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Aswani Dutt Vadlapudi, Kishore Cholkar, Ramya Krishna Vadlapatla, Ashim Mitra; Development of Aqueous Nanomicellar Formulation for Topical Delivery of Biotinylated Lipid Prodrug of Acyclovir to Treat Herpetic Keratitis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5053.
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© ARVO (1962-2015); The Authors (2016-present)
The objective of this study was to develop a clear, aqueous nanomicellar formulation and evaluate its in vitro ocular biocompatibility as a novel carrier for topical delivery of biotinylated lipid prodrug to the eye for treatment of herpetic keratitis (HK).
Biotin-12Hydroxystearic acid-acyclovir (B-12HS-ACV) was synthesized and a micellar formulation was prepared by solvent evaporation/film hydration method using two non-ionic surfactants - vitamin E TPGS and octoxynol-40. The optimized formulation was characterized for various parameters including in vitro prodrug release. Human corneal epithelial cells (HCEC) were employed for studying the cytotoxicity of the formulation. Further, the mRNA expression levels of various cytokines were also studied with quantitative real-time PCR (qPCR).
B-12HS-ACV was successfully synthesized and confirmed by LC-MS/MS and NMR. The micelle average size was 10.46 ± 0.05 nm with a PDI of 0.086 for blank micelles, and 10.78 ± 0.09 nm with a PDI of 0.075 for prodrug loaded micelles. Both unloaded and prodrug loaded micelles had negative zeta potential. The prodrug encapsulation efficiency of mixed micelles was calculated to be ≈ 90%. TEM analysis showed that the micelles were spherical, homogenous and devoid of aggregates. B-12HS-ACV release from micelles was slow and without a significant burst effect. Results showed a sustained release of the prodrug from the micelles over a period of 4 days. Neither the blank formulation nor prodrug loaded micellar formulation demonstrated any cytotoxic effects. Further, incubation of HCEC cells with blank and prodrug loaded micelles groups did not significantly alter the expression levels of IL-1β, IL-6, IL-8, IL-17, TNF-α and IFN-γ.
In summary, a topical aqueous nanomicellar formulation comprised of vitamin E TPGS and octoxynol-40 loaded with 0.1% B-12HS-ACV was successfully developed for the treatment of HK. B-12HS-ACV loaded nanomicelles are relatively small in size, spherical and homogenous, and devoid of aggregates. The micelle formulations were perfectly transparent comparable to water. Ocular biocompatibility studies indicated that mixed nanomicelles were non-toxic and non-inflammatory to corneal epithelial cells. Therefore, nanomicellar technology represents a promising strategy for delivery of biotinylated lipid prodrugs of ACV to treat HK.
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