A potential in situ gel formulation loaded with novel fabricated poly(lactide-co-glycolide) nanoparticles for enhancing and sustaining the ophthalmic delivery of ketoconazole

Abstract

Oral ketoconazole therapy is commonly associated with serious hepatotoxicity. Improving ocular drug delivery could be sufficient to treat eye fungal infections. The purpose of this study was to develop optimized ketoconazole poly(lactide-co-glycolide) nanoparticles (NPs) with subsequent loading into in situ gel (ISG) formulation for ophthalmic drug delivery. Three formulation factors were optimized for their effect on particle size (Y1) and entrapment efficiency (Y2) utilizing central composite experimental design. Interaction among components was studied using differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy. Ketoconazole crystalline state was studied using X-ray powder diffraction. Six different polymeric ISG formulations were prepared and loaded with either optimized NPs or a pure drug. The prepared ISG formulations were characterized for in vitro gelation, drug release and antifungal activity. The permeation through human epithelial cell line was also investigated. The results revealed that all the studied formulation parameters significantly affected Y1 and Y2 of the developed NPs. DSC and FTIR studies illustrated compatibility among NP components, while there was a change from the crystalline state to the amorphous state of the NPs. The in vitro release from the ISG formulations loaded with drug NPs showed sustained and enhanced drug release compared to pure drug formulations. In addition, ISG loaded with NPs showed enhanced anti-fungal activity compared to pure drug formulations. Alginate–chitosan ISG formulation loaded with optimized ketoconazole NPs illustrated higher drug permeation through epithelial cell lines and is considered as an effective ophthalmic drug delivery in the treatment of fungal eye infections.

Chitosan and its Derivatives for Ocular Delivery Formulations: Recent Advances and Developments

“…In contrast, the gel formulation was retained for a longer period in the corneal region, and no significant radioactivity was observed in systemic circulation. As mentioned earlier, Ahmed et al prepared in situ gelling formulations of CS (0.5%) and with ALG (1%) or poloxamer 407 (16%), containing ketoconazole-loaded PLGA NPs [239]. Drug diffusion was higher from the CS/ALG formulation.…”

“…The in vitro release of ibuprofen from the NLC/CS/PF127 hydrogel was slower than from either NLC or NLC/CS. Ahmed et al prepared a series of in situ gelling formulations of CS (0.5%), with ALG (1%) or P407 (16%) loaded with ketoconazole-loaded PLGA NPs [239]. Pure CS exhibited the longest gelation time (90 min), while the gelation time of the two CS mixtures were comparable (approximately 45 min).…”

Chitosan-Based In Situ Gels for Ocular Delivery of Therapeutics: A State-of-the-Art Review

“…Chitosan and HPMC formulations had the longest gelation time. Addition of HPMC to chitosan-based formulations increased the viscosity after dilution with simulated lacrimal fluid [ 67 ].…”

“…The antifungal activity of ocular in situ gels with ketoconazole was tested on Candida albicans strains using agar diffusion technique. A large diameter of the inhibition zone was observed in the formulation based on chitosan and alginate [ 67 ].…”

Waterborne poly(urethane-urea)s films as a sustained release system for ketoconazole

“…In this way, KTZ is widely used for the treatment of fungal infections, especially against thrush, gastrointestinal infections, and infections of the skin, nails, and scalp (25,27). In the market there are immediate release tablets of ketoconazole 200 mg administered once daily, with a short half-life time of only 2 h (28,29). Thus, the production of a sustained release system of ketoconazole would be interesting and convenient in order to increase the drug time of pharmacological action.…”