Plourde François, Motulsky Aude, Couffin-Hoarau Anne-Claude, Hoarau Didier, Ong Huy, Leroux Jean-Christophe
Canada Research Chair in Drug Delivery, Faculty of Pharmacy, University of Montreal, C.P. 6128 Succ. Centre-Ville, Montreal, Canada.
J Control Release. 2005 Nov 28;108(2-3):433-41. doi: 10.1016/j.jconrel.2005.08.016. Epub 2005 Sep 21.
The recent advent of biotechnologies has led to the development of labile macromolecular therapeutic agents that require complex formulations for their efficient administration. This work reports a novel concept for the systemic, sustained delivery of such agents. The proposed approach is based on the spontaneous self-assembly of low-molecular weight amphiphilic amino acid derivatives in a hydrophobic pharmaceutical vehicle. The injectable, in situ-forming organogels were obtained by mixing N-stearoyl l-alanine (m)ethyl esters with a vegetable oil and a biocompatible hydrophilic solvent. The gels' in vivo-delivering properties were evaluated in rats with leuprolide, a luteinizing hormone-releasing hormone agonist used in prostate cancer, endometriosis and precocious puberty treatment. Following subcutaneous injection, the gels degraded and gradually released leuprolide for 14 to 25 days. Drug release was accompanied by sustained castration lasting up to 50 days, as assessed by testosterone levels. This study demonstrates that in situ-forming implants based on l-alanine derivatives represent a novel injectable platform for the controlled delivery of hydrophilic compounds, which is simpler than currently available implant and microsphere technologies.
生物技术的最新进展催生了不稳定的大分子治疗剂，这类药剂需要复杂的配方才能有效给药。这项研究报告了一种用于这类药剂全身持续递送的新概念。所提出的方法基于低分子量两亲性氨基酸衍生物在疏水性药物载体中的自发自组装。通过将N-硬脂酰-L-丙氨酸（m）乙酯与植物油和生物相容性亲水性溶剂混合，得到可注射的原位形成有机凝胶。用亮丙瑞林（一种用于前列腺癌、子宫内膜异位症和性早熟治疗的促黄体生成素释放激素激动剂）在大鼠体内评估了凝胶的体内递送特性。皮下注射后，凝胶降解并逐渐释放亮丙瑞林达14至25天。通过睾酮水平评估，药物释放伴随着持续长达50天的去势。这项研究表明，基于L-丙氨酸衍生物的原位形成植入物代表了一种用于亲水性化合物控释的新型可注射平台，它比目前可用的植入物和微球技术更简单。
