Wang Juan, Wang Barbara M, Schwendeman Steven P
Pharmaceutical Analytical and Development Department, Novartis Pharmaceuticals Corp., 59 Route 10, East Hanover, NJ 07936, USA.
Biomaterials. 2004 May;25(10):1919-27. doi: 10.1016/j.biomaterials.2003.08.019.
One major obstacle for development of injectable biodegradable microspheres for controlled peptide and protein delivery is the high initial burst of drug release occurring over the first day of incubation. We describe here the significant reduction in initial burst release of a highly water-soluble model peptide, octreotide acetate, from poly(D,L-lactide-co-glycolide) microspheres by the co-encapsulation of a small amount of glucose (e.g., 0.2%w/w), i.e., from 30+/-20% burst - glucose to 8+/-3% + glucose (mean+/-SD, n=4). This reduction is unexpected since hydrophilic additives are known to increase porosity of microspheres, causing an increase in permeability to mass transport and a higher burst. Using the double emulsion-solvent evaporation method of encapsulation, the effect of glucose on initial burst in an acetate buffer pH 4 was found to depend on polymer concentration, discontinuous phase/continuous phase ratio, and glucose content. Extensive characterization studies were performed on two microsphere batches, +/-0.2% glucose, to elucidate the mechanism of this effect. However, no significant difference was observed with respect to specific surface area, porosity, internal and external morphology and drug distribution. Continuous monitoring of the first 24-h release of octreotide acetate from these two batches disclosed that even though their starting release rates were close, the microspheres + glucose exhibited a much lower release rate between 0.2 and 24h compared to those - glucose. The microspheres + glucose showed a denser periphery and a reduced water uptake at the end of 24-h release, indicating decreased permeability. However, this effect at times was offset as glucose content was further increased to 1%, causing an increase in surface area and porosity. In summary, we conclude that the effect of glucose on initial burst are determined by two factors: (1) increased initial burst due to increased osmotic pressure during encapsulation and drug release, and (2) decreased initial burst due to decreased permeability of microspheres.
用于控制肽和蛋白质递送的可注射生物可降解微球开发的一个主要障碍是在孵育的第一天出现的药物高初始突释。我们在此描述了通过共包封少量葡萄糖（例如0.2%w/w），从聚（D，L-丙交酯-共-乙交酯）微球中显著降低了高水溶性模型肽醋酸奥曲肽的初始突释，即从含葡萄糖时的30±20%突释降至含葡萄糖时的8±3%（平均值±标准差，n = 4）。这种降低是出乎意料的，因为已知亲水性添加剂会增加微球的孔隙率，导致传质渗透率增加和更高的突释。使用双乳液-溶剂蒸发包封方法，发现葡萄糖对pH 4醋酸盐缓冲液中初始突释的影响取决于聚合物浓度、分散相/连续相比和葡萄糖含量。对两批含±0.2%葡萄糖的微球进行了广泛的表征研究，以阐明这种作用的机制。然而，在比表面积、孔隙率、内部和外部形态以及药物分布方面未观察到显著差异。对这两批微球中醋酸奥曲肽的前24小时释放进行连续监测发现，尽管它们的起始释放速率相近，但含葡萄糖的微球在0.2至24小时之间的释放速率比不含葡萄糖的微球低得多。含葡萄糖的微球在24小时释放结束时显示出更致密的周边和更低的吸水率，表明渗透率降低。然而，当葡萄糖含量进一步增加到1%时，这种作用有时会被抵消，导致表面积和孔隙率增加。总之，我们得出结论，葡萄糖对初始突释的影响由两个因素决定：（1）由于包封和药物释放过程中渗透压增加导致初始突释增加，以及（2）由于微球渗透率降低导致初始突释降低。
