Brodbeck K J, Pushpala S, McHugh A J
Department of Chemical Engineering, University of Illinois, Urbana, USA.
Pharm Res. 1999 Dec;16(12):1825-9. doi: 10.1023/a:1018943107688.
The effects of altering the dynamics of phase inversion of a polylactic glycolic acid (PLGA) solution depot on the sustained-release delivery profile of human growth hormone (hGH) were evaluated. The impact of adjusting the protein particle composition was also studied in a slow phase-inverting formulation.
Protein release profiles of depots prepared from four model solvents were generated by injecting formulations into the subcutaneous space of normal rats and monitoring hGH serum levels over the course of 1 month. Scanning electron microscopy, Coulometric Karl Fischer titration, size-exclusion liquid chromatography, and reversed-phase liquid chromatography were used to observe depot morphologies, bulk water absorption, PLGA degradation, and protein particle dissolution rates, respectively.
An extended-release profile and significantly reduced burst effect resulted when the aqueous affinity of the depot solvent was reduced. As seen earlier in in vitro experiments, lowering the solvent's aqueous affinity slows the phase inversion rate, which in turn produces depot morphologies favorable to prolonged release. Protein burst on injection was entirely eliminated in a slow phase-inverting formulation by densifying the lyophilized protein particles. Unlike the use of metal cations to prolong release of some proteins in PLGA microsphere depots, this technique is more universal, and thus is potentially usable with any protein or highly soluble drug agent. The onset of biodegradation was observed to occur at 14 days for all depot formulations, however the bulk biodegradation rate slowed as the aqueous affinity of the depot solvent decreased. This result supports the hypothesis that, in a slow phase-inverting system, drug release over the first few weeks is governed by the diffusion rate of drug through the polymer solution.
By taking advantage of the effects of low aqueous affinity and protein particle densification, a PLGA solution depot was produced with the capability of sustaining hGH levels in normal rats at a serum level of 10 to 200 ng/ml for 28 days.
评估改变聚乳酸乙醇酸共聚物（PLGA）溶液储库相转变动力学对人生长激素（hGH）缓释递送曲线的影响。还研究了在缓慢相转变制剂中调整蛋白质颗粒组成的影响。
通过将制剂注射到正常大鼠的皮下空间并在1个月内监测hGH血清水平，生成由四种模型溶剂制备的储库的蛋白质释放曲线。分别使用扫描电子显微镜、库仑卡尔费休滴定法、尺寸排阻液相色谱法和反相液相色谱法观察储库形态、总体吸水率、PLGA降解和蛋白质颗粒溶解速率。
当储库溶剂的水亲和力降低时，出现了延长释放曲线并显著降低了突释效应。如早期在体外实验中所见，降低溶剂的水亲和力会减慢相转变速率，这反过来会产生有利于延长释放的储库形态。通过使冻干的蛋白质颗粒致密化，在缓慢相转变制剂中完全消除了注射时的蛋白质突释。与在PLGA微球储库中使用金属阳离子来延长某些蛋白质的释放不同，该技术更具通用性，因此可能适用于任何蛋白质或高溶性药物制剂。观察到所有储库制剂在14天时开始发生生物降解，然而随着储库溶剂的水亲和力降低，总体生物降解速率减慢。该结果支持了这样的假设，即在缓慢相转变系统中，最初几周的药物释放受药物通过聚合物溶液的扩散速率控制。
通过利用低水亲和力和蛋白质颗粒致密化的作用，制备了一种PLGA溶液储库，能够在正常大鼠中将hGH水平维持在血清水平10至200 ng/ml达28天。
