Preparation and pharmacodynamic assessment of ezetimibe nanocrystals: Effect of P-gp inhibitory stabilizer on particle size and oral absorption

• Drug nanocrystals of ezetimibe were prepared by amalgamation using AA2G and TPGS.
• AA2G has been successfully investigated as a nanocrystal stabilizer.
• Solubility of poorly soluble ezetimibe was improved by nanonization.
• Solubility, dissolution and pharmacodynamics of TPGS nanocrystals were superior.
• The work proposes low cost and rational formulations of ezetimibe.

Drug nanocrystals have been widely accepted as potent formulations to overcome poor solubility, dissolution and bioavailability problems of hydrophobic drugs. The present study aimed to develop drug nanocrystals of ezetimibe (Eze), a model BCS class II and hypocholesterolemic drug using bottom up precipitation methods. d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS), and l-ascorbic acid-2-glucoside (AA2G), were the two stabilizers whose potential in developing Eze nanocrystals was investigated. Particle size and zeta potential portrayed the potential of both the stabilizers in producing Eze nanocrystals. The optimized nanocrystal formulations were evaluated for in-vitro solubility, dissolution, solid state characters and in-vivo pharmacodynamic performance. The nanocrystal formulations remarkably increased the solubility of the drug (p < 0.05 compared to pure drug). Pure drug could not dissolve more than 28.9% during the 60 min dissolution study whereas the drug nanocrystals prepared with AA2G and TPGS presented t90% at 41.33 ± 2.58 and 16.07 ± 2.32 min, respectively. The PXRD and DSC studies confirmed the retention of crystallinity and the SEM images indicated lack of aggregation in dried nanocrystals. The TPGS nanocrystals presented significantly superior pharmacodynamic activity upon oral administration. The current study corroborated TPGS nanocrystals to be a promising choice of formulation for the oral delivery of Eze.

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