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Nanomicellar Topical Aqueous Drop Formulation of Rapamycin for Back-of-the-Eye Delivery

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Abstract

The objective of this study was to develop a clear, aqueous rapamycin-loaded mixed nanomicellar formulations (MNFs) for the back-of-the-eye delivery. MNF of rapamycin (0.2%) was prepared with vitamin E tocopherol polyethylene glycol succinate (TPGS) (Vit E TPGS) and octoxynol-40 (Oc-40) as polymeric matrix. MNF was characterized by various parameters such as size, charge, shape, and viscosity. Proton nuclear magnetic resonance (1H NMR) was used to identify unentrapped rapamycin in MNF. Cytotoxicity was evaluated in human retinal pigment epithelial (D407) and rabbit primary corneal epithelial cells (rPCECs). In vivo posterior ocular rapamycin distribution studies were conducted in male New Zealand white rabbits. The optimized MNF has excellent rapamycin entrapment and loading efficiency. The average size of MNF was 10.98 ± 0.089 and 10.84 ± 0.11 nm for blank and rapamycin-loaded MNF, respectively. TEM analysis revealed that nanomicelles are spherical in shape. Absence of free rapamycin in the MNF was confirmed by 1H NMR studies. Neither placebo nor rapamycin-loaded MNF produced cytotoxicity on D407 and rPCECs indicating formulations are tolerable. In vivo studies demonstrated a very high rapamycin concentration in retina-choroid (362.35 ± 56.17 ng/g tissue). No drug was identified in the vitreous humor indicating the sequestration of rapamycin in lipoidal retinal tissues. In summary, a clear, aqueous MNF comprising of Vit E TPGS and Oc-40 loaded with rapamycin was successfully developed. Back-of-the-eye tissue distribution studies demonstrated a very high rapamycin levels in retina-choroid (place of drug action) with a negligible drug partitioning into vitreous humor.

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Acknowledgments

This study was supported by NIH grants R01EY09171-16 and R01EY010659-14. We would like to thank Dr. Vladimir Dusevich, UMKC School of Dentistry, for helping with the operation of transmission electron microscopy. The authors also acknowledge LUX Biosciences, NJ, USA, for the financial support.

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  1. Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri—Kansas City, 5258 Health Science Building 2464 Charlotte Street, Kansas, Missouri, 64108, USA

    Kishore Cholkar, Sriram Gunda, Ravinder Earla, Dhananjay Pal & Ashim K. Mitra

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  1. Kishore Cholkar
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  2. Sriram Gunda
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  3. Ravinder Earla
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  5. Ashim K. Mitra
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Correspondence to Ashim K. Mitra.

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Cholkar, K., Gunda, S., Earla, R. et al. Nanomicellar Topical Aqueous Drop Formulation of Rapamycin for Back-of-the-Eye Delivery. AAPS PharmSciTech 16, 610–622 (2015). https://doi.org/10.1208/s12249-014-0244-2

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