School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland.
J Control Release. 2013 Feb 10;165(3):199-206. doi: 10.1016/j.jconrel.2012.11.014. Epub 2012 Dec 3.
Hexylsubstituted poly(lactic acid) (hexPLA) is a viscous polymer, which degrades in the presence of water similar to the structure related poly(lactic acid). With hydrophilic active compounds, like Triptorelin acetate, the lipophilic polymer was formulated in form of parenterally injectable suspensions. This first in vivo study toward the biocompatibility of hexPLA implants in rats over 3 months in comparison to in situ forming poly(lactic-co-glycolic acid) (PLGA) formulations is presented here. The hexPLA implants showed only a mild acute inflammation at the injection site after application, which continuously regressed. In contrast to the PLGA formulations, hexPLA did not provoke an encapsulation of the implant with extracellular matrix. Prior to the formulation application, the stability of Triptorelin inside the hexPLA matrix was assessed under different storage conditions and in the presence of buffer to simulate a peptide degrading environment. At 5°C Triptorelin showed a stability of 98% inside the polymer for at least 6 months. The stability was still 78% at an elevated temperature of 40°C. HexPLA protected the incorporated peptide from the surrounding aqueous environment, which resulted in 20% less degradation inside the polymer compared to the solution. This protection effect supports the use of Triptorelin-hexPLA formulations for parenteral sustained-release formulations. In a second in vivo evaluation in Wistar Hannover rats, formulations containing 5% and 10% Triptorelin in the polymeric matrix released the active compound continuously for 6 months. The formulations showed a higher release during the initial 7 days, which is necessary for the clinical use to down-regulate all GnRH-receptors. Afterwards, a zero order drug release was observed over the first 3 months. After 3 months, the plasma levels decreased slowly but remained at effective concentrations for the total of 6 months. Furthermore, a qualitative in vitro-in vivo correlation was observed, possibly facilitating future optimization of the Triptorelin-hexPLA sustained-release formulations.
己基取代聚乳酸（hexPLA）是一种粘性聚合物，在存在水的情况下类似于相关结构的聚乳酸一样降解。将亲水性活性化合物，如醋酸曲普瑞林，与疏水性聚合物一起配制为可注射混悬剂。与原位形成的聚乳酸-共-乙醇酸（PLGA）制剂相比，本文首次报道了己基取代聚乳酸植入物在大鼠体内长达 3 个月的生物相容性的体内研究。与 PLGA 制剂相反，己基取代聚乳酸不会引发细胞外基质对植入物的包裹。在制剂应用之前，在不同的储存条件下并在缓冲液存在下评估了三普瑞林在己基取代聚乳酸基质中的稳定性，以模拟肽降解环境。在 5°C 下，三普瑞林在聚合物中至少 6 个月的稳定性为 98%。在 40°C 的高温下，稳定性仍为 78%。己基取代聚乳酸保护掺入的肽免受周围水相环境的影响，导致聚合物内的降解减少 20%。这种保护作用支持将三普瑞林-己基取代聚乳酸制剂用于注射用缓释制剂。在 Wistar Hannover 大鼠的第二次体内评估中，聚合物基质中含有 5%和 10%三普瑞林的制剂持续释放活性化合物长达 6 个月。在最初的 7 天内，制剂显示出更高的释放，这对于临床使用以下调所有 GnRH 受体是必要的。之后，在最初的 3 个月内观察到零级药物释放。3 个月后，血浆水平缓慢下降，但在整个 6 个月内仍保持有效浓度。此外，观察到体外-体内相关性，这可能有助于未来优化三普瑞林-己基取代聚乳酸缓释制剂。
