Darunavir has a low oral bioavailability (37%) due to its lipophilic nature, metabolism by cytochrome P450 enzymes and P-gp efflux. Lipid nanoparticles were prepared in order to overcome its low bioavailability and to increase the binding efficacy of delivery system to the lymphoid system. Darunavir-loaded lipid nanoparticles were prepared using high-pressure homogenization technique. Hydrogenated castor oil was used as lipid. Peptide, having affinity for CD4 receptors, was grafted onto the surface of nanoparticles. The nanoparticles were evaluated for various parameters. The nanoparticles showed size of less than 200 nm, zeta potential of - 35.45 mV, and a high drug entrapment efficiency (90%). 73.12% peptide was found conjugated to nanoparticles as studied using standard BSA calibration plot. Permeability of nanoparticles in Caco-2 cells was increased by 4-fold in comparison to plain drug suspension. Confocal microscopic study revealed that the nanoparticles showed higher uptake in HIV host cells (Molt-4 cells were taken as model containing CD4 receptors) as compared to non-CD4 receptor bearing Caco-2 cells. In vivo pharmacokinetic in rats showed 569% relative increase in bioavailability of darunavir as compared to plain drug suspension. The biodistribution study revealed that peptide-grafted nanoparticles showed higher uptake in various organs (also in HIV reservoir organs namely the spleen and brain) except the liver compared to non-peptide-grafted nanoparticles. The prepared nanoparticles resulted in increased binding with the HIV host cells and thus could be promising carrier in active targeting of the drugs to the HIV reservoir.

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T his study deals with development and optimization of nanostructured lipid carriers (NLCs) of candesartan cilexetil (CC) for improving its oral bioavailability. From solubility and lipid-water partition studies of CC in various lipids, glyceryl monostearate (GMS) and glyceryl monocaprylate were selected as solid lipid and liquid lipid, respectively. NLCs were formulated by hot melt-emulsification-ultrasonication method. A three-factor, three-level Box-Behnken design was used to optimize the independent variables, lipid: drug ratio (X1), solid lipid: liquid lipid ratio (X2) and surfactant concentration (X3). Different batches were prepared and evaluated for responses, particle size (Y1), zeta potential (Y2) and % entrapment efficiency (Y3). Response surface plots and perturbation plots were constructed to study the effect of factors on responses. The optimized formulation containing X1 -22.47:1, X2 -7.23:1 and X3 -1.97% was prepared and evaluated. Observed values for Y1, Y2, and Y3 were found to be closer to the predicted values thus validating the optimization method. Differential scanning calorimetry thermograms of pure drug, GMS and lyophilized drug loaded NLCs indicated complete miscibility of drug into lipids. The release of CC from the NLCs conducted in artificial gastric fluid (pH 1.2) was much higher than in phosphate buffer solution (pH 6.8). The formulated NLCs were found to be more stable at refrigerated condition (5°C ± 3°C) as compared with room temperature (25°C ± 2°C/60% RH% ± 5% RH). The use of design approach helped to identify critical formulation parameters in CC loaded NLCs preparation.

Abstract. Cisplatin, first (platinum) compound to be evolved as an anticancer agent, has found its important place in cancer chemotherapy. However, the dose-dependent toxicities of cisplatin, namely nephrotoxicity, ototoxicity, peripheral neuropathy, and gastrointestinal toxicity hinder its widespread use. Liposomes can reduce the toxicity of cisplatin and provide a better therapeutic action, but the low lipid solubility of cisplatin hinders its high entrapment in such lipid carrier. In the present investigation, positively charged reactive aquated species of cisplatin were complexed with negatively charged caprylate ligands, resulting in enhanced interaction of cisplatin with lipid bilayer of liposomes and increase in its encapsulation in liposomal carrier. Prepared cisplatin liposomes were found to have a vesicular size of 107.9±6.2 nm and zeta potential of −3.99±3.45 mV. The optimized liposomal formulation had an encapsulation efficiency of 96.03±1.24% with unprecedented drug loading (0.21 mg cisplatin/mg of lipids). The in vitro release studies exhibited a pH-dependent release of cisplatin from liposomes with highest release (67.55 ± 3.65%) at pH 5.5 indicating that a maximum release would occur inside cancer cells at endolysosomal pH. The prepared liposomes were found to be stable in the serum and showed a low hemolytic potential. In vitro cytotoxicity of cisplatin liposomes on A549 lung cancer cell line was comparable to that of cisplatin solution. The developed formulation also had a significantly higher median lethal dose (LD 50 ) of 23.79 mg/kg than that of the cisplatin solution (12 mg/kg). A promising liposomal formulation of cisplatin has been proposed that can overcome the disadvantages associated with conventional cisplatin therapy and provide a higher safety profile.