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Jean-Louis Bourges, Claudia Di Tommaso, Françine Behar-Cohen, Alicia Torriglia, Marta Rodriguez-Aller, Robert Gurny, Michael Möller; A Novel Drug Carrier For The Delivery Of Cyclosporine A To The Eye. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3212.
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Biodegradable hexyl-substituted poly(lactides) (hexPLA) and methoxy polyethylenglycole (MPEG) form a copolymer (MPEG-hexPLA) which assembles in water into micelles. It easily incorporates hydrophobic drugs. We loaded so-formed micelles with Cyclosporine A (CsA). Their toxicity and penetration ability were tested on corneas and corneal cells.
Micelles were prepared by solvent evaporation method associating the copolymer (3 mg/mL) and the CsA (0.5 mg/mL) . The micelles were characterized for size, morphology and drug loading by DLS, TEM and HPLC, respectively. Cytotoxicity tests (MTT tests) and indirect immunofluorescence were carried out on Human Corneal Epithelial cell (HCE). Unloaded and CsA loaded micelles with various copolymer concentrations were compared. The ocular tolerance was assessed on rabbit eyes by Confocal Scanning Laser Ophthalmoscope (CSLO). The kinetics of CsA/MPEG-hexPLA micelles was tested in rabbit tears. The results were compared to a commercial CsA formulation. Corneal penetration was studied after drop instillation of CsA/Nile Red loaded micelles on rat eyes. Rat corneas were flat-mounted and analyzed with fluorescence microscopy (FM and CLSM).
The preparation of micelles provided particle sizing 50 nm diameter. No toxicity was observed on HCE with MPEG-hexPLA polymeric micelles, neither beyond 3 mg/mL of copolymer, nor when loaded with 0.5 mg/mL CsA. Less than 7% of the corneal area was damaged on CSLO, indicating that topical formulations were well tolerated. The in vivo corneal penetration shown that MPEG-hexPLA micelles accumulated in the corneal epithelium and in the stroma. Fluorescent micelles were also observed in the endothelium. The precorneal kinetics study revealed a sustained release of CsA.
Polymeric micelles based on MPEG-hexPLA excel at formulating hydrophobic drugs. Their nanosize of micelles enable to penetrate and carry drugs throughout the cornea toward the anterior segment of the eye. CsA/MPEG-hexPLA micelles are promising to deliver drug in a sustained manner for ophthalmic applications.
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