Department of Chemistry, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455-0431, United States.
Biomacromolecules. 2014 Feb 10;15(2):500-11. doi: 10.1021/bm401431t. Epub 2014 Jan 3.
Spray dried dispersions (SDDs), solid dispersions of polymer excipients and active pharmaceuticals, are important to the field of oral drug delivery for improving active stability, bioavailability, and efficacy. Herein, we examine the influence of solution-state polymer assemblies on amorphous spray-dried dispersion (SDD) performance with two BCS II model drugs, phenytoin and probucol. These drugs were spray dried with 4 model polymer excipients consisting of poly(ethylene-alt-propylene) (PEP), N,N,-dimethylacrylamide (DMA), or 2-methacrylamido glucopyranose (MAG): amphiphilic diblock ter- and copolymers, PEP-P(DMA-grad-MAG) and PEP-PDMA, and their respective hydrophilic analogues, P(DMA-grad-MAG) and PDMA. Selective and nonselective solvents for the hydrophilic block of the diblock ter- and copolymers were used to induce or repress solution-state assemblies prior to spray drying. Prespray dried solution-state assemblies of these four polymers were probed with dynamic light scattering (DLS) and showed differences in solution assembly size and structure (free polymer versus aggregates versus micelles). Solid-state structures of spray dried dispersions (SDDs) showed a single glass transition event implying a homogeneous mixture of drug/polymer. Crystallization temperatures and enthalpies indicated that the drugs interact mostly with the DMA-containing portions of the polymers. Scanning electron microscopy was used to determine SDD particle size and morphology for the various polymer-drug pairings. In vitro dissolution tests showed excellent performance for one system, spray-dried PEP-PDMA micelles with probucol. Dissolution structures were investigated through DLS to determine drug-polymer aggregates that lead to enhanced SDD performance. Forced aggregation of the polymer into regular micelle structures was found to be a critical factor to increase the dissolution rate and supersaturation maintenance of SDDs, and may be an attractive platform to exploit in excipient design for oral drug delivery.
喷雾干燥分散体（SDD），即聚合物赋形剂和活性药物的固体分散体，对于改善口服药物的活性稳定性、生物利用度和疗效具有重要意义。在此，我们研究了溶液态聚合物组装对两种 BCS II 模型药物（苯妥英和普罗布考）无定形喷雾干燥分散体（SDD）性能的影响。这两种药物分别与 4 种模型聚合物赋形剂喷雾干燥，这 4 种模型聚合物赋形剂包括聚（乙烯-共-丙烯）（PEP）、N，N-二甲基丙烯酰胺（DMA）或 2-甲基丙烯酰胺基-D-吡喃葡萄糖（MAG）：两亲性二嵌段 ter-和共聚物，PEP-P（DMA-grad-MAG）和 PEP-PDMA，以及它们各自的亲水类似物，P（DMA-grad-MAG）和 PDMA。用于二嵌段 ter-和共聚物亲水嵌段的选择性和非选择性溶剂在喷雾干燥前诱导或抑制溶液态组装。对这四种聚合物的预喷雾干燥溶液态组装体进行了动态光散射（DLS）探测，结果表明溶液组装体的尺寸和结构（游离聚合物与聚集物与胶束）存在差异。喷雾干燥分散体（SDD）的固态结构显示出单一的玻璃化转变事件，这意味着药物/聚合物是均匀混合的。结晶温度和焓表明，药物主要与聚合物中含 DMA 的部分相互作用。扫描电子显微镜用于确定各种聚合物-药物配对物的 SDD 粒径和形态。体外溶解试验表明，喷雾干燥 PEP-PDMA 胶束与普罗布考的一个系统具有优异的性能。通过 DLS 研究了溶解结构，以确定导致 SDD 性能提高的药物-聚合物聚集体。发现将聚合物强制聚集为规则的胶束结构是提高 SDD 溶解速率和维持过饱和度的关键因素，这可能是口服药物传递赋形剂设计中极具吸引力的平台。
