Alonso M J, Cohen S, Park T G, Gupta R K, Siber G R, Langer R
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge 02139.
Pharm Res. 1993 Jul;10(7):945-53. doi: 10.1023/a:1018942118148.
Controlled-release formulations based on poly(lactic) (PLA) and poly(lactic/glycolic) acid (PLGA) microspheres containing tetanus vaccine were designed. The polymers forming the microspheres were L-PLA of different molecular weights and DL-PLGA, 50:50. These microspheres were prepared by two solvent elimination procedures, both using a double emulsion, and were characterized for size, morphology, and toxoid release kinetics. The influence of formulation variables such as polymer type, vaccine composition, and vaccine/polymer ratio was also investigated. Both techniques yielded microspheres with similar size, morphology, and release properties. Microsphere size was dependent on the type of polymer and the presence of the surfactant L-alpha-phosphatidylcholine, which led to a reduction in microsphere size. On the other hand, the release kinetics of encapsulated protein were affected by the polymer properties (ratio lactic/glycolic acid and molecular weight) as well as by the vaccine composition, vaccine loading, and microsphere size. Moreover, for some formulations, a decrease in microsphere size occurred simultaneously, with an increase in porosity leading to an augmentation of release rate. The changes in the PLA molecular weight during in vitro release studies indicated that release profiles of tetanus toxoid from these microspheres were only marginally influenced by polymer degradation. A significant fraction of protein (between 15 and 35%) was initially released by diffusion through water-filled channels. In contrast, the decrease in the PLGA molecular weight over the first 10 days of incubation suggested that erosion of the polymer matrix substantially affects protein release from these microspheres. Among all formulations developed, two differing in microsphere size, polymer hydrophobicity, and release profile were selected for in vivo administration to mice.(ABSTRACT TRUNCATED AT 250 WORDS)
设计了基于聚乳酸（PLA）和聚乳酸/乙醇酸共聚物（PLGA）微球的破伤风疫苗控释制剂。形成微球的聚合物是不同分子量的L-PLA和50:50的DL-PLGA。这些微球通过两种溶剂去除程序制备，均采用复乳法，并对其尺寸、形态和类毒素释放动力学进行了表征。还研究了制剂变量如聚合物类型、疫苗组成和疫苗/聚合物比例的影响。两种技术制备的微球在尺寸、形态和释放特性方面相似。微球尺寸取决于聚合物类型和表面活性剂L-α-磷脂酰胆碱的存在，后者导致微球尺寸减小。另一方面，包封蛋白的释放动力学受聚合物性质（乳酸/乙醇酸比例和分子量）以及疫苗组成、疫苗负载量和微球尺寸的影响。此外，对于某些制剂，微球尺寸减小同时伴随着孔隙率增加，导致释放速率提高。体外释放研究期间PLA分子量的变化表明，这些微球中破伤风类毒素的释放曲线仅受到聚合物降解的轻微影响。相当一部分蛋白质（15%至35%）最初通过充满水的通道扩散释放。相比之下，在孵育的前10天PLGA分子量的降低表明聚合物基质的侵蚀对这些微球中蛋白质的释放有实质性影响。在所有开发的制剂中，选择了两种微球尺寸、聚合物疏水性和释放曲线不同的制剂用于小鼠体内给药。（摘要截断于250字）
