauryl ester implants further increased drug release (approximately 21% and 73% release after 1 and 28 days, respectively), attributable to improved drug solubility/dissolution, higher matrix porosity, and accelerated polymer degradation. Blending of PLGA 50:50 (M(w)=24 kDa, end group=COOH) (PLGA-COOH) with the PLGA-lauryl ester also provided moderate enhancement of 2-ME release over a period of 28 days. PLGA-COOH (M(w)=24 kDa) implants with 3-5% w/w pore-forming MgCO(3) exhibited the most desirable drug release among all the formulations tested, and, demonstrated 1-month slow and continuous in vitro release of approximately 80% 2-ME after a minimal initial burst. Hence, these formulation approaches provide several possible avenues to improve release rates of the hydrophobic drug, 2-ME, from PLGA for future application in regional anti-cancer therapy.
本研究的目的是探讨各种制剂策略的潜力，以实现新型抗癌药物2-甲氧基雌二醇（2-ME）从可注射圆柱形聚（DL-丙交酯-共-乙交酯）（PLGA）植入物中持续1个月（改善的）释放。PLGA植入物通过溶剂挤出法制备。负载3-30 wt% 2-ME的PLGA 50:50（M(w)=51 kDa，端基=月桂酸酯）（PLGA-月桂酸酯）植入物表现出明显的延迟期（即，对应于聚合物质量损失的诱导时间）和三相释放曲线。在PLGA-月桂酸酯植入物中加入5 wt%羟丙基-β-环糊精（HP-β-CD）（28天后约57%释放）或普朗尼克F127（28天后约42%释放）可减少延迟期，并在28天内适度改善药物释放。在PLGA-月桂酸酯植入物中形成并加入2-ME/聚乙二醇（PEG）8000固体分散体进一步提高了药物释放（1天和28天后分别约21%和73%释放），这归因于药物溶解度/溶解的改善、更高的基质孔隙率和加速的聚合物降解。将PLGA 50:50（M(w)=24 kDa，端基=COOH）（PLGA-COOH）与PLGA-月桂酸酯混合也在28天内适度增强了2-ME的释放。含有3-5% w/w成孔MgCO(3)的PLGA-COOH（M(w)=24 kDa）植入物在所有测试制剂中表现出最理想的药物释放，并在最小初始突释后证明1个月内约80%的2-ME在体外缓慢持续释放。因此，这些制剂方法为提高疏水性药物2-ME从PLGA中的释放速率提供了几种可能的途径，以供未来在区域抗癌治疗中应用。
