PLGA Microparticles Encapsulating Prostaglandin E1-Hydroxypropyl-β-cyclodextrin (PGE1-HPβCD) Complex for the Treatment of Pulmonary Arterial Hypertension (PAH)
PLGA Microparticles Encapsulating Prostaglandin E1-Hydroxypropyl-β-cyclodextrin (PGE1-HPβCD) Complex for the Treatment of Pulmonary Arterial Hypertension (PAH)
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DOI：
10.1007/s11095-011-0409-6
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发表时间：
2011-07-01
影响因子：
3.7
通讯作者：
Ahsan, Fakhrul
中科院分区：
文献类型：
--
作者：
Gupta, Vivek;Davis, Marauo;Ahsan, Fakhrul
为考察前列腺素E-1(PGE(1)和2-羟丙基-β-环糊精(HP-βCD)包合物聚乳酸-羟基乙醇酸(PLGA)微球肺内给药治疗肺循环疾病--肺动脉高压(PAH)的疗效和活性。以HP-β-CD为络合剂，增加PGE(1)在水中的溶解度，形成大孔道颗粒，促进PGE(1)的吸收。微球的特性包括微粒化、体内吸收、代谢降解和急性安全性。在微球中加入HPβCD会导致大颗粒的内孔形成，尽管平均直径很大，但其空气动力学直径在1到5微米的可吸入范围内。HPβCD的加入也导致模拟肺间质液体中的体外释药量显著增加，显示出即时血流动力学效应所需的理想的突释曲线。与普通PLGA微球相比，与HPβCD络合后包封率降低。体内吸收情况表明，在肺部给药优化的微粒制剂后，前列腺素E(1)在循环中的可利用度延长，半衰期延长近4小时。代谢降解和急性毒性研究表明，微球制剂在生理条件下是稳定的，对肺和呼吸道上皮细胞是安全的。本研究证明了PLGA微球包裹的PGE(1)-HPβCD复合体作为一种潜在的控释系统的可行性。
To test the efficacy and viability of poly (lactic-co-glycolic acid) (PLGA) microspheres encapsulating an inclusion complex of prostaglandin E-1 (PGE(1)) and 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) for pulmonary delivery of PGE(1) for treatment of pulmonary arterial hypertension (PAH), a disease of pulmonary circulation.PLGA-based microparticulate formulations of PGE(1)-HP beta CD inclusion complex or plain PGE(1) were prepared by a double-emulsion solvent evaporation method. HP beta CD was used as a complexing agent to increase the aqueous solubility of PGE(1), act as a porosigen to produce large porous particles, and promote absorption of PGE(1). Particles were characterized for micromeritic properties, in vivo absorption, metabolic degradation, and acute safety.Incorporation of HP beta CD in the microparticles resulted in development of large particles with internal pores, which, despite large mean diameters, had aerodynamic diameters in the inhalable range of 1 to 5 mu m. HP beta CD incorporation also resulted in a significant increase in the amount of drug released in vitro in simulated interstitial lung fluid, showing a desirable burst release profile required for immediate hemodynamic effects. Compared to plain PLGA microparticles, entrapment efficiency was decreased upon complexation with HP beta CD. In vivo absorption profile indicated prolonged availability of PGE(1) in circulation following pulmonary administration of the optimized microparticulate formulations, with an extended half-life of almost 4 hours. Metabolic degradation and acute toxicity studies suggested that microparticulate formulations were stable under physiological conditions and safe for the lungs and respiratory epithelium.This study demonstrates the feasibility of PGE(1)-HP beta CD complex encapsulated in PLGA microparticles as a potential delivery system for controlled release of inhaled PGE(1).