Mechanistic evaluation of the glucose-induced reduction in initial burst release of octreotide acetate from poly(D,L-lactide-co-glycolide) microspheres.
Mechanistic evaluation of the glucose-induced reduction in initial burst release of octreotide acetate from poly(D,L-lactide-co-glycolide) microspheres.
复制标题
葡萄糖诱导的聚（D,L-丙交酯-乙交酯）微球中醋酸奥曲肽初始爆发释放减少的机制评估。
DOI：
10.1016/j.biomaterials.2003.08.019
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发表时间：
2004
期刊：
影响因子：
14
通讯作者：
Schwendeman,StevenP
中科院分区：
文献类型：
--
作者：
Wang,Juan;Wang,BarbaraM;Schwendeman,StevenP
开发用于受控肽和蛋白质递送的可注射生物可降解微球的一个主要障碍是在孵育的第一天发生的药物释放的高初始爆发。我们在此描述了通过共包封少量葡萄糖（例如，0.2%w/w），即，从30±20%破裂-葡萄糖到8±3% +葡萄糖（平均值±SD，n=4）。这种降低是出乎意料的，因为已知亲水性添加剂增加微球的孔隙率，导致对质量传输的渗透性增加和更高的爆裂。使用双乳液-溶剂蒸发法的封装，葡萄糖在pH 4的乙酸盐缓冲液中的初始突释的效果被发现取决于聚合物浓度，不连续相/连续相的比例，和葡萄糖含量。对两个微球批次（±0.2%葡萄糖）进行了广泛的表征研究，以阐明该效应的机制。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没有观察到显著差异。连续监测这两个批次的醋酸奥曲肽的前24小时释放，发现尽管它们的起始释放速率接近，但与葡萄糖相比，微球+葡萄糖在0.2 - 24小时之间的释放速率要低得多。微球+葡萄糖在24小时释放结束时显示出更致密的外围和减少的水吸收，表明渗透性降低。然而，当葡萄糖含量进一步增加至1%时，这种效果有时会被抵消，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期间渗透压增加而增加的初始突释，以及（2）由于微球渗透性降低而降低的初始突释。
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.