Formulation and In Vivo Evaluation of Ticagrelor Self-nanoemulsifying Drug Delivery Systems.

BACKGROUND: Ticagrelor (TGR), being an antiplatelet agent, belongs to BCS class IV drug with low solubility and permeability that undergoes first-pass metabolism, leading to reduced bioavailability of 36%. OBJECTIVE: The main objective of this study is to develop TGR SNEDDS for enhancing solubility and oral bioavailability. METHODS: An oil, surfactant and co-surfactant (miglyol 810, brij 35 and lauro glycol FCC) are chosen based on the maximum solubility of TGR. The selected vehicles are mixed in different ratios and are agitated mildly. Transmittance values that are more than 80 were noted and are used for constructing pseudo ternary phase diagram. Formulations that passed stability testing were evaluated for % transmission, drug content and in vitro drug release analysis. In vivo bioavailability studies of optimized SNEDDS are performed in Wistar rats. RESULTS: From evaluation studies of TGR, formulation F13 with maximum drug release of 98.99% in 60 minutes, that is higher than 31.99% of the pure drug is considered as an optimised formulation. The particle size, Z average and zeta potential of the optimized TGR formulation F13 was 289.6 nm, 185.1 nm and -18.3 mV respectively. The FTIR and SEM studies do not indicate any drug excipient interaction and confirm nano size which is stable for 3 months. From in vivo bioavailability studies in rats, the Cmax of optimized TGR SNEDDS (302.43±4.78 ng/ml) is higher than pure TGR suspension (47.32±2.75 ng/ml) and optimized SNEDDS exhibited 5 folds increase in oral bioavailability when compared to pure drug. CONCLUSION: Hence the results reveal that, application of SNEDDS formulation technique for TGR Increases solubility and oral bioavailability.

P-Glycoprotein- and cytochrome P-450-mediated herbal drug interactions.

P-Glycoprotein (P-gp), the most extensively studied ATP-binding cassette transporter, functions as a biological barrier by extruding toxic substances and xenobiotics out of cells. Drug efflux pumps such as P-gp play a functional role in determining the pharmacokinetics of drugs administered by oral and parenteral routes. Determining the activity of drug efflux transport proteins has important implications in the identification of substrates and/or inhibitors. The significant role of the small intestine in reducing the oral bioavailability of drugs is due to metabolic enzymes and efflux transporters. The role of cytochrome P-450 3A (CYP3A) and P-gp in intestinal drug disposition has been highlighted. This review examines the structure, localisation and functional role of P-gp, the mechanism of drug efflux and drug-herb interactions.

Effect of ketoconazole on the pharmacokinetics of ornidazole--a possible role of p-glycoprotein and CYP3A.

The influence of ketoconazole, a modulator of P-glycoprotein (P-gp), on the exsorption of ornidazole from everted sacs of rat intestine (duodenum, jejunum and ileum) was investigated. The effect of ketoconazole pretreatment on the pharmacokinetics of ornidazole was also studied in eight healthy human volunteers. After overnight fasting ornidazole 500 mg was administered before and after pretreatment with ketoconazole 200 mg once daily for 7 days. Serum samples were analyzed by reversed phase HPLC. Significant differences were observed in pharmacokinetic parameters C(max), AUC(0-t), AUC(0-infinity), T(max) and clearance. Ornidazole is believed to be metabolized through CYP3A and it has considerable intestinal efflux, which was observed from the in vitro study. The altered pharmacokinetic parameters can be attributed to ornidazole efflux from the blood to the intestine and its metabolism by CYP3A in the intestine.