Ansari Huda, Singh Prabha
Department of Pharmaceutics, Mumbai University, Mumbai, India.
Curr HIV Res. 2018;16(4):270-279. doi: 10.2174/1570162X16666180924101650.
Lopinavir is a specific reversible inhibitor of the enzyme HIV protease with mean oral bioavailability of less than 20 % due to extensive hepatic metabolism by cytochrome P450 3A4. The reported half-life of Lopinavir is 5-6 hours and the maximum recommended daily dose is 400 mg/day. All the marketed tablet and capsule formulations of lopinavir are generally combined with Ritonavir, a potent inhibitor of cytochrome P450 3A4, to minimize presystemic metabolism of lopinavir. Hence, to overcome limitations associated with oral administration of lopinavir and to promote single drug administration, utilization of vesicular nanocarriers through topical route could prove to be effective, as the approach combines the inherent advantages of topical route and the drug-carrying potential of vesicular nanocarriers across the tough and otherwise impervious skin barrier layer, i.e., stratum corneum.
The objective was to develop solid lipid nanoparticles (SLN) of lopinavir and formulate a topical gel for improved systemic bioavailability of lopinavir.
SLNs were prepared using high-pressure homogenization technique and optimized. The nanoparticles were characterized by SEM to confirm their spherical shape. Differential Scanning Calorimetry (DSC) analysis was carried out to ensure the entrapment of drug inside the SLNs. A comparative evaluation was done between SLN based gel and plain gel of drug by performing exvivo skin permeation studies using Franz diffusion cell. To explore the potential of topical route, invivo bioavailability study was conducted in male Wistar rats.
The optimized formulation composed of Compritol 888ATO (0.5 %) as a lipid, Poloxamer 407 (0.25 %) as a surfactant and Labrasol (0.25 %) as a co-surfactant gave the maximum entrapment of 69.78 % with mean particle size of 48.86nm. The plain gel of the drug gave a release of 98.406 ± 0.007 % at the end of 4hours whereas SLN based gel gave a more sustained release of 71.197 ±0.006 % at the end of 12hours ex-vivo. As observed from the results of in-vivo studies, highest Cmax was found with SLN based gel (20.3127 ± 0.6056) µg/ml as compared to plain gel (8.0655 ± 1.6369) µg/ml and oral suspension (4.2550 ± 16.380) µg/ml of the drug. Also, the AUC was higher in the case of SLN based gel indicating good bioavailability as compared to oral suspension and plain gel of drug.
Lopinavir SLN based gel was found to have modified drug release pattern providing sustained release as compared to plain drug gel. This indicates that Lopinavir when given topically has a good potential to target the HIV as compared to when given orally.
洛匹那韦是一种特异性的HIV蛋白酶可逆抑制剂，由于细胞色素P450 3A4介导的广泛肝脏代谢，其平均口服生物利用度低于20%。据报道，洛匹那韦的半衰期为5 - 6小时，最大推荐日剂量为400mg/天。所有市售的洛匹那韦片剂和胶囊制剂通常都与细胞色素P450 3A4的强效抑制剂利托那韦联合使用，以尽量减少洛匹那韦的首过代谢。因此，为了克服洛匹那韦口服给药的局限性并促进单药给药，通过局部途径利用囊泡纳米载体可能被证明是有效的，因为这种方法结合了局部途径的固有优势以及囊泡纳米载体跨越坚韧且原本不可渗透的皮肤屏障层（即角质层）携带药物的潜力。
目的是制备洛匹那韦的固体脂质纳米粒（SLN）并配制一种局部用凝胶，以提高洛匹那韦的全身生物利用度。
采用高压均质技术制备并优化SLN。通过扫描电子显微镜（SEM）对纳米粒进行表征以确认其球形形状。进行差示扫描量热法（DSC）分析以确保药物包封在SLN内部。使用Franz扩散池进行离体皮肤渗透研究，对基于SLN的凝胶和药物普通凝胶进行比较评估。为了探索局部途径的潜力，在雄性Wistar大鼠中进行体内生物利用度研究。
优化后的制剂由0.5%的Compritol 888ATO作为脂质、0.25%的泊洛沙姆407作为表面活性剂和0.25%的Labrasol作为助表面活性剂组成，最大包封率为69.78%，平均粒径为48.86nm。药物普通凝胶在4小时结束时释放率为98.406±0.007%，而基于SLN的凝胶在离体12小时结束时释放更持久，为71.197±0.006%。从体内研究结果可以看出，与药物普通凝胶（8.0655±1.6369）μg/ml和口服混悬液（4.2550±16.380）μg/ml相比，基于SLN的凝胶的最高血药浓度（Cmax）为（20.3127±0.6056）μg/ml。此外，与药物口服混悬液和普通凝胶相比，基于SLN的凝胶的曲线下面积（AUC）更高，表明生物利用度良好。
与普通药物凝胶相比，发现基于洛匹那韦SLN的凝胶具有改变的药物释放模式，提供持续释放。这表明与口服给药相比，洛匹那韦局部给药时靶向HIV具有良好的潜力。
