Dong Bingxue, Hadinoto Kunn
a School of Chemical and Biomedical Engineering, Nanyang Technological University , Singapore.
Drug Dev Ind Pharm. 2017 Jun;43(6):996-1002. doi: 10.1080/03639045.2017.1287721. Epub 2017 Feb 13.
The objective of this study is to develop a new solubility enhancement strategy of antipsychotic drug - perphenazine (PPZ) - in the form of its amorphous nanoparticle complex (or nanoplex) with polyelectrolyte dextran sulfate (DXT).
Poor bioavailability of PPZ necessitated the development of fast-dissolving PPZ formulations regardless of delivery routes. Existing fast-dissolving formulations, however, exhibited low PPZ payload. The high-payload PPZ-DXT nanoplex represents an attractive fast-dissolving formulation, as dissolution rate is known to be proportional to payload.
The nanoplex was prepared by electrostatically driven complexation between PPZ and DXT in a simple process that involved only ambient mixing of PPZ and DXT solutions. We investigated the effects of key variables in drug-polyelectrolyte complexation (i.e. pH and charge ratio R) on the physical characteristics and preparation efficiency of the nanoplex produced. Subsequently, we characterized the colloidal and amorphous state stabilities, dissolution enhancement, and supersaturation generation of the nanoplex prepared at the optimal condition.
The physical characteristics of nanoplex were governed by R, while the preparation efficiency was governed by the preparation pH. Nanoplex having size of ≈80 nm, zeta potential of ≈(-) 60 mV, and payload of ≈70% (w/w) were prepared at nearly 90% PPZ utilization rate and ≈60% yield. The nanoplex exhibited superior dissolution than native PPZ in simulated intestinal juice, resulting in high and prolonged apparent solubility with good storage stabilities.
The simple yet efficient preparation, excellent physical characteristics, fast dissolution, and high apparent solubility exhibited by the PPZ-DXT nanoplex established its potential as a new bioavailability enhancement strategy of PPZ.
本研究的目的是开发一种新的抗精神病药物奋乃静（PPZ）的溶解度增强策略，以其与聚电解质硫酸葡聚糖（DXT）形成的无定形纳米颗粒复合物（或纳米复合物）的形式。
PPZ的生物利用度差，因此无论给药途径如何，都需要开发快速溶解的PPZ制剂。然而，现有的快速溶解制剂显示出较低的PPZ载药量。高载药量的PPZ-DXT纳米复合物代表了一种有吸引力的快速溶解制剂，因为已知溶解速率与载药量成正比。
通过PPZ和DXT之间的静电驱动络合反应制备纳米复合物，该过程简单，仅涉及PPZ和DXT溶液的常温混合。我们研究了药物-聚电解质络合反应中的关键变量（即pH值和电荷比R）对所制备纳米复合物的物理特性和制备效率的影响。随后，我们对在最佳条件下制备的纳米复合物的胶体和无定形状态稳定性、溶解增强和过饱和生成进行了表征。
纳米复合物的物理特性受R的控制，而制备效率受制备pH值的控制。制备出了尺寸约为80nm、ζ电位约为（-）60mV、载药量约为70%（w/w）的纳米复合物，PPZ利用率接近90%，产率约为60%。该纳米复合物在模拟肠液中的溶解性能优于天然PPZ，具有高且持久的表观溶解度以及良好的储存稳定性。
PPZ-DXT纳米复合物表现出的简单而高效的制备方法、优异的物理特性、快速溶解和高表观溶解度，确立了其作为PPZ生物利用度增强新策略的潜力。
