Abstract
Purpose: The present work endeavors to report a systematic approach of developing the lipidic self-nanoemulsifying formulation of olmesartan medoxomil (OMT) on the principles of Quality by Design (QbD). Methods: For preparing the self-nanoemulsifying formulation, a mixture of oil, surfactant and cosurfactant were used as vehicles. The excipients were selected after screening by solubility as well as pseudoternary phase titration studies. Mixture design was adopted for systematic optimization of the composition of nanolipidic formulations, which were evaluated for smaller globule size, stable zeta potential and lower values of polydispersity index. The optimized liquid self-nanoemulsifying formulation was identified using numerical and graphical optimization techniques, followed by validation of the experimental model. Solidification of self-nanoemulsifying formulation was carried out using porous carriers, and then optimized on the basis of oil adsorption potential, powder flow property and drug release performance. Pharmacokinetic study was performed in male Wistar rats for evaluating the drug absorption parameters. All the experimental data obtained were subjected to statistical analysis using oneway ANOVA followed by post hoc analysis using Student’s t test. Results: The optimized liquid self-nanoemulsifying formulation showed globule size <100 nm, emulsification efficiency <5 minutes andin vitro drug release >85% within in 30 minutes. Further, the solid SNEDDS formulation was effectively formulated using Neusilin US2 with maximum oil adsorption capacity and good micromeritic properties. Pharmacokinetic evaluation indicated 4 to 5-folds increase (P <0.05) in the values of Cmax, AUC, and reduction in Tmax from the nanoformulations vis-à-vis the marketed formulation. Conclusion: Overall, the developed nanolipidic formulation of olmesartan indicated superior efficacy in augmenting the drug dissolution and absorption performance.
Highlights
Quality by Design (QbD), a concept proposed by American quality expert, J.M
Mixture design was adopted for systematic optimization of the composition of nanolipidic formulations, which were evaluated for smaller globule size, stable zeta potential and lower values of polydispersity index
Target product profile (TPP) was defined for target liquid SNEDDS formulation of olmesartan medoxomil (OMT), in order to augment the oral bioavailability of the drug
Summary
Quality by Design (QbD), a concept proposed by American quality expert, J.M. Juran for systematic planning and execution of manufacturing operations for avoiding quality crisis.[1,2] Later, United States Food and Drug Administration (USFDA) adopted the Juran’s concept of QbD into pharmaceutical drug product development. The product development as per QbD paradigm provides enhanced product and process understanding, and robust performance.[3,4,5]. Olmesartan medoxomil (OMT), a potential antihypertensive agent, inhibits the synthesis of angiotensin II by blocking the angiotensin type I receptor. Despite its efficacy, it shows poor aqueous solubility and high lipophilicity, as the major rate-limiting factors for low and inconsistent oral bioavailability.[6,7] Several literature reports have demonstrated the application different solubility enhancement technologies for improving biopharmaceutical performance of the drug.[8,9,10,11,12] beyond solubility, many other rate-limiting factors tend to affect the oral bioavailability of OMT.
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