Natural bioadhesive biodegradable nanoparticles-based topical ophthalmic formulations for sustained celecoxib release: in vitro study

Abstract

Background: Our goal was to prepare and evaluate topical ophthalmic formulations containing optimized celecoxib-loaded bioadhesive cationic chitosan or anionic alginate nanoparticles for sustained release of celecoxib. Methods: Nanoparticles were prepared using a spontaneous emulsification solvent diffusion method. Different concentrations of polymers, emulsifier and stabilizers were used to optimize our formulations. The formulation that gave the lowest particle size and polydispersity index and the highest zeta potential was selected and subjected to further studies. The optimized celecoxibloaded NPs were characterized with regard to their particle size, polydispersity index, zeta potential, morphology and drug content. Celecoxib-loaded NPs were incorporated in topical ophthalmic dosage forms including eye drops, temperature-triggered in situ gelling system and preformed gel. All formulations were then characterized regarding their pH, viscosity, uniformity of drug content, in vitro release study and in vitro cytotoxicity. Results: Results of the optimization studies of both celecoxib-loaded chitosan and alginate nanoparticles respectively, are: particle size of 113.33 ± 4.08 nm and 154.67 ± 5.06 nm; zeta potential of +36.92 ± 3.38 mV and -36.5 ± 4.7 mV; and encapsulation efficiencies of 89.88 ± 4.17% and 75.38 ± 2.98%. Transmission electron microscopic analysis revealed that all nanoparticles have distinct spherical shapes comprising of a solid dense core covered with evenly distributed coat. oreover, all formulations possessed pH and viscosity values that are compatible with the eye and have uniform drug contents that complied with the US Pharmacopeial (USP) official requirement. In vitro release data of ophthalmic formulations showed a sustained release without any burst effect and the formulations followed a Higuchi non-Fickian diffusion mechanism. The results of in vitro cell toxicity revealed that all the prepared formulations are non-toxic, as the percentage cell viability ranged from 89.9 to 97.7%. Conclusions: These formulations provide a great deal of flexibility to the formulation scientist whereby the sizes and zeta potentials of the formulations can be tuned to suit the need using scalable and robust methodologies. This could thus serve as a potential drug delivery system for both the anterior and posterior eye diseases.

Chitosan: A Good Candidate for Sustained Release Ocular Drug Delivery Systems

“…With TEM, spherical particles with an incorporation efficiency of over 75% have been shown. The release of active substance followed the Higuchi model, and the formulations proved to be non-toxic according to in vivo studies [112].…”

Nanoparticles for drug delivery to the anterior segment of the eye

“…The combination of these properties makes polysaccharides versatile biopolymers for ocular drug delivery [71, 84–89]. Drugs such as cyclosporine A (CsA) [90], dorzolamide hydrochloride [91, 92], pramipexole hydrochloride [91], acyclovir [93], 5-flurouracil [94], carteolol [92], gatifloxacin [95], betamethasone sodium phosphate [96], gene [97], pilocarpine [98], econazole nitrate [99], natamycin [100], daptomycin [89], amphotericin B [101], celecoxib [102], timolol maleate [103, 104], fluconazole [105], sodium diclofenac [106], and tropicamide [107] were loaded into nanoparticles made of polysaccharides for ocular delivery. The release of the drugs from these hydrophilic polymer nanoparticle matrices relies on various factors such as polymer hydration, solvent penetration, drug diffusion, drug dissolution, and/or polymer erosion [95].…”

“…Synthesized chitosan nanoparticles were reported to have an average size of several hundred nanometers depending on the synthetic conditions, and an almost constant zeta potential of about +35 to +37 mV [80, 90, 93, 102, 112] which was higher than +30 mV implying that the nanoparticles were stable due to the prevention of the aggregations of the nanoparticles by the surface charges [93]. In vitro studies of chitosan nanoparticles in simulated fluids containing mucus components (mucin and lysozyme) showed that the presence of lysozyme did not compromise the stability of chitosan nanoparticles in the tear fluid.…”

“…Hybrid nanoparticles made of chitosan and lecithin had a particle size of ~100 nm and zeta potential value of around 27 to 43 mV, and were used for controlled release of natamycin [100], amphotericin B [101], and celecoxib [102]. In vitro release of natamycin showed a biphasic release profile with an initial burst release ~41.23% in 2 h followed by a slow release ~64.22% in 7 h [100].…”

“…In vitro release of natamycin showed a biphasic release profile with an initial burst release ~41.23% in 2 h followed by a slow release ~64.22% in 7 h [100]. However, in vitro release of celecoxib showed 24 h sustained release without initial burst [102]. In vivo ocular pharmacokinetics study of natamycin in New Zealand rabbits showed that the hybrid chitosan-lecithin nanoparticles increased the AUC (0 -∞ ) of natamycin 1.47-fold and decreased the clearance of natamycin 7.4-fold compared with the marketed natamycin suspension [100, 101].…”