School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
Eur J Pharm Biopharm. 2012 Aug;81(3):591-9. doi: 10.1016/j.ejpb.2012.04.015. Epub 2012 Apr 26.
Poly(lactic acid) is a widely used polymer for parenteral sustained-release formulations. But its solid state at room-temperature complicates the formulation process, and elaborate formulation systems like microparticles and self-precipitating implants are required for administration. In contrast, hexylsubstituted poly(lactic acid) (hexPLA) is a viscous, biodegradable liquid, which can simply be mixed with the active compound. In this study, the feasibility to prepare injectable suspension formulations with peptides was addressed on the example of the GnRH-agonist Triptorelin. Two formulation procedures, of which one was a straight forward one-step cryo-milling-mixing process, were compared regarding the particle size of the peptide in the polymer matrix, distribution, and drug release. This beneficial method resulted in a homogeneous formulation with an average particle diameter of the incorporated Triptorelin of only 4.1 μm. The rheological behavior of the Triptorelin-hexPLA formulations was assessed and showed thixotropic and shear-thinning behavior. Viscosity and injectability were highly dependent on the drug loading, polymer molecular weight, and temperature. Nine formulations with drug loadings from 2.5% to 10% and hexPLA molecular weights between 1500 and 5000 g/mol were investigated in release experiments, and all displayed a long-term release for over 3 months. Formulations with hexPLA of 1500 g/mol showed a viscosity-dependent release and hexPLA-Triptorelin formulations of over 2500 g/mol a molecular weight-dependent release profile. In consequence, the burst release and rate of release were controllable by adapting the drug loading and the molecular weight of the hexPLA. The degradation characteristics of the hexPLA polymer during the in vitro release experiment were studied by following the molecular weight decrease and weight loss. Triptorelin-hexPLA formulations had interesting sustained-release characteristics justifying further investigations in the drug-polymer interactions and the in vivo behavior.
聚乳酸（PLA）是一种广泛应用于注射型缓控释制剂的聚合物。但由于其在室温下为固态，这给制剂带来了一定的困难，需要采用复杂的制剂系统，如微球和自沉淀植入剂等。相比之下，己基取代的聚乳酸（hexPLA）是一种粘性的、可生物降解的液体，可以与活性化合物简单混合。在这项研究中，以 GnRH 激动剂曲普瑞林（Triptorelin）为例，探讨了制备肽类可注射混悬剂的可行性。两种制剂工艺，其中一种是直接的一步法冷冻-研磨-混合工艺，对肽在聚合物基质中的粒径、分布和药物释放进行了比较。该方法有利于制备均一的制剂，所加入的 Triptorelin 的平均粒径仅为 4.1μm。评估了 Triptorelin-hexPLA 制剂的流变行为，结果表明其具有触变性和剪切稀化行为。黏度和可注射性高度依赖于药物载药量、聚合物分子量和温度。对载药量为 2.5%至 10%、hexPLA 分子量在 1500 至 5000g/mol 之间的 9 种制剂进行了释放实验，所有制剂均显示出超过 3 个月的长效释放。载药量为 1500g/mol 的 hexPLA 制剂表现出黏度依赖性释放，载药量超过 2500g/mol 的 hexPLA-Triptorelin 制剂则表现出分子量依赖性释放特征。因此，通过调整药物载药量和 hexPLA 的分子量，可以控制突释和释放速率。通过跟踪分子量降低和重量损失，研究了体外释放实验中 hexPLA 聚合物的降解特性。Triptorelin-hexPLA 制剂具有良好的持续释放特性，值得进一步研究药物-聚合物相互作用和体内行为。
