Microporation-Mediated Transdermal Delivery of In Situ Gel Incorporating Etodolac-Loaded PLGA Nanoparticles for Management of Rheumatoid Arthritis.

Management of rheumatoid arthritis (RA) requires long-term administration of different medications since there has been no cure until now. Etodolac (ETD) is a nonsteroidal anti-inflammatory drug commonly used for RA management. However, its long-term administration resulted in severe side effects. This study aimed to develop a transdermal in situ gel incorporating ETD-loaded polymeric nanoparticles (NPs) to target the affected joints for long-term management of RA. Several PLGA NPs incorporating 1% ETD were prepared by nanoprecipitation and optimized according to the central composite design. The optimum NPs (F1) exhibited 96.19 ± 2.31% EE, 282.3 ± 0.62 nm PS, 0.383 ± 0.04 PDI, and -6.44 ± 1.69 ZP. A hyaluronate coating was applied to F1 (H-F1) to target activated macrophages at inflammation sites. H-F1 exhibited 287.4 ± 4.2 nm PS, 0.267 ± 0.02 PDI, and -23.7 ± 3.77 ZP. Pluronic F-127 in situ gel (H-F1G) showed complete gelation at 29 °C within 5 min. ETD permeation from H-F1G was sustained over 48 h when applied to microporated skin and exhibited significant enhancement of all permeation parameters. Topical application of H-F1G (equivalent to 8 mg ETD) to Wistarrat microporated skin every 48 h resulted in antirheumatic therapeutic efficacy comparable to commercial oral tablets (10 mg/kg/day).

Development of antifungal fibrous ocular insert using freeze-drying technique.

Candida species is one of the pathogenic fungi of the eye responsible for keratitis that frequently causes vision impairment and blindness. Effective treatment requires long-term use of antifungal drugs, which is opposed by the defensive mechanisms of the eye and inadequate corneal penetration. The objective of this study was to develop a carrier for prolonged ocular application of fluconazole (FLZ) to treat keratitis. FLZ was encapsulated into chitosan fibrous matrices (F1-F4) using different chitosan concentrations (0.02, 0.1, 0.5, and 1%w/v, respectively) by freeze-drying as a single-step technique. Studying the morphology and surface properties of the inserts revealed a porous matrix with fibrous features with a large surface area. Thermal stability and chemical compatibility were confirmed by DSC/TGA/DTA and FT-IR, respectively. Loading capacity (LC) and entrapment efficiency (EE) were determined. According to the in vitro release study, F4 (0.11 mg mg-1 LC and 87.53% EE) was selected as the optimum insert because it had the most sustained release, with 15.85% burst release followed by 75.62% release within 12 h. Ex vivo corneal permeation study revealed a 1.2-fold increase in FLZ permeation from F4 compared to FLZ aqueous solution. Also, in the in vivo pharmacokinetic study in rabbits, F4 increased the AUC0-8 of FLZ by 9.3-fold and its concentration in aqueous humor was maintained above the MIC through the experimentation time. Studies on cytotoxicity (MTT assay) provide evidence for the safety and biocompatibility of F4. Therefore, the freeze-dried FLZ-loaded chitosan fibrous insert could be a promising candidate for treating ocular keratitis.

Novel cubosome based system for ocular delivery of acetazolamide.

Acetazolamide is the drug of choice for glaucoma treatment in an emergency. However, it is not available in any topical formulation and it is available only as systemic tablets. Despite its efficiency as a drug in decreasing intraocular pressure, it has negative systemic effects as renal toxicity and metabolic acidosis. Moreover, it suffers from poor aqueous solubility and low corneal permeability limiting its ocular bioavailability and its use topically. Cubosomes have enormous advantages as a drug delivery system, most importantly, high surface area, thermal stability, and ability to encapsulate hydrophobic, amhiphilic, and hydrophilic molecules. Herein, we have exploited the unique properties of cubosomes as a novel nano-delivery system for acetazolamide as eye drops dosage form for glaucoma treatment. Different acetazolamide-loaded cubosomes have been developed and evaluated. The best-optimized formulation (F5), was cubic shaped structure, with an average particle size of 359.5 ± 2.8 nm, surface charge -10.8 ± 3.2 mV, and 59.8% entrapment efficiency. Ex-vivo corneal permeation studies have revealed a 4-fold increase in acetazolamide permeability coefficient compared to that stated in the literature. F5 showed superior therapeutic efficacy represented by a 38.22% maximum decrease in intraocular pressure vs. 31.14 and 21.99% decrease for the commercial Azopt® eye drops and Cidamex® tablets, respectively. It also exhibited higher (AUC0-10) compared to Azopt® eye drops and Cidamex® tablets by 2.3 and 3 times, respectively. F5 showed mean residence time 4.22 h vs. 2.36 and 2.62 h for Azopt® and Cidamex® with no eye irritation observed according to the modified Draize test. To the best of our knowledge, this is the first study for developing acetazolamide-loaded cubosomes as the topical delivery system for glaucoma treatment.