An experimental study of the wound healing effect of ophthalmic drug films with 6-methyl-3-(thietan-3-yl)uracil and methyluracil

Purpose: to study experimentally the wound-healing effect of ophthalmic drug films (ODF) with 6-methyl-3-(thietan-3-yl) uracil and methyluracil. Material and methods. The study involved 17 Chinchilla rabbits (34 eyes), whose corneas were histomorphologically studied after an experimental chemical acid burn and treatment. ODF with 6-methyl-3-(thietan-3-yl)uracil were deposited in the right eyes of 15 rabbits (15 eyes), and ODF with methyluracil — in the left eyes of these rabbits. Two rabbits served as control: their right eyes were left without wound healing therapy, while the left eyes received dexpanthenol 5 % gel (corneregel) 4 times a day. All animals were monitored daily for 21 days. The morphological changes in the cornea were recorded on the 2nd, 7th, 14th and 21st days after the experimental chemical burn.Results. The course of reparative processes of the chemical burns of the cornea was found to be different depending on the drugs used. Our results show that the ODF with methyluracil led to the resorption of the edema and the turbidity, as well as to a total closure of the desquamation sites of the corneal epithelium on the 7th day. With the ODF containing 6-methyl-3-(thietan-3-yl) uracil, the effect was achieved on the 14th day. In contrast to the control, ODF enhanced the growth and reproduction of cells, rapidly improved the trophism, and stimulated the regeneration process in damaged corneal tissues. ODFs produced no toxic reactions, such as destruction of the collagen framework, maceration, pronounced edema, and hyperemia. On the 21st day of observation, the microscopic picture of rabbit cornea showed the usual normal structure. Conclusion. ODF therapy with methyluracil and 6-methyl-3-(thietan-3-yl)uracil leads to accelerated centripetal epithelialization of corneal erosion, more structured and histologically correct restoration of the epithelial-stromal layer.

Posterior Segment Ophthalmic Drug Delivery: Role of Muco-Adhesion with a Special Focus on Chitosan

Posterior segment eye diseases (PSEDs) including age macular degeneration (AMD) and diabetic retinopathy (DR) are amongst the major causes of irreversible blindness worldwide. Due to the numerous barriers encountered, highly invasive intravitreal (IVT) injections represent the primary route to deliver drugs to the posterior eye tissues. Thus, the potential of a more patient friendly topical route has been widely investigated. Mucoadhesive formulations can decrease precorneal clearance while prolonging precorneal residence. Thus, they are expected to enhance the chances of adherence to corneal and conjunctival surfaces and as such, enable increased delivery to the posterior eye segment. Among the mucoadhesive polymers available, chitosan is the most widely explored due to its outstanding mucoadhesive characteristics. In this review, the major PSEDs, their treatments, barriers to topical delivery, and routes of topical drug absorption to the posterior eye are presented. To enable the successful design of mucoadhesive ophthalmic drug delivery systems (DDSs), an overview of mucoadhesion, its theory, characterization, and considerations for ocular mucoadhesion is given. Furthermore, chitosan-based DDs that have been explored to promote topical drug delivery to the posterior eye segment are reviewed. Finally, challenges of successful preclinical to clinical translation of these DDSs for posterior eye drug delivery are discussed.

Electrospun coaxial hyaluronan-based fiber networks for ophthalmic drug release

A micro-sized core-shell drug release device has been prepared by coaxial electrospinning based on a polylactide shell and the inner core phase made of high molecular weight hyaluronan or a cross-linked hyaluronan network. Timolol, which was inserted into the core phase, is widely used as drug for glaucoma treatment to depress the intraocular eye pressure and should be released over a longer time period from this fiber networks. Release studies of drug loaded fiber devices showed an only moderate burst release of timolol in the first days followed by a continuous longlasting drug release period over several weeks. With these findings, coaxial electrospinning represents a promising approach for the development of drug release systems with long-lasting, relatively constant drug delivery.

Inulin-Based Polymeric Micelles Functionalized with Ocular Permeation Enhancers: Improvement of Dexamethasone Permeation/Penetration through Bovine Corneas

Ophthalmic drug delivery is still a challenge due to the protective barriers of the eye. A common strategy to promote drug absorption is the use of ocular permeation enhancers, while an innovative approach is the use of polymeric micelles. In the present work, the two mentioned approaches were coupled by conjugating ocular permeation enhancers (PEG2000, carnitine, creatine, taurine) to an inulin-based co-polymer (INU-EDA-RA) in order to obtain self-assembling biopolymers with permeation enhancer properties for the hydrophobic drug dexamethasone (DEX). Inulin derivatives were properly synthetized, were found to expose about 2% mol/mol of enhancer molecules in the side chain, and resulted able to self-assemble at various concentrations by varying the pH and the ionic strength of the medium. Moreover, the ability of polymeric micelles to load dexamethasone was demonstrated, and size, mucoadhesiveness, and cytocompatibility against HCE cells were evaluated. Furthermore, the efficacy of the permeation enhancer was evaluated by ex vivo permeation studies to determine the performance of the used enhancers, which resulted in PEG2000 > CAR > TAU > CRE, while entrapment ability studies resulted in CAR > TAU > PEG2000 > CRE, both for fluorescent-labelled and DEX-loaded micelles. Finally, an increase in terms of calculated Kp and Ac parameters was demonstrated, compared with the values calculated for DEX suspension.

Novel Contact Lenses Embedded with Drug-Loaded Zwitterionic Nanogels for Extended Ophthalmic Drug Delivery

Therapeutic ophthalmic contact lenses with prolonged drug release and improved bioavailability have been developed to circumvent tedious eye drop instillation. In this work, zwitterionic nanogels based on poly(sulfobetaine methacrylate) (PSBMA) were easily fabricated by one-step reflux-precipitation polymerization, with the advantages of being surfactant-free and morphology controlled. Then, the ophthalmic drug levofloxacin (LEV) was encapsulated into the nanogels. A set of contact lenses with varied nanogel-loading content was fabricated by the cast molding method, with the drug-loaded nanogels dispersed in pre-monomer solutions composed of 2-hydroxyethyl methacrylate (HEMA) and N-vinyl-2-pyrrolidone (NVP). The structure, surface morphology, water contact angle (WCA), equilibrium water content (EWC), transmittance, and mechanical properties of the contact lenses were subsequently investigated, and in vitro drug release and biocompatibility were further evaluated. As a result, the optimized contact lens with nanogel-loading content of 8 wt% could sustainably deliver LEV for ten days, with critical lens properties within the range of recommended values for commercial contact lenses. Moreover, cell viability assays revealed that the prepared contact lenses were cytocompatible, suggesting their significant potential as an alternative to traditional eye drops or ointment formulations for long-term oculopathy treatment.

Gel-Based Materials for Ophthalmic Drug Delivery

The most common route of administration of ophthalmic drugs is the topical route because it is convenient, non-invasive, and accessible to all patients. Unfortunately, drugs administered topically are not able to reach effective concentrations. Moreover, their bioavailability must be improved to decrease the frequency of administrations and their side effects, and to increase their therapeutic efficiency. For this purpose, in recent decades, particular attention has been given to the possibility of developing prolonged-release forms that are able to increase the precorneal residence time and decrease the loss of the drug due to tearing. Among these forms, gel-based materials have been studied as an ideal delivery system because they are an extremely versatile class with numerous prospective applications in ophthalmology. These materials are used in gel eye drops, in situ gelling formulations, intravitreal injections, and therapeutic contact lenses. This review is intended to describe gel-based materials and their main applications in ophthalmology.

Nanoparticulate ophthalmic drug delivery of norfloxacin to prevent ocular infection after cataract surgery: Evaluation in animal model

Post cataract surgery, patients generally experience bacterial infection called endophthalmitis which is considered as potent blinding complication. This infection arises from the colonization of Staphylococcus epidermidis on the newly implanted lense. To overcome this problem, we developed nanoparticulate ophthalmic drug delivery of Norfloxacin to prevent ocular infection after cataract surgery. Sustained release Norfloxacin loaded polymeric nanoparticles were developed by high pressure homogenization method. The nanoparticles were characterized for particle size, zeta potential, polydispersity index (PDI), encapsulation efficiency (EE), in vitro Norfloxacin release and surface characteristics using scanning electron microscopy (SEM). The optimized nanoparticulate formulation was further used for the development of thermoreversible ophthalmic gel using poloxamer polymer. The formulated ophthalmic gel was evaluated for gelation temperature, pH, bioadhesiveness, and in vitro corneal permeation study. The antibacterial efficacy testing of thermoreversible gel was assessed in animal model (rabbit) infected with Staphylococcus epidermidis. At the end of study period the inhibitory effect of thermoreversible gel was determined on test animals. The antibacterial effects were compared with control group and plain thermoreversible gel (without nanoparticle formulation). The optimized nanoparticulate formulation of Norfloxacin showed slow and gradual sustained release over the period of 72 hours, encapsulation efficiency of between 90.12 to 98.50%, particle size 95–210 nm, PDI 0.18 to 0.212 and zeta potential between 20 to 25 mV. The nanoparticles were found spherical and smooth in nature. The optimized formulation of nanoparticle was used in thermoreversible gel. The results obtained showed that the thermoreversible gel was clear and transparent (prime requirement for ophthalmic product) with high gelling capacity and moderately viscous liquid (1170 cp), highest bioadhesive strength of 2312.90 dyne/cm2. The exvivo corneal study showed excellent permeation through cornea as compare to control sample. Norfloxacin released from thermoreversible gel killed Staphylococcus epidermidis in animal models as compare to control group and showed effect up to 14 days. With these findings, we demonstrate a new and effective system for sustained drug release of Norfloxacin from thermoreversible gel with specific application to prevent ocular infection after cataract surgery.