SURFACE MODIFIED NANOSTRUCTURED LIPID CARRIER FOR IMPROVED OCULAR DELIVERY: IN VITRO AND EX-VIVO STUDY

Nano structured lipid carrier (NLC) is a new generation Nano particulate system that offers several advantages over polymeric nanoparticles. However, NLC possesses less muco-adhesiveness in the eye due to its anionic nature. Therefore, the present study aimed to modify the surface of NLC with cationic compounds to improve corneal permeability. The objective of the present study was to prepare and optimize Dexamethasone NLC, surface modification of NLC with carboxymethyl chitosan, and comparative evaluation of both with the marketed formulation. A combined melt emulsification and ultrasonication method was used to prepare NLC. The optimized NLC formulations shown particle size (64±2.3 nm), polydispersity in Dexamethasone (0.270±0.008), zeta potential (-12±3.42 mV), and entrapment efficiency (96.66±0.41%). Carboxymethyl chitosan modified dexamethasone loaded NLC showed particle size (260.73±4.66 nm) and dexamethasone (10.8±6.0 mV). It exhibited sustained drug release than NLC and marketed eye drop. In the ex vivo study, surface modified NLC had a permeability coefficient of 228.88 cm h-1, which is 2.60-and 1.61-times greater than eye drop and NLC, respectively. Surface-modified NLC has shown comparatively sustained release with plain NLC and commercial eye drops. The surface-modified form can adhere firmly with mucin and shown improved trans corneal permeability. Therefore, CNLC would be the potential nanocarrier for dexamethasone to minimize dose requirement and overcome systemic adverse events.

Celastrol-based nanomedicine promotes corneal allograft survival

Effectively promoting corneal allograft survival remains a challenge in corneal transplantation. The emerging therapeutic agents with high pharmacological activities and their appropriate administration routes provide attractive solutions. In the present study, a celastrol-loaded positive nanomedicine (CPNM) was developed to enhance corneal penetration and to promote corneal allograft survival. The in vitro, in vivo and ex vivo results demonstrated the good performance of CPNM prolonging the retention time on ocular surface and opening the tight junction in cornea, which resulted in enhanced corneal permeability of celastrol. Both in vitro and in vivo results demonstrated that celastrol inhibited the recruitment of M1 macrophage and the expression of TLR4 in corneal allografts through the TLR4/MyD88/NF-κB pathway, thereby significantly decreasing secretion of multiple pro-inflammatory cytokines to promote corneal allograft survival. This is the first celastrol-based topical instillation against corneal allograft rejection to provide treatment more potent than conventional eye drops for ocular anterior segment diseases. Graphical Abstract

Introducing an Efficient In Vitro Cornea Mimetic Model for Testing Drug Permeability

There is a growing need for novel in vitro corneal models to replace animal-based ex vivo tests in drug permeability studies. In this study, we demonstrated a corneal mimetic that models the stromal and epithelial compartments of the human cornea. Human corneal epithelial cells (HCE-T) were grown on top of a self-supporting porcine collagen-based hydrogel. Cross-sections of the multi-layers were characterized by histological staining and immunocytochemistry of zonula oc-cludens-1 protein (ZO-1) and occludin. Furthermore, water content and bssic elastic properties of the synthetized collagen type I-based hydrogels were measured. The apparent permeability coefficient (Papp) values of a representative set of ophthalmic drugs were measured and correlated to rabbit cornea Papp values found in the literature. A multilayered structure of HCE-T cells and the expression of ZO-1 and occludin in the full thickness of the multilayer were observed. The hydrogel-based corneal model exhibited an excellent correlation to rabbit corneal permeability (r = 0.96), whereas the insert-grown HCE-T multilayer was more permeable and the correlation to the rabbit corneal permeability was lower (r = 0.89). The hydrogel-based human corneal model predicts the rabbit corneal permeability more reliably in comparison to HCE-T cells grown in inserts. This in vitro human corneal model can be successfully employed for drug permeability tests whilst avoiding ethical issues and reducing costs.

Introducing an Efficient In Vitro Cornea Mimetic Model for Testing Drug Permeability

There is a growing need for novel in vitro corneal models to replace animal-based ex vivo test in drug permeability studies. In this study we demonstrate a corneal mimetic that models the stromal and epithelial compartments of human cornea. Human corneal epithelial cells (HCE-T) were grown on top of a self-supporting porcine collagen-based hydrogel. Cross sections of the multilayers were characterized by histological staining and immunocytochemistry of zonula occludens-1 protein (ZO-1) and occludin. Furthermore, water content and elastic properties of the synthetized collagen type I-based hydrogels were measured. The apparent permeability coefficient (Papp) values of a representative set of ophthalmic drugs were measured and correlated to rabbit cornea Papp values found in the literature. Multilayered structure of HCE-T cells and expression of ZO-1 and occludin in full thickness of multilayer were observed. The hydrogel-based corneal model exhibited excellent correlation to rabbit corneal permeability (r=0.96), whereas insert-grown HCE-T multilayer was more permeable and the correlation to the rabbit corneal permeability was lower (r=0.89). The hydrogel-based human corneal model predicts the rabbit corneal permeability more reliably in comparison to HCE-T cells grown in inserts. This in vitro human corneal model can be successfully employed for drug permeability tests whilst avoiding ethical issues and reducing costs.

Formulation and Characterization of Acetazolamide/Carvedilol Niosomal Gel for Glaucoma Treatment: In Vitro, and In Vivo Study

Acetazolamide (ACZ) is a diuretic used in glaucoma treatment; it has many side effects. Carvedilol (CAR) is a non-cardioselective beta-blocker used in the treatment of elevated intraocular pressure; it is subjected to the first-pass metabolism and causes fluids accumulation leading to edema. This study focuses on overcoming previous side effects by using a topical formula of a combination of the two previous drugs. Sixty formulations of niosomes containing Span 20, Span 60, Tween 20, and Tween 60 with two different ratios were prepared and characterized. Formulation with the lowest particle size (416.30 ± 0.23), the highest zeta potential (72.04 ± 0.43 mv), and the highest apparent coefficient of corneal permeability (0.02 ± 0.29 cm/h) were selected. The selected formula was incorporated into the gel using factorial design 23. Niosomes (acetazolamide/carvedilol) consisting of Span 60 and cholesterol in the molar ratio (7:6), HMPC, and carbopol with two different ratios were used. The selected formula was subjected to an in vivo study of intraocular pressure in ocular hypertensive rabbits for 60 h. The sustained gel formula of the combination decreased (IOP) to normal after 1 h and sustained efficacy for 4 days. Histological analysis of rabbit eyeballs treated with the selected formula showed improvement in glaucomatous eye retinal atrophy.

Curcumin In Situ Gelling Polymeric Insert with Enhanced Ocular Performance

The search for an ocular drug delivery system that could provide long-acting effects without a detriment to the anatomy and physiology of the eye remains a challenge. Polyphenolic compounds (curcumin in particular) have recently gained popularity due to their powerful antioxidant properties; yet curcumin suffers poor stability and water solubility. A conventional eye drop formulation of curcumin in the form of a suspension is likely to suffer a short duration of action requiring multiple instillations. On the other hand, polymeric in-situ gelling inserts offer the prospect of overcoming these limitations. The aim of this study was to prepare, characterize and evaluate in vivo, polymeric, in-situ gelling and mucoadhesive inserts for ocular surface delivery of curcumin. Different types and ratios of biocompatible polymers (HPMC, CMC, PL 127 and PVA) and three plasticizers along with the solvent casting method were adopted to prepare curcumin inserts. The inserts were investigated for their physicochemical characteristics, applicability, and suitability of use for potential placement on the ocular surface. The prepared inserts revealed that curcumin was mainly dispersed in the molecular form. Insert surfaces remained smooth and uniform without cracks appearing during preparation and thereafter. Improved mechanical and mucoadhesive properties, enhanced in vitro release (7.5- to 9-fold increases in RRT300 min) and transcorneal permeation (5.4- to 8.86-fold increases in Papp) of curcumin was achieved by selected in-situ gelling inserts compared to a control curcumin suspension. The developed inserts demonstrated acceptable ocular tolerability, enhanced corneal permeability, and sustained release of curcumin along with retention of insert formulation F7 on the ocular surface for at least two-hours. This insert provides a viable alternative to conventional eye drop formulations of curcumin.

Design and Evaluation of Eudragit RS-100 based Itraconazole Nanosuspension for Ophthalmic Application

Background: Poor water soluble compounds are difficult to develop as drug products using conventional formulation techniques. Objective: In the present study, the potential of Eudragit RS-100 nanosuspension as a new vehicle for the improvement of the delivery of drugs to the intraocular level was investigated. Methods : Solvent evaporation technique has been employed for nanosuspension preparation. Surfactant concentration and drug to polymer ratio has been optimized using 32 factorial design to achieve desired particle size, entrapment efficiency and percent permeation responses as dependent variables. All the formulations were characterized for particle size, zeta potential, polydispersity index (PDI), Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetery (DSC), X-ray diffraction (XRD) analysis, viscosity, antifungal study and Transmission electron microscopy (TEM). Secondly, itraconazole eye drop was prepared by using sulfobuty ether-β-cyclodextrin and comparatively studied its antifungal efficacy. Results: The nanosuspension had a particle size range of 332.7-779.2nm, zeta potential +0.609-16.3, entrapment efficiency 61.32±1.36%-76.34±2.04%. Ex vitro corneal permeability study showed that optimized Itraconazole nanosuspension produced higher permeation as compared to market formulation and Itraconazole eye drop. Moreover, optimized nanosuspension was found as more active against Candida albicans & Aspergillus flavus compared to market formulation and Itraconazole eye drop. Conclusion: The nanosuspension approach could be an ideal, promising approach to increases the solubility and dissolution of Itraconazole.