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Self-Assembling Raloxifene Loaded Mixed Micelles: Formulation Optimization, In Vitro Cytotoxicity and In Vivo Pharmacokinetics

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Abstract

Raloxifene (RLX) has been strongly recommended for postmenopausal women at high risk of invasive breast cancer and for prevention of osteoporosis. However, low aqueous solubility and reduced bioavailability hinder its clinical application. The objective of this study was to explore the potential of RLX loaded mixed micelles (RLX-MM) using Pluronic F68 and Gelucire 44/14 for enhanced bioavailability and improved anticancer activity on human breast cancer cell line (MCF-7). RLX-MM were prepared by solvent evaporation method and optimized using 32 factorial design. The average size, entrapment efficiency and zeta potential of the optimized formulation were found to be 190 ± 3.3 nm, 79 ± 1.3%, 13 ± 0.8 mV, respectively. In vitro study demonstrated 74.68% drug release from RLX-MM in comparison to 42.49% drug release from RLX dispersion. According to the in vitro cytotoxicity assay, GI50 values on MCF-7 breast cancer cell line for RLX-MM and free RLX were found to be 22.5 and 94.71 μg/mL, respectively. Significant improvement (P < 0.05) in the anticancer activity on MCF-7 cell line was observed in RLX-MM over RLX pure drug. Additionally, oral bioavailability of RLX-MM was improved by 1.5-fold over free RLX when administered in female Wistar rats. Incorporation of RLX in the hydrophobic core and improved solubility of the drug due to hydrophilic shell attributed to the enhanced cytotoxicity and bioavailability of RLX-MM. This research establishes the potential of RLX loaded mixed micelles of Pluronic F68 and Gelucire 44/14 for improved bioavailability and anticancer activity on MCF-7 cell line.

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Acknowledgments

The authors thank Zim Laboratories (Nagpur, India) and Novartis Pharmaceuticals (Hyderabad, India) for providing us gift samples of raloxifene and carbamazepine, respectively. The authors are much obliged to Alembic Pharmaceuticals (Mumbai, India) and Gattefossé S.A.S. (Saint Priest, France) for providing Pluronic F68 and GL44 gift samples, respectively. Radhika Kanade would also like to thank AICTE (New Delhi, India) for providing financial support during the entire research study.

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  1. Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune, Maharashtra, 411038, India

    Radhika Kanade, Mithila Boche & Varsha Pokharkar

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  1. Radhika Kanade
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Correspondence to Varsha Pokharkar.

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Kanade, R., Boche, M. & Pokharkar, V. Self-Assembling Raloxifene Loaded Mixed Micelles: Formulation Optimization, In Vitro Cytotoxicity and In Vivo Pharmacokinetics. AAPS PharmSciTech 19, 1105–1115 (2018). https://doi.org/10.1208/s12249-017-0919-6

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