Mande Prashant P, Bachhav Sagar S, Devarajan Padma V
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N. P. Marg, Matunga (E), Mumbai, Maharashtra, India.
Asian J Pharm Sci. 2017 Nov;12(6):569-579. doi: 10.1016/j.ajps.2017.07.001. Epub 2017 Aug 3.
Tadalafil (TDL) a BCS-II drug is recently reported for repurposing nephroprotective effect in Pyelonephritis (PN). However, poor water solubility and dissolution rate limited oral bioavailability pose serious challenges in its therapeutic applications. We present an advanced third generation Solid Dispersion (SD) of TDL comprising a polymer in combination with a Self Micro-emulsifying Composition (SMEC) to achieve high drug loading, improved stability and rapid dissolution of TDL for enhancing bioavailability and efficacy in PN. TDL-SMEC-SD was coated onto rapidly disintegrating inert tablet cores which disintegrated rapidly in water to release SD as a film. TDL-SMEC-SD was evaluated for oral bioavailability and efficacy in lipopolysaccharide-induced PN in rats. TDL exhibited high solubility (45.6 mg/ml) in the SMEC. TDL-SMEC-SD exhibited remarkably high TDL loading (45%w/w), exceptionally low contact angle (9°), rapid in-vitro release (t 7.3 min), microemulsion formation (globule size ~100 nm) in aqueous dispersion, and stability as per ICH guidelines. SEM, DSC, and XRD confirmed high physical stability. A relative bioavailability of 350% and 150% compared to TDL and TDL-SD without SMEC respectively, established the superiority of TDL-SMEC-SD. A significant reduction in serum creatinine, blood urea nitrogen and nitric oxide levels in the lipopolysaccharide-induced PN confirmed the benefit of the TDL-SMEC-SD. The advanced third generation SMEC SDs presents the possibility of platform technology for bioenhancement of poorly water soluble drugs.
他达拉非（TDL）是一种BCS-II类药物，最近有报道称其可用于肾盂肾炎（PN）的肾保护作用。然而，其水溶性差和溶出速率低限制了口服生物利用度，这在其治疗应用中带来了严峻挑战。我们展示了一种先进的第三代他达拉非固体分散体（SD），它由一种聚合物与自微乳化组合物（SMEC）组合而成，以实现高载药量、提高稳定性以及他达拉非的快速溶解，从而增强其在PN中的生物利用度和疗效。TDL-SMEC-SD被包衣在快速崩解的惰性片剂芯上，该片剂芯在水中迅速崩解，以薄膜形式释放固体分散体。对TDL-SMEC-SD在大鼠脂多糖诱导的PN中的口服生物利用度和疗效进行了评估。他达拉非在SMEC中表现出高溶解度（45.6毫克/毫升）。TDL-SMEC-SD表现出非常高的他达拉非载药量（45%w/w）、极低的接触角（9°）、快速的体外释放（t 7.3分钟）、在水性分散体中形成微乳液（液滴尺寸约100纳米）以及符合ICH指南的稳定性。扫描电子显微镜（SEM）、差示扫描量热法（DSC）和X射线衍射（XRD）证实了其高物理稳定性。与他达拉非和不含SMEC的TDL-SD相比，相对生物利用度分别为350%和150%，确立了TDL-SMEC-SD的优势。脂多糖诱导的PN中血清肌酐、血尿素氮和一氧化氮水平的显著降低证实了TDL-SMEC-SD的益处。先进的第三代SMEC SDs为生物增强难溶性药物提供了平台技术的可能性。
