Krull Scott M, Ma Zhelun, Li Meng, Davé Rajesh N, Bilgili Ecevit
a Otto H. York Department of Chemical, Biological, and Pharmaceutical Engineering , New Jersey Institute of Technology , Newark , NJ , USA.
Drug Dev Ind Pharm. 2016;42(7):1073-85. doi: 10.3109/03639045.2015.1107094. Epub 2015 Nov 15.
The aim of this study is to assess pullulan as a novel steric stabilizer during the wet-stirred media milling (WSMM) of griseofulvin, a model poorly water-soluble drug, and as a film-former in the preparation of strip films via casting-drying the wet-milled drug suspensions for dissolution and bioavailability enhancement. To this end, pullulan films, with xanthan gum (XG) as thickening agent and glycerin as plasticizer, were loaded with griseofulvin nanoparticles prepared by WSMM using pullulan in combination with sodium dodecyl sulfate (SDS) as an ionic stabilizer. The effects of drug loading and milling time on the particle size and suspension stability were investigated, as well as XG concentration and casting thickness on film properties and dissolution rate. The nanosuspensions prepared with pullulan-SDS combination were relatively stable over 7 days; hence, this combination was used for the film preparation. All pullulan-based strip films exhibited excellent content uniformity (most <3% RSD) despite containing only 0.3-1.3 mg drug, which was ensured by the use of precursor suspensions with >5000 cP viscosity. USP IV dissolution tests revealed fast/immediate drug release (t80 < 30 min) from films <120 μm thick. Thinner films, films with lower XG loading, or smaller drug particles led to faster drug dissolution, while drug loading had no discernible effect. Overall, these results suggest that pullulan may serve as an acceptable stabilizer for media milling in combination with surfactant as well as a fast-dissolving film former for the fast release of poorly water-soluble drug nanoparticles.
本研究的目的是评估支链淀粉作为一种新型空间稳定剂在灰黄霉素（一种典型的难溶性药物）的湿搅拌介质研磨（WSMM）过程中的作用，并评估其作为成膜剂在通过流延干燥湿磨药物悬浮液制备条带薄膜以提高溶出度和生物利用度方面的作用。为此，以黄原胶（XG）作为增稠剂、甘油作为增塑剂的支链淀粉薄膜，负载了通过WSMM制备的灰黄霉素纳米颗粒，其中使用支链淀粉与十二烷基硫酸钠（SDS）作为离子稳定剂。研究了药物负载量和研磨时间对粒径和悬浮液稳定性的影响，以及XG浓度和流延厚度对薄膜性能和溶出速率的影响。用支链淀粉-SDS组合制备的纳米悬浮液在7天内相对稳定；因此，该组合用于薄膜制备。尽管所有基于支链淀粉的条带薄膜仅含有0.3-1.3 mg药物，但均表现出优异的含量均匀性（大多数<3% RSD），这是通过使用粘度>5000 cP的前体悬浮液来确保的。美国药典IV溶出度试验显示，厚度<120μm的薄膜能实现快速/即时药物释放（t80<30分钟）。较薄的薄膜、较低XG负载量的薄膜或较小的药物颗粒导致更快的药物溶出，而药物负载量没有明显影响。总体而言，这些结果表明，支链淀粉可作为与表面活性剂组合用于介质研磨的可接受稳定剂，以及用于快速释放难溶性药物纳米颗粒的快速溶解成膜剂。
