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Kishore Cholkar, Sriram Gunda, Ravinder Earla, Ashim Mitra, ; An aqueous clear rapamycin topical drop for retinal delivery. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1072.
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© ARVO (1962-2015); The Authors (2016-present)
The objectives of this study are (i) to develop an aqueous, clear mixed nanomicellar formulation (MNF) of rapamycin, optimization and characterization, (ii) to determine MNF cytotoxicity and transport across ocular cells and (iii) to determine in vivo ocular tissue distribution of optimized novel rapamycin loaded MNF post topical drop administration into rabbit cul-de-sac.
Polymers such as Vitamin E TPGS (D-alpha-tocopheryl polyethylene glycol 1000 succinate), octoxynol-40 and rapamycin are mixed in varying ratios to obtain an optimized formulation. The novel MNF was prepared by solvent evaporation technique. In vitro release studies were conducted with a dialysis bag method and cytotoxicity and transport studies were conducted on HCEC and ARPE-19 cells. In vivo studies were conducted in New Zealand (NZW) male white rabbits.
Rapamycin was loaded into MNF to generate an overall loading of 2 and 4mg/mL. Optimized formulation was characterized for its improvement in drug loading, entrapment efficiency, size, polydispersity, surface charge, morphology and rapamycin release. Optimized MNF showed a size range of 28-35 nm and encapsulation percentage > 95% respectively. Absence of free or unentrapped rapamycin in the MNF was confirmed by proton NMR spectroscopy. The MNF drug release was found to be sustained. Cytotoxicity studies on HCEC and ARPE-19 cells treated with placebo and rapamycin loaded optimal MNF’s showed no significant difference in cell survival relative to untreated (medium) cells. Transport studies showed higher rapamycin permeability. In vivo rapamycin ocular tissue distribution studies show higher rapamycin concentrations (362.35 ± 56.17 ng/g tissue) in back of the eye tissues (retina-choroid) with no rapamycin detected in vitreous humor (VH).
An optimized and characterized clear aqueous MNF of rapamycin was prepared. The novel MNF had no cytotoxic effect on HCEC and ARPE-19 cells and had higher permeability. In vivo ocular tissue distribution studies show that therapeutic levels of rapamycin were observed in retina-choroid with no rapamycin in VH, post topical drop administration. Results indicate rapamycin loaded MNF follows conjunctival-scleral pathway to reach back of the eye tissues (retina-choroid).
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