Ocular drug delivery is very challenging due to the anatomical and physiological barriers of the eye. Poor aqueous solubility of many drugs and short retention time at ocular surfaces makes the formulation of topical dosage forms even more challenging. Several approaches have been reported to enhance drug bioavailability at the ocular tissues. Cyclodextrin-based nanocarriers have been selected due to their well-known capability of cyclodextrins to enhance the solubility of lipophilic drugs and its permeability through biological membranes. They can also prolong the retention time of ophthalmic formulations on the ocular surface and, as a consequence, increase their bioavailability. The aim of this project was to apply cyclodextrin technology and cyclodextrin-amphiphilic copolymers to enhance the aqueous solubility of two poorly soluble drugs, Nepafenac and Natamycin, as well as their corneal or scleral accumulation. Nepafenac is a non-steroidal anti-inflammatory drug (NSAID) prescribed for the treatment of pain and inflammation that usually occurred after cataract surgery. Nepafenac has low water solubility and ocular permeability. The complexation of nepafenac with six CDs and various water-soluble polymers was investigated. Results showed that HPβ-CD showed the highest solubilizing capacity, while γ-CD led to the highest aggregate formation. Complex formation was investigated and supported by phase solubility analysis, DSC, FT-IR and ¹H-NMR. The optimized complex, which contained 15% (w/v) γ-CD and 8% (w/v) HPβ-CD, was selected for additional studies. Nine formulations containing nepafenac/γ-CD/HPβ-CD complexes and various water-soluble polymers were prepared. Physicochemical and rheological characterization, mucoadhesive capacity, ocular tolerance, diffusion studies, corneal and scleral permeability, and anti-inflammatory activity of these formulations were investigated and compared to the marketed nepafenac suspension, Nevanac® 3 mg/mL. The formulations displayed zeta potential from –6 to –27 mV, microparticle size in the range of 340-5950 nm, neutral pH and high sclera permeation. Moreover, they were found to be non-toxic and non-irritant. Compared to Nevanac®, formulations containing poly(vinyl)-alcohol (PVA), methylcellulose (MC) and carboxymethyl cellulose (CMC) presented the best results in relation to sclera accumulation and anti-inflammatory activity. Natamycin is approved for the treatment of fungal keratitis but its use is restricted due to its low water solubility and low ocular penetration. Soluplus® and Pluronic® P103 were selected as surfactants to prepare single and mixed micelles and poly(pseudo)rotaxanes for Natamycin encapsulation. Soluplus, Pluronic P103 and a mixture of Soluplus/ Pluronic in ratio 4:1 dispersions were prepared with and without 10% α-CD in 0.9% sodium chloride or buffer pH 6.4. They were investigated in relation to their solubility, particle size, zeta potential, pH, rheological properties, diffusion studies, ocular irritancy, and ex vivo cornea and sclera permeation. All formulations revealed zeta potentials close to zero while differences were found with respect to their size. Soluplus micelles and mixed micelles revealed larger sizes (range 90-150 nm) followed by Pluronic P103 micelles. Soluplus micelles led to the highest Natamicyn solubility, followed by Pluronic P103 and their mixed micelles. All formulations were found cytocompatible on murine fibroblasts and did not display irritation. Although Soluplus nanomicelles and poly(pseudo)rotaxanes showed in situ gel behavior at 35 ºC and the highest solubilizing capacity, Pluronic and Soluplus poly(pseudo)rotaxanes led to the lowest diffusion rate and corneal and sclera permeation. Moreover, poly(pseudo)rotaxanes of mixed micelles showed intermediate diffusion release and permeability through cornea and sclera comparing to only Soluplus and Pluronic poly(pseudo)rotaxanes. To conclude, we would like to point out that both optimized Nepafenac formulation and Natamycin-based mixed poly(pseudo)rotaxanes may represent a new approach for topical instillation of drugs to the posterior segment of the eye.
|Published - 26 Oct 2020
- Ocular drug delivery