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 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

Development of Controlled-Release microspher Systems containing gentamycin for ophthalmic drug delivery: Preparation and Release Characteristics

Introduction: Targeting the therapeutic agents to the anterior and posterior segments of the eye has attracted extensive attention from the scientific community. Significant key factor in the success of ocular therapy is the development of safe, effective, economic and non-invasive novel drug delivery systems.  Microspheres of poly carbolactone(PCL) and poly ethylene glycol containing gentamycine were prepared by a solvent diffusion-evaporation method as non-invasive ocular drug delivery systems.Methods: The oil-in-water emulsion prepared in an aqueous solution of 0.05% poly(vinyl alcohol) medium with PCL and PEG , a water-soluble and less toxic solvent, was used as the dispersing solvent. The yield of the microspheres was up to 80%. Result: Scanning electron microscopy (SEM) confirmed the microspheres had smooth surfaces, with sizes in the range of 489–550 μm. The drug loaded in microspheres was in an amorphous state, as confirmed by differential scanning microscopy (DSC). The release of the drugs was controlled for 2-7 days. The release kinetics followed different transport mechanisms depending on the drug to polymer ratio. Based on microbial assay of antibiotic test the microspheres showed excellent antibacterial activity against Staphylococcus aureus. Conclusion: Therefore, a floating dosage form that is able to sustain release hydrophilic drugs within its extended retention time has been developed. We will be able to manufacture biodegradable biomimetic microsphere for long-term drug delivery of gentamycine  in ocular

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

Preparation and Characterization of Alginate and Psyllium Beads Containing Lactobacillus acidophilus

This paper describes preparation and characterization of beads of alginate and psyllium containing probiotic bacteria of Lactobacillus acidophilus DMSZ20079. Twelve different formulations containing alginate (ALG) and alginate-psyllium (ALG-PSL) were prepared using extrusion technique. The prepared beads were characterized in terms of size, morphology and surface properties, encapsulation efficiency, viabilities in acid (pH 1.8, 2 hours) and bile (0.5% w/v, 2 hours) conditions, and release in simulated colon pH conditions. The results showed that spherical beads with narrow size distribution ranging from 1.59 ± 0.04 to 1.67 ± 0.09 mm for ALG and from 1.61 ± 0.06 to 1.80 ± 0.07 mm for ALG-PSL with encapsulation efficiency higher than 98% were achieved. Furthermore, addition of PSL into ALG enhanced the integrity of prepared beads in comparison with ALG formulations. The results indicated that incorporation of PSL into alginate beads improved viability of the bacteria in acidic conditions as well as bile conditions. Also, stimulating effect of PSL on the probiotic bacteria was observed through 20-hour incubation in simulated colonic pH solution. According to our in vitro studies, PSL can be a suitable polymer candidate for partial substitution with ALG for probiotic coating

Optimization of a Self-microemulsifying Drug Delivery System for Oral Administration of the Lipophilic Drug, Resveratrol: Enhanced Intestinal Permeability in Rat

Purpose: This study aimed to formulate Resveratrol, a practically water-insoluble antioxidant in a self-microemulsifying drug delivery system (SMEDDS) to improve the solubility, release rate, and intestinal permeability of the drug. Methods: The suitable oil, surfactant, and co-surfactant were chosen according to the drug solubility study. Utilizing the design of experiment (DoE) method, the pseudo-ternary phase diagram was plotted based on the droplet size. In vitro dissolution study and the single-pass intestinal perfusion were performed for the investigation of in vitro and in-situ permeability for drugs formulated as SMEDDS in rat intestine using High-Performance Liquid Chromatography. Results: Castor oil, Cremophor RH60, and PEG 1500 were selected as oil, surfactant, and co-surfactant. According to the pseudo-ternary phase diagram, nine formulations developed microemulsions with sizes ranging between 145-967 nm. Formulations passed the centrifuge and freeze-thaw stability tests. The optimum formulation possessed an almost 2.5-fold higher cumulative percentage of in vitro released resveratrol, in comparison to resveratrol aqueous suspension within 120 minutes. The results of the in-situ permeability study suggested a 2.6-fold higher intestinal permeability for optimum formulation than that of the resveratrol suspension. Conclusions: SMEDDS can be considered suitable for the oral delivery of resveratrol according to the observed increased intestinal permeability, which could consequently enhance the bioavailability and therapeutic efficacy of the drug

Metronidazole-and amoxicillin-loaded plga and pcl nanofibers as potential drug delivery systems for the treatment of periodontitis: in vitro and in vivo evaluations

The purpose of this study was to prepare poly (D-L) lactide-co-glycolide (PLGA) and poly ε-caprolactone (PCL) nanofibers containing metronidazole and amoxicillin using an electrospinning process as intrapocket sustained-release drug delivery systems for the treatment of periodontal diseases. Scanning electron microscopy showed that the drug containing PLGA and PCL nanofibers produced from the electrospinning process was uniform and bead-free in morphology. The obtained nanofibers had a strong structure and resisted external tension according to the tensiometry results. The cytotoxicity results indicated acceptable cell viability (>80%). Quantification by high-performance liquid chromatography showed almost complete in vitro drug release between 7 and 9 days, whereas 14 days were required for complete drug release in vivo. No significant signs of irritation or inflammatory reaction were detected after three weeks of subcutaneous implantation of nanofibers in the animal models, thus indicating suitable compatibility. The results therefore suggest that the designed nanofibers can be used as potential commercial formulations in the treatment of periodontitis as controlled-release intrapocket drug delivery systems that can increase patient compliance. This is due to their ability to reduce the frequency of administration from three times daily in a systemic manner to once weekly as local 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

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

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