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Development of surface stabilized candesartan cilexetil nanocrystals with enhanced dissolution rate, permeation rate across CaCo-2, and oral bioavailability.
Drug Deliv Transl Res. 2016 10; 6(5):498-510.DD

Abstract

Candesartan cilexetil (CC), an ester prodrug of candesartan, is BCS class II drug with extremely low aqueous solubility limiting its oral bioavailability. The present research aimed to develop a nanocrystalline formulation of CC with improved saturation solubility in gastrointestinal fluids and thereby, exhibiting enhanced oral bioavailability. CC nanocrystals were prepared using a low energy antisolvent precipitation methodology. A combination of hydroxypropyl methylcellulose (HPMC) and Pluronic® F 127 (50:50 w/w) was found to be optimum for the preparation of CC nanocrystals. The particle size, polydispersity index (PDI), and zeta potential of optimized formulation was found to be 159 ± 8.1 nm, 0.177 ± 0.043, and -23.7 ± 1.02 mV, respectively. Optimized formulation was found to possess irregular, plate-like morphology as evaluated by scanning electron microscopy and crystalline as evaluated by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). A significant increase in saturation solubility and dissolution rate of the optimized nanosuspension was observed at all the tested pH conditions. Optimized CC nanocrystals exhibited a storage stability of more than 3 months when stored under cold and room temperature conditions. In vitro Caco-2 permeability further revealed that CC nanocrystals exhibited nearly 4-fold increase in permeation rate compared to the free CC. In vivo oral bioavailability studies of optimized CC nanocrystals in murine model revealed 3.8-fold increase in the oral bioavailability and twice the C max as compared with the free CC when administered orally. In conclusion, this study has established a crystalline nanosuspension formulation of CC with improved oral bioavailability in murine model. Graphical Abstract Antisolvent precipitation methodology for the preparation of Candesartan Cilexetil nanocrystals for enhanced solubility and oral bioavailability.

Authors+Show Affiliations

Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar (Mohali), Punjab, 160062, India. sanyogjain@niper.ac.in.Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar (Mohali), Punjab, 160062, India.Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar (Mohali), Punjab, 160062, India.Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar (Mohali), Punjab, 160062, India.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27129488

Citation

Jain, Sanyog, et al. "Development of Surface Stabilized Candesartan Cilexetil Nanocrystals With Enhanced Dissolution Rate, Permeation Rate Across CaCo-2, and Oral Bioavailability." Drug Delivery and Translational Research, vol. 6, no. 5, 2016, pp. 498-510.
Jain S, Reddy VA, Arora S, et al. Development of surface stabilized candesartan cilexetil nanocrystals with enhanced dissolution rate, permeation rate across CaCo-2, and oral bioavailability. Drug Deliv Transl Res. 2016;6(5):498-510.
Jain, S., Reddy, V. A., Arora, S., & Patel, K. (2016). Development of surface stabilized candesartan cilexetil nanocrystals with enhanced dissolution rate, permeation rate across CaCo-2, and oral bioavailability. Drug Delivery and Translational Research, 6(5), 498-510. https://doi.org/10.1007/s13346-016-0297-8
Jain S, et al. Development of Surface Stabilized Candesartan Cilexetil Nanocrystals With Enhanced Dissolution Rate, Permeation Rate Across CaCo-2, and Oral Bioavailability. Drug Deliv Transl Res. 2016;6(5):498-510. PubMed PMID: 27129488.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development of surface stabilized candesartan cilexetil nanocrystals with enhanced dissolution rate, permeation rate across CaCo-2, and oral bioavailability. AU - Jain,Sanyog, AU - Reddy,Venkata Appa, AU - Arora,Sumit, AU - Patel,Kamlesh, PY - 2016/5/1/entrez PY - 2016/5/1/pubmed PY - 2018/1/2/medline KW - Antisolvent precipitation KW - Candesartan cilexetil KW - Nanocrystals KW - Oral bioavailability KW - Saturation solubility SP - 498 EP - 510 JF - Drug delivery and translational research JO - Drug Deliv Transl Res VL - 6 IS - 5 N2 - Candesartan cilexetil (CC), an ester prodrug of candesartan, is BCS class II drug with extremely low aqueous solubility limiting its oral bioavailability. The present research aimed to develop a nanocrystalline formulation of CC with improved saturation solubility in gastrointestinal fluids and thereby, exhibiting enhanced oral bioavailability. CC nanocrystals were prepared using a low energy antisolvent precipitation methodology. A combination of hydroxypropyl methylcellulose (HPMC) and Pluronic® F 127 (50:50 w/w) was found to be optimum for the preparation of CC nanocrystals. The particle size, polydispersity index (PDI), and zeta potential of optimized formulation was found to be 159 ± 8.1 nm, 0.177 ± 0.043, and -23.7 ± 1.02 mV, respectively. Optimized formulation was found to possess irregular, plate-like morphology as evaluated by scanning electron microscopy and crystalline as evaluated by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). A significant increase in saturation solubility and dissolution rate of the optimized nanosuspension was observed at all the tested pH conditions. Optimized CC nanocrystals exhibited a storage stability of more than 3 months when stored under cold and room temperature conditions. In vitro Caco-2 permeability further revealed that CC nanocrystals exhibited nearly 4-fold increase in permeation rate compared to the free CC. In vivo oral bioavailability studies of optimized CC nanocrystals in murine model revealed 3.8-fold increase in the oral bioavailability and twice the C max as compared with the free CC when administered orally. In conclusion, this study has established a crystalline nanosuspension formulation of CC with improved oral bioavailability in murine model. Graphical Abstract Antisolvent precipitation methodology for the preparation of Candesartan Cilexetil nanocrystals for enhanced solubility and oral bioavailability. SN - 2190-3948 UR - https://www.unboundmedicine.com/medline/citation/27129488/Development_of_surface_stabilized_candesartan_cilexetil_nanocrystals_with_enhanced_dissolution_rate_permeation_rate_across_CaCo_2_and_oral_bioavailability_ DB - PRIME DP - Unbound Medicine ER -