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.

Efficacy and Safety of Loteprednol 0.5% and Fluorometholone 0.1% After Strabismus Surgery in Children.

PURPOSE: To compare the effects of topical loteprednol and fluorometholone in children who underwent strabismus surgery. METHODS: This is a retrospective observational case series. A total of 60 Korean children who underwent strabismus surgery between January 2016 and September 2016 were included. Patients were prescribed topical loteprednol etabonate 0.5% or fluorometholone 0.1% until 3 weeks after surgery. Four parameters (intraocular pressure [IOP], conjunctival injection, conjunctival inflammation, and patient discomfort) were assessed every week for up to 4 weeks after surgery. Main outcome measures were comparison of parameters between the 2 groups at each following week after surgery. In addition, factors associated with clinically meaningful IOP elevation were evaluated. RESULTS: IOP was significantly elevated at the second and third postoperative week compared with baseline (P = 0.028 and 0.001) in the loteprednol group but not significantly in the fluorometholone group. The mean IOP of the loteprednol group at 1 and 3 weeks after surgery were significantly higher than that of the fluorometholone group (P = 0.032 and 0.017, respectively). Multivariate analysis revealed that age ≤8 years (odds ratio 14.52, 95% confidence interval 1.16-139.05) was associated with IOP >21 mmHg. There was no significant difference between the 2 groups in patient discomfort, conjunctival inflammation, and conjunctival injection. CONCLUSIONS: Loteprednol and fluorometholone showed similar anti-inflammatory effect after strabismus surgery in children. Loteprednol appeared to have more effect on IOP elevation than fluorometholone, especially in children ≤8 years of age. When treating young patients with loteprednol, clinicians should be aware of IOP elevation.

Effect of topical loteprednol etabonate with lid hygiene on tear cytokines and meibomian gland dysfunction in prosthetic eye wearers.

PurposeTo assess tear cytokine levels and clinical outcomes in meibomian gland dysfunction (MGD) in the blind eye of patients wearing an ocular prosthesis after 2 months of treatment with topical loteprednol etabonate and eyelid scrubs with warm compresses.Patients and methodsThis study included patients with MGD wearing a unilateral ocular prosthesis for more than 1 year. All patients topically received 0.5% loteprednol etabonate and were instructed to scrub their eyelids with warm compresses on the prosthetic eye for 2 months. We evaluated tear cytokine levels using Multiplex Bead Immunoassays, performed biomicroscopic examination of the lid margins and meibomian gland, conducted meibography imaging, and assessed MGD-related ocular symptoms using a questionnaire for the prosthetic eye before and 2 months after treatment.ResultsThirty consecutive patients were included. There were significant reductions in the levels of interleukin (IL)-6, interferon-γ, monocyte chemotactic protein-1, IL-8, tumor necrosis factor-α, and IL-1ß (P<0.001 for each cytokine). Moreover, there were improvements in ocular symptoms (P=0.001), lid margin abnormalities (P<0.001), meibomian gland expressibility (P<0.001) and meibography findings (P=0.037).ConclusionTopical loteprednol etabonate in conjunction with eyelid scrubs and warm compresses were effective in treating MGD in prosthetic eye wearers. Furthermore, tear cytokine measurements may serve as an additional approach for evaluating the efficacy of anti-inflammatory treatment for MGD in prosthetic eye wearers.

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.

Impact of the Topical Ophthalmic Corticosteroid Loteprednol Etabonate on Intraocular Pressure.

Corticosteroids are a mainstay therapeutic option for the treatment of ocular inflammation. However, safety remains a concern for clinicians, particularly with long-term use. Though highly effective at suppressing inflammatory and allergic responses, topical ophthalmic corticosteroids carry an inherent risk of side effects, including elevated intraocular pressure (IOP), a risk factor for the development of glaucoma. The corticosteroid loteprednol etabonate (LE) contains an ester rather than a ketone at the C-20 position, minimizing the potential for side effects, including IOP elevation. In early pivotal clinical trials of LE ophthalmic suspension for conjunctivitis (allergic, giant papillary), anterior uveitis, and post-operative inflammation, LE had minimal impact on IOP over short-term (<28 days) and long-term (≥28 days) use. Since then, new LE formulations-including a gel, an ointment, and a suspension of LE in combination with tobramycin-have become commercially available. Multiple studies evaluating the safety and efficacy of LE for inflammatory conditions have been reported, including those requiring longer-term treatment such as photorefractive keratectomy, corneal transplantation, and dry eye disease. We review the available published data on the effect of LE on IOP and report on the cumulative incidence of clinically significant IOP elevations (≥10 mm Hg from baseline) with short-term and long-term LE use. In all studies, LE consistently demonstrated a low propensity to elevate IOP, regardless of formulation, dosage regimen, or treatment duration, including in known steroid responders. The cumulative proportion of patients exhibiting clinically significant IOP increases was 0.8% (14/1725 subjects) in studies evaluating short-term LE treatment and 1.5% (21/1386 subjects) in long-term studies. Furthermore, use of LE was associated with significantly lower rates of IOP elevation ≥10 mm Hg as compared to prednisolone acetate or dexamethasone (when used in combination with tobramycin). The cumulative data to date substantiates a favorable IOP-safety profile for LE with both short-term and long-term use.