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Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances.
AAPS PharmSciTech. 2016 Apr; 17(2):272-83.AP

Abstract

The purpose of this study was to improve the aqueous solubility, dissolution, and pharmacodynamic properties of a BCS class II drug, ezetimibe (Eze) by preparing ternary cyclodextrin complex systems. We investigated the potential synergistic effect of two novel hydrophilic auxiliary substances, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and L-ascorbic acid-2-glucoside (AA2G) on hydroxypropyl-β-cyclodextrin (HPBCD) solubilization of poorly water-soluble hypocholesterolemic drug, Eze. In solution state, the binary and ternary systems were analyzed by phase solubility studies and Job's plot. The solid complexes prepared by freeze-drying were characterized by Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR), and scanning electron microscopy (SEM). The log P values, aqueous solubility, dissolution, and antihypercholesterolemic activity of all systems were studied. The analytical techniques confirmed the formation of inclusion complexes in the binary and ternary systems. HPBCD complexation significantly (p < 0.05) reduced the log P and improved the solubility, dissolution, and hypocholesterolemic properties of Eze, and the addition of ternary component produced further significant improvement (p < 0.05) even compared to binary system. The remarkable reduction in log P and enhancement in solubility, dissolution, and antihypercholesterolemic activity due to the addition of TPGS or AA2G may be attributed to enhanced wetting, dispersibility, and complete amorphization. The use of TPGS or AA2G as ternary hydrophilic auxiliary substances improved the HPBCD solubilization and antihypercholesterolemic activity of Eze.

Authors+Show Affiliations

Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, 221005, India.Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, 221005, India. bmishrabhu@rediffmail.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26077622

Citation

Srivalli, Kale Mohana Raghava, and Brahmeshwar Mishra. "Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe On Formulating With Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances." AAPS PharmSciTech, vol. 17, no. 2, 2016, pp. 272-83.
Srivalli KM, Mishra B. Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances. AAPS PharmSciTech. 2016;17(2):272-83.
Srivalli, K. M., & Mishra, B. (2016). Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances. AAPS PharmSciTech, 17(2), 272-83. https://doi.org/10.1208/s12249-015-0344-7
Srivalli KM, Mishra B. Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe On Formulating With Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances. AAPS PharmSciTech. 2016;17(2):272-83. PubMed PMID: 26077622.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances. AU - Srivalli,Kale Mohana Raghava, AU - Mishra,Brahmeshwar, Y1 - 2015/06/16/ PY - 2015/02/16/received PY - 2015/05/28/accepted PY - 2015/6/17/entrez PY - 2015/6/17/pubmed PY - 2016/12/17/medline KW - dissolution KW - ezetimibe–HPBCD KW - ezetimibe–HPBCD–AA2G KW - ezetimibe–HPBCD–TPGS KW - phase solubility SP - 272 EP - 83 JF - AAPS PharmSciTech JO - AAPS PharmSciTech VL - 17 IS - 2 N2 - The purpose of this study was to improve the aqueous solubility, dissolution, and pharmacodynamic properties of a BCS class II drug, ezetimibe (Eze) by preparing ternary cyclodextrin complex systems. We investigated the potential synergistic effect of two novel hydrophilic auxiliary substances, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and L-ascorbic acid-2-glucoside (AA2G) on hydroxypropyl-β-cyclodextrin (HPBCD) solubilization of poorly water-soluble hypocholesterolemic drug, Eze. In solution state, the binary and ternary systems were analyzed by phase solubility studies and Job's plot. The solid complexes prepared by freeze-drying were characterized by Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR), and scanning electron microscopy (SEM). The log P values, aqueous solubility, dissolution, and antihypercholesterolemic activity of all systems were studied. The analytical techniques confirmed the formation of inclusion complexes in the binary and ternary systems. HPBCD complexation significantly (p < 0.05) reduced the log P and improved the solubility, dissolution, and hypocholesterolemic properties of Eze, and the addition of ternary component produced further significant improvement (p < 0.05) even compared to binary system. The remarkable reduction in log P and enhancement in solubility, dissolution, and antihypercholesterolemic activity due to the addition of TPGS or AA2G may be attributed to enhanced wetting, dispersibility, and complete amorphization. The use of TPGS or AA2G as ternary hydrophilic auxiliary substances improved the HPBCD solubilization and antihypercholesterolemic activity of Eze. SN - 1530-9932 UR - https://www.unboundmedicine.com/medline/citation/26077622/Improved_Aqueous_Solubility_and_Antihypercholesterolemic_Activity_of_Ezetimibe_on_Formulating_with_Hydroxypropyl_β_Cyclodextrin_and_Hydrophilic_Auxiliary_Substances_ L2 - https://dx.doi.org/10.1208/s12249-015-0344-7 DB - PRIME DP - Unbound Medicine ER -