TEAM Academy of Pharmaceutical Sciences Co. Ltd., Beijing 102488, China.
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Curr Drug Deliv. 2021;18(5):620-633. doi: 10.2174/1567201817666200904172626.
The current study aimed to investigate the potential of Solid Self-Emulsifying Drug Delivery Systems (solid SEDDS) loaded with Testosterone Undecanoate (TU) (solid TUSEDDS). The solid TU-SEDDS was composed of TU, Medium-Chain Triglycerides (MCT, oil), 2- Chloro-1-(chloromethyl) ethyl carbamate (EL-35, surfactant) and polyethylene glycol (PEG400, cosurfactant). It was expected to improve the dissolution and oral bioavailability of TU, as a result of investigating the feasibility of the clinical application of SEDDS.
First, a TU-SEDDS was developed by using rational blends of components with the good solubilizing ability for TU. Next, a ternary phase diagram was constructed to determine the self-emulsifying region, and the formulation was optimized. Then, the solid TU-SEDDS formulation was established by screening suitable solid adsorptions. Finally, the prepared SEDDS, TUSEDDS and solid TU-SEDDS formulations were evaluated in vitro and in vivo.
The size of the solid TU-SEDDS was 189.1 ± 0.23 nm. The Transmission Electron Microscopy (TEM) results showed that the oil droplets were homogenous and spherical with good integrity. The Differential Scanning Calorimetry (DSC) and X-Ray Powder Dffraction (XRD) results indicated that the solid TU-SEDDS formulation almost preserves the amorphous state. Scanning Electron Microscopy (SEM) indicated that neusilin US2 successfully adsorbed the TU-SEDDS. Drug release indicated that the dissolution of the solid TU-SEDDS was faster than that of Andriol Testocaps ®. Furthermore, in vivo pharmacokinetic (PK) studies in Sprague-Dawley (SD) rats showed that the Area Under the Curve (AUC) of the solid TU-SEDDS (487.54±208.80 μg/L×h) was higher than that of Andriol Testocaps® (418.93±273.52 μg/L×h, P < 0.05). In beagles not fed a high-fat diet, the AUC of the solid TU-SEDDS (5.81±4.03 μg/L×h) was higher than that of Andriol Testocaps ® (5.53±3.43 μg/L×h, P > 0.05). In beagles fed a high-fat diet, the AUC of the solid TUSEDDS (38.18±21.90 μg/L×h) was higher than that of Andriol Testocaps® (37.17±13.79 μg/L×h, P > 0.05).
According to the results of this research, oral solid TU-SEDDS is expected to be another alternative delivery system for the late-onset hypogonadism. This is beneficial to the transformation of existing drug delivery systems into preclinical and clinical studies.
本研究旨在探讨负载十一酸睾酮（TU）的固体自乳化药物传递系统（固体 TU-SEDDS）的潜力。固体 TU-SEDDS 由 TU、中链甘油三酯（MCT，油）、2-氯-1-（氯甲基）乙基氨基甲酸酯（EL-35，表面活性剂）和聚乙二醇 400（PEG400，助表面活性剂）组成。预计通过研究 SEDDS 临床应用的可行性，能够改善 TU 的溶解和口服生物利用度。
首先，通过合理混合具有良好 TU 增溶能力的成分来开发 TU-SEDDS。接下来，构建三元相图以确定自乳化区域，并进行配方优化。然后，通过筛选合适的固体吸附剂来建立固体 TU-SEDDS 配方。最后，对制备的 SEDDS、TUSEDDS 和固体 TU-SEDDS 制剂进行了体外和体内评价。
固体 TU-SEDDS 的粒径为 189.1±0.23nm。透射电子显微镜（TEM）结果表明，油滴均匀且完整，呈球形。差示扫描量热法（DSC）和 X 射线粉末衍射（XRD）结果表明，固体 TU-SEDDS 制剂几乎保持无定形态。扫描电子显微镜（SEM）表明 Neusilin US2 成功吸附了 TU-SEDDS。药物释放表明固体 TU-SEDDS 的溶解速度快于 Andriol Testocaps®。此外，在 Sprague-Dawley（SD）大鼠中的体内药代动力学（PK）研究表明，固体 TU-SEDDS 的 AUC（487.54±208.80μg/L×h）高于 Andriol Testocaps®（418.93±273.52μg/L×h，P<0.05）。在未喂食高脂肪饮食的比格犬中，固体 TU-SEDDS 的 AUC（5.81±4.03μg/L×h）高于 Andriol Testocaps®（5.53±3.43μg/L×h，P>0.05）。在喂食高脂肪饮食的比格犬中，固体 TUSEDDS 的 AUC（38.18±21.90μg/L×h）高于 Andriol Testocaps®（37.17±13.79μg/L×h，P>0.05）。
根据本研究结果，口服固体 TU-SEDDS 有望成为治疗迟发性性腺功能减退症的另一种新型给药系统。这有利于将现有药物传递系统转化为临床前和临床研究。
