The Development and Optimization of Lipid-Based Self-Nanoemulsifying Drug Delivery Systems for the Intravenous Delivery of Propofol.

PURPOSE: Propofol is a relatively short-acting potent anesthetic lipophilic drug used during short surgical procedures. Despite the success of propofol intravenous emulsions, drawbacks to such formulations include inherent emulsion instability, the lack of a safe vehicle to prevent sepsis, and concern regarding hyperlipidemia-related side effects. The aim of the current investigation was to develop a novel, lipid-based self-nanoemulsifying drug delivery system (SNEDDS) for propofol with improved stability and anesthetic activity for human use. METHODS: A series of SNEDDS formulations were developed using naturally obtained medium-chain/long-chain mono-, di-, and triglycerides, glyceryl monocaprylate, and water-soluble cosolvents with hydrogenated castor oil constructing ternary phase diagrams for propofol. The developed SNEDDS formulations were characterized using visual observation, particle size analysis, zeta potential, transmission electron microscopy, equilibrium solubility, in vitro dynamic dispersion and stability, and in vivo sleeping disorder studies in rats. The in vivo bioavailability of the SNEDDSs in rats was also studied to compare the representative formulations with the marketed product Diprivan®. RESULTS: Medium-chain triglycerides (M810) with mono-diglycerides (CMCM) as an oil blend and hydrogenated castor oil (KHS15) as a surfactant were selected as key ingredients in ternary phase diagram studies. The nanoemulsifying regions were identified from the studies and a number of SNEDDSs were formulated. Results from the characterization studies demonstrated the formation of efficient nanosized particles (28-45 nm globule size, 0.10-0.20 PDI) in the optimized SNEDDS with a drug loading of 50 mg/g, which is almost 500-fold higher than free propofol. TEM analysis showed the formation of spherical and homogeneous nanoparticles of less than 50 nm. The dissolution rate of the representative SNEDDS was faster than raw propofol and able to maintain 99% propofol in aqueous solution for around 24 h. The optimized liquid SNEDDS formulation was found to be thermodynamically stable. The intravenous administration of the SNEDDS in male Wistar rats induced a sleeping time of 73-88 min. The mean plasma concentrations after the IV administration of propofol nano-formulations PF2-SNEDDS and PF8-SNEDDS were 1348.07 ± 27.31 and 1138.66 ± 44.97 µg/mL, as compared to 891.44 ± 26.05 µg/mL (p = 0.05) observed after the IV administration of raw propofol. CONCLUSION: Propofol-loaded SNEDDS formulations could be a potential pharmaceutical product with improved stability, bioavailability, and anesthetic activity.

A fraction of Pueraria tuberosa extract, rich in antioxidant compounds, alleviates ovariectomized-induced osteoporosis in rats and inhibits growth of breast and ovarian cancer cells.

Pueraria tuberosa (Roxb. ex Willd.) DC., known as Indian Kudzu belongs to family Fabaceae and it is solicited as "Rasayana" drugs in Ayurveda. In the present study, we analyzed the efficacy of an ethyl acetate fraction from the tuber extract of Pueraria tuberosa (fraction rich in antioxidant compounds, FRAC) against menopausal osteoporosis, and breast and ovarian cancer cells. The FRAC from Pueraria tuberosa was characterized for its phenolic composition (total phenolic and flavonoid amount). Antioxidant property (in vitro assays) of the FRAC was also carried out followed by the analysis of the FRAC for its antiosteoporotic and anticancer potentials. The antiosteoporotic activity of FRAC was investigated in ovariectomy-induced osteoporosis in rats. The cytotoxicity effect was determined in breast and ovarian cancer cells. Gas chromatography/mass spectrometry (GC/MS) analysis of the FRAC was performed to determine its various phytoconstituents. Docking analysis was performed to verify the interaction of bioactive molecules with estrogen receptors (ERs). The FRAC significantly improved various biomechanical and biochemical parameters in a dose-dependent manner in the ovariectomized rats. FRAC also controlled the increased body weight and decreased uterus weight following ovariectomy in rats. Histopathology of the femur demonstrated the restoration of typical bone structure and trabecular width in ovariectomized animals after treatment with FRAC and raloxifene. The FRAC also exhibited in vitro cytotoxicity in the breast (MCF-7 and MDA-MB-231) and ovarian (SKOV-3) cancer cells. Furthermore, genistein and daidzein exhibited a high affinity towards both estrogen receptors (α and ß) in the docking study revealing the probable mechanism of the antiosteoporotic activity. GC/MS analysis confirmed the presence of other bioactive molecules such as stigmasterol, ß-sitosterol, and stigmasta-3,5-dien-7-one. The FRAC from Pueraria tuberosa has potential for treatment of menopausal osteoporosis. Also, the FRAC possesses anticancer activity.

Development and optimization of sitagliptin and dapagliflozin loaded oral self-nanoemulsifying formulation against type 2 diabetes mellitus.

Control of hyperglycemia and prevention of glucose reabsorption (glucotoxicity) are important objectives in the management of type 2 diabetes. This study deals with an oral combined dosage form design for two anti-diabetic drugs, sitagliptin and dapagliflozin using self-nanoemulsifying drug delivery systems (SNEDDS). The SNEDDS were developed using naturally obtained bioactive medium-chain/long-chain triglycerides oil, mixed glycerides and nonionic surfactants, and droplet size was measured followed by the test for antioxidant activities. Equilibrium solubility and dynamic dispersion experiments were conducted to achieve the maximum drug loading. The in vitro digestion, in vivo bioavailability, and anti-diabetic effects were studied to compare the representative SNEDDS with marketed product Dapazin®. The representative SNEDDS containing black seed oil showed excellent self-emulsification performance with transparent appearance. Characterization of the SNEDDS showed nanodroplets of around 50-66.57 nm in size (confirmed by TEM analysis), in addition to the high drug loading capacity without causing any precipitation in the gastro-intestinal tract. The SNEDDS provided higher antioxidant activity compared to the pure drugs. The in vivo pharmacokinetic parameters of SNEDDS showed significant increase in C max (1.99 ± 0.21 µg mL-1), AUC (17.94 ± 1.25 µg mL-1), and oral absorption (2-fold) of dapagliflozin compared to the commercial product in the rat model. The anti-diabetic studies showed the significant inhibition of glucose level in treated diabetic mice by SNEDDS combined dose compared to the single drug therapy. The combined dose of sitagliptin-dapagliflozin using SNEDDS could be a potential oral pharmaceutical product for the improved treatment of type 2 diabetes mellitus.