Preparation and Characterization of Novel, Mucoadhesive chloramphenicol Nanoparticles for Ocular Drug Delivery

Introduction: For the treatment of eye infections using anti-infective agents, topical ocular application is the most convenient route of administration. Topical delivery of drug agents is associated with a number of problems and challenges owing to the unique structure of the eye. The efficacy of conventional ocular formulations is limited by poor corneal retention and permeation, resulting in low ocular bioavailability. The objective of the present study was to develop ocular delivery for Chloramphenicol used to treat bacterial infections of the eye, which can prevent frequent drug administration and enhance patient compliance. Methods and Results: Chitosan/TPP nanoparticles were prepared by an ionic gelation method. CS was dissolved in acetic acid (1% v/v) to obtain the cationic phase. CS-NPs were obtained upon the addition of TPP by drop-wise to chitosan solution under magnetic. The chloramphenicol-loaded nanoparticles were characterized for particle size, morphology, zeta potential, drug encapsulation efficiency, and subsequent release and corneal penetration study.  HPLC Method was prepared for chloramphenicol determination. Stability of NPs has been tested. The obtained nanoparticles had small particle size and positive surface charges, which improved good stability in six months. The NPs thus produced improved high penetration through isolated sheep cornea due to the interaction with negatively charged biological membranes. These coatings achieved pronounced penetration enhancing effect as compared to chloramphenicol solution. This formulation of nanoparticles has a strong potential for a sustained release effect of the drug, when applied to the eye topically. Conclusions: It is notable that the chitosan coating as biocompatible and biodegradable polymer, has the potential to be used as a non-toxic penetration enhancer in nanoparticle form, especially for ocular drug delivery

Eudragit® Nanoparticles Based on Drug–polymer Coprecipitation for Ocular-Controlled Delivery of Erythromycin: In-vivo Evaluation in Rabbit

Introduction: Frequent use of highly concentrated solutions may induce toxic side effects and cellular damage at the ocular surface. To enhance the amount of active substance reaching the target tissue or exerting a local effect in the cul-de-sac, the residence time of the drug in the tear film should be lengthened. The purpose of the study was to formulate biodegradable film loading nanoparticles (NPs) as ophthalmic insert, which could be easily placed into the cul-de-sac, and be capable of delivering therapeutic concentrations of Erythromycin for a prolonged period of time in a much lower dose.  Methods and Results: A Novel quasi-emulsion solvent diffusion method to prepare the controlled-release nanoparticles of drug model with Eudragit polymers has been developed. FTIR and scanning electron microscopy (SEM), loading analyses of the nanoparticles, mechanical properties, water vapor permeability, thermal stability of the films were analyzed. An agar well diffusion bioassay method for determination of erythromycin in ophthalmic samples, using Micrococcus Luteus ATCC 9341 as the assay organism, was carried out. In vivo studies were performed in New Zealand albino rabbits using a film loading nanoparticles. SEM revealed irregularly shaped particles. Mean particle size of nanoparticles ranged between 118 and 203 nm, while zeta potential ranged between +15 and +22 mV. The inserts were found to be uniform, tough, elastic and bioadhesive. In-vitro release studies were performed and slowed release up to 28 h with non-Fickian diffusion behavior. Drug levels in the ocular tears in rabbit were significantly higher in comparison to treatment with a pomade formulation. Conclusions: Erythromycin NPs loaded Eudragit were successfully prepared by spontaneous emulsification technique. The insert would degrade during the specified time with no residue to be removed after the medication

Preparation and characterization of novel, mucoadhesive ofloxacin nanoparticles for ocular drug delivery

The efficacy of conventional ocular formulations is limited by poor corneal retention and permeation, resulting in low ocular bioavailability. Mucoadhesive chitosan (CS)/ tripolyphosphatesodium (TPP) and chitosan (CS)/ tripolyphosphatesodium (TPP)-alginate (ALG) nanoparticles were investigated for the prolonged topical ophthalmic delivery of ofloxacin. A modified ionotropic gelation method was used to produce ofloxacin-loaded nanoreservoir systems. The ofloxacin-loaded CS/TPP and CS/TPP-ALG nanoparticles were characterized for particle size, morphology, zeta potential, encapsulation efficiency, subsequent release and corneal penetration study. The designed nanoparticles have a particle size from 113.8 nm to 509 nm and zeta potential from 16.2 mV to 40.3 mV and encapsulation efficiency values ranging from 19.7% to 33.1%. Nanoparticles revealed a release during the first hours, followed by a more gradual drug release. The ofloxacin-loading CS/TPP or CS/TPP-ALG NPs developed are pronounced penetration enhancing effect as compared to OFX solution (5-6.5 times). Thus, these nanoparticles have a strong potential for ocular drug delivery

Polymeric inserts containing Eudragit® L100 nanoparticle for improved ocular delivery of azithromycin

Polymeric inserts containing azithromycin-loaded Eudragit® L100 nanoparticles were developed to sustain the drug release and enhance its ocular performance. The solvent diffusion technique was employed to prepare nanoparticles. The developed nanoparticles (NPs) were fully characterized and investigated. The solvent casting method was used to prepare azithromycin ocular inserts (azithromycin, AZM film) by adding hydroxypropyl methylcellulose (HPMC) or hydroxyethyl cellulose (HEC) solutions after the incorporation of AZM-loaded Eudragit® L100 nanoparticles into plasticized PVA (polyvinyl alcohol) solutions. The optimized nanoparticles had a particle size of 78.06 ± 2.3 nm, zeta potential around −2.45 ± 0.69 mV, polydispersity index around 0.179 ± 0.007, and entrapment efficiency 62.167 ± 0.07%. The prepared inserts exhibited an antibacterial effect on Staphylococcus aureus and Escherichia coli cultures. The inserts containing AZM-loaded nanoparticles showed a burst release during the initial hours, followed by a sustained drug release pattern. Higher cumulative corneal permeations from AZM films were observed for the optimized formulation compared to the drug solution in the ex-vivo trans-corneal study. In comparison to the AZM solution, the inserts significantly prolonged the release of AZM in rabbit eyes (121 h). The mucoadhesive inserts containing azithromycin-loaded Eudragit® L100 nanoparticles offer a promising approach for the ocular delivery of azithromycin (antibacterial and anti-inflammatory) to treat ocular infections that require a prolonged drug delivery

Polyvinyl Alcohol/Chitosan single-layered and Polyvinyl Alcohol/Chitosan/Eudragit RL100 multi-layered electrospun nanofibers as an ocular matrix for the controlled release of ofloxacin: an in vitro and in vivo evaluation

A novel nanofiber insert was prepared with a modified electrospinning method to enhance the ocular residence time of ofloxacin (OFX) and to provide a sustained release pattern by covering hydrophilic polymers, chitosan/polyvinyl alcohol (CS/PVA) nanofibers, with a hydrophobic polymer, Eudragit RL100 in layers, and by glutaraldehyde (GA) cross-linking of CS-PVA nanofibers for the treatment of infectious conjunctivitis. The morphology of the prepared nanofibers was studied using scanning electron microscopy (SEM). The average fiber diameter was found to be 123 ± 23 nm for the single electrospun nanofiber with no cross-linking (OFX-O). The single nanofibers, cross-linked for 10 h with GA (OFX-OG), had an average fiber diameter of 159 ± 30 nm. The amount of OFX released from the nanofibers was measured in vitro and in vivo using UV spectroscopy and microbial assay methods against Staphylococcus aureus, respectively. The antimicrobial efficiency of OFX formulated in cross-linked and non-cross-linked nanofibers was affirmed by observing the inhibition zones of Staphylococcus aureus and Escherichia coli. In vivo studies using the OFX nanofibrous inserts on a rabbit eye confirmed a sustained release pattern for up to 96 h. It was found that the cross-linking of the nanofibers by GA vapor could reduce the burst release of OFX from OFX-loaded CS/PVA in one layer and multi-layered nanofibers. In vivo results showed that the AUC0–96 for the nanofibers was 9–20-folds higher compared to the OFX solution. This study thus demonstrates the potential of the nanofiber technology is being utilized to sustained drug release in ocular drug delivery systems

Eudragit® L100/Polyvinyl Alcohol nanoparticles impregnated mucoadhesive films as ocular inserts for controlled delivery of erythromycin : development, characterization and in vivo evaluation

The fast elimination of drugs from the cornea is one of many challenges associated with the topical administration of conventional dosage forms. The present manuscript aimed to prepare modified-release inserts containing erythromycin (ERY) to enhance drug delivery and address the aforementioned limitation. Film formulations were developed using Eudragit(®) L100 (EUD) and Polyvinyl Alcohol (PVA) polymers. ERY-loaded EUD-based nanoparticles were developed by the colloidal dispersion method using PVA as the emulsifier. The film-casting method was applied to form the mucoadhesive films using sodium alginate, gelatin, cyclodextrin-α, and β as polymeric film matrices. Different physicochemical properties of the optimized formulations and in vitro release profiles were evaluated. The in vivo evaluation was performed by collecting tear samples of rabbits using a novel, non-invasive method following the administration of inserts in the cul-de-sac. The ERY amount was assayed using a microbiological assay. The developed films showed prolonged in vitro and in vivo release profiles over five to six days; they had suitable physicochemical properties and a tensile strength of 2–3 MPa. All formulations exhibited antibacterial efficacy against E. coli and S. aureus with more than 20 mm diameter of inhibited growth zones. None of the formulations caused irritation to the rabbit’s eye. The inserts showed promising pharmacokinetics with AUC(0–120) of 30,000–36,000 µg·h/mL, a C(max) of more than 1800 µg/mL at 4 h, and maintained drug concentration over the threshold of 5 µg/mL during the following 120 h of study. Nanoparticle-containing, mucoadhesive films could be fabricated as ocular inserts and can prolong the topical ocular delivery of ERY

Preparation and Evaluation of Nanofibrous and Film-Structured Ciprofloxacin Hydrochloride Inserts for Sustained Ocular Delivery: Pharmacokinetic Study in Rabbit’s Eye

Conventional anti-infective eye drops are the most common forms of drugs prescribed for the management of topical ocular infections. Despite their convenience, topical eye drops face multiple challenges, including limited bioavailability and repetitive administration. The present study aimed to prepare, evaluate, and compare film-structured and nanofibrous ocular inserts using biocompatible polymers of polyvinyl alcohol (PVA) and polycaprolactone (PCL) to achieve sustained ciprofloxacin Hydrochloride (CIP) delivery. The nanofibrous formulations were prepared by electrospinning and glutaraldehyde crosslinking while the film formulation was prepared by solvent casting. Nanofibrous inserts had mean diameters in the range 330–450 nm. Both film and nanofibrous inserts were strong, although the nanofibers had higher flexibility. In vitro antibacterial efficacy against Staphylococcus aureus and Escherichia coli was observed for all formulations and cell viability of more than 70% confirmed their non-toxicity. In vitro release studies showed prolonged release of 2 days for the film and 5 days for the nanofibers compared with a 10-h release of CIP from the eye drop. Pharmacokinetic studies of rabbits’ eyes showed 4.5–5-folds higher AUC for the nanofiber formulations compared with the eye drop. Thus, prolonged-release film-structured and nanofibrous inserts are suitable carriers for ocular delivery of CIP