Prolonged Release Niosomes For Ocular Delivery of Loteprednol: Ocular Distribution Assessment on Dry Eye Disease Induced Rabbit Model.

Loteprednol etabonate (LE) is a topical corticosteroid for the symptomatic management of ocular conditions, encompassing both allergic and infectious etiologies. Owing to the dynamic and static barriers of the eye, LE exhibits significantly low bioavailability, necessitating an increase in the frequency of drug administration. The objective of this study is to overcome the limitations by developing niosomal systems loaded with LE. Design of Experiments (DoE) approach was used for the development of optimal niosome formulation. The optimal formulation was characterized using DLS, FT-IR, and DSC analysis. In vitro and ex vivo release studies were performed to demonstrate drug release patterns. After that HET-CAM evaluation was conducted to determine safety profile. Then, in vivo studies were carried out to determine therapeutic activity of niosomes. Zeta potential (ZP), particle size, polydispersity index (PI), and encapsulation efficacy (EE) were -33.8 mV, 89.22 nm, 0.192, and 89.6%, respectively. Medicated niosomes had a broad distribution within rabbit eye tissues and was absorbed by the aqueous humor of the bovine eye for up to 6 h after treatment. Cumulative permeated drug in the bovine eye and rabbit eye were recorded 52.45% and 54.8%, respectively. No irritation or hemorrhagic situation was observed according to the results of HET-CAM study. Thus, novel LE-loaded niosomal formulations could be considered as a promising treatment option for the dry-eye-disease (DED) due to enhanced bioavailability and decreased side effects.

Rheological Properties, Dissolution Kinetics, and Ocular Pharmacokinetics of Loteprednol Etabonate (Submicron) Ophthalmic Gel 0.38.

Purpose: To evaluate rheological properties, in vitro dissolution, and in vivo ocular pharmacokinetics of loteprednol etabonate (LE) (submicron) ophthalmic gel 0.38%. Methods: The viscosity of the LE gel 0.38% formulation was measured with a controlled stress rheometer. Dissolution kinetics were evaluated in a fixed-volume and flow-through assay. Rabbits received a single instillation of LE (submicron) gel 0.38% (both eyes), and concentrations of LE in ocular tissues were determined through 24 h by liquid chromatography with tandem mass spectrometry. Where indicated, comparators included micronized LE gel 0.38%, 0.5% (Lotemax® gel), and 0.75%. Results: LE (submicron) gel 0.38% exhibited shear-thinning characteristics similar to LE gel 0.5% with nearly identical yield stress. LE (submicron) gel 0.38% released 2.6-fold more LE into the dissolution medium than micronized LE gel 0.5% over 30 s in the fixed-volume dissolution assay, and submicron LE attained higher concentrations of dissolved LE than micronized LE gel 0.38% in the flow-through dissolution assay. In rabbits, the maximal concentration and area-under-the-curve over 24 h for LE in aqueous humor were 2.5- and 1.8-fold higher, respectively, for LE (submicron) gel 0.38% versus micronized LE gel 0.5% (both P < 0.001). Pharmacokinetic parameters were similar for most other tissues. Conclusions: LE (submicron) gel 0.38% demonstrated similar rheological properties to micronized LE gel 0.5% but faster dissolution, thus providing similar or higher LE concentrations in the aqueous humor, cornea, and iris-ciliary body after ocular dosing in rabbits despite a lowered concentration of drug in the formulation.

Development of simultaneous quantification method of loteprednol etabonate (LE) and its acidic metabolites, and analysis of LE metabolism in rat.

Loteprednol etabonate (LE) is a soft corticosteroid with two labile ester bonds at 17α- and 17ß-positions. Its corticosteroidal activity disappears upon hydrolysis of either ester bond. Hydrolysis of both ester bonds produces the inactive metabolite, Δ1-cortienic acid (Δ1-CA). The simple high-performance liquid chromatography method using acetic acid gradient was developed for the simultaneous determination of LE and its acidic metabolites. LE was hydrolyzed in rat plasma with a half-life of 9 min. However, LE hydrolysis was undetectable in rat liver and intestine. LE hydrolysis in rat plasma was completely inhibited by paraoxon and bis(p-nitrophenyl) phosphate, thus identifying carboxylesterase as the LE hydrolase. Rat plasma carboxylesterase had a Km of 6.7 µM for LE. In contrast to the disappearance rate of LE in rat plasma, the formation rate of 17α-monoester and Δ1-CA was markedly low, and a main hydrolysate of LE was not detected in rat plasma. The metabolism of LE proceeded via different pathways in human and rat plasma. LE was slowly hydrolyzed by paraoxonase in human plasma to 17α-monoester with a half-life of 12 h, but by carboxylesterase in rat plasma to yield undetectable products, presumed to include the unstable 17ß-monoester.

PLGA nanoparticles for ocular delivery of loteprednol etabonate: a corneal penetration study.

The purpose of the present study was to develop loteprednol etabonate (LE) loaded poly(d,l-lactide co-glycolide) (PLGA) nanoparticles (NPs) and study their penetration profile into the excised goat cornea. In the present study, LE loaded PLGA NPs were prepared by solvent evaporation with high speed homogenization method and the penetration profile was studied using confocal laser scanning microscopy (CLSM). Rhodamine (Rd) was used as a fluorescent marker to prepare Rd-LE-PLGA-NPs. The NPs were characterized for particle size, X-ray diffraction (XRD), differential scanning calorimetry (DSC), transmission electron microscopy (TEM), drug entrapment, and permeation profile. Intense fluorescence observed across the depths of goat corneal tissue suggested an improved penetration profile of NPs. The entrapment efficiency and mean diameter of the optimized formulation (F5) were found to be 96.31 ± 1.68% and 167.6 ± 0.37 nm, respectively. These findings indicate that LE loaded PLGA NPs may serve as a potential drug carrier for ocular administration in eye disease.

Potential Use of Cyclodextrin Complexes for Enhanced Stability, Anti-inflammatory Efficacy, and Ocular Bioavailability of Loteprednol Etabonate.

Loteprednol etabonate (LE) is a soft corticosteroid that maintains therapeutic activity with much reduced adverse effects. Yet, its ocular bioavailability is hindered by its poor aqueous solubility. Early attempts of LE complexation with cyclodextrins (CDs) did not involve the study of the effects of various complexation methods on the characteristics of the complexes formed. Formulation of complexes into different delivery systems as well in vitro and in vivo assessments has not been accomplished in the earlier studies. In this study, complexation of LE with each of hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and ß-cyclodextrin (ß-CD) by kneading, freeze drying, and co-precipitation was attempted. These complexes were incorporated into gels, drops, and ocuserts using hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), and sodium alginate (ALG). These formulae were examined with respect to drug content, pH, viscosity, in vitro release, and stability for 6 months. Kinetic analysis of release data was done. Selected formulations were assessed for their efficacy in the treatment of ocular allergic conjunctivitis and their ocular bioavailability in rabbits' eyes. All formulations exhibited accepted drug content, pH, and viscosity. The drug release was increased by complexation particularly with HP-ß-CD in the order of ocuserts ≥ drops > gels, being the highest for HPMC preparations that also exhibited the greatest stability and anti-inflammatory activity especially in case of LE-HP-ß-CD complexes. Ocuserts of co-precipitated LE-HP-ß-CD using HPMC (5% w/w) and Carbopol 934P (0.1% w/w) provided a significantly enhanced stability (p < 0.05), ocular anti-inflammatory efficacy (p < 0.05), and ocular bioavailability (p < 0.0001), to be represented as a potential ocular delivery system of LE.