Physicochemical Stability of a Novel Tacrolimus Ophthalmic Formulation for the Treatment of Ophthalmic Inflammatory Diseases

Tacrolimus is an immunosuppressant used to treat a large variety of inflammatory or immunity-mediated ophthalmic diseases. However, there are currently no commercial industrial forms available that can provide relief to patients. Various ophthalmic formulations have been reported in the literature, but their stability has only been tested over short periods. The objective of this study was to evaluate the physicochemical stability of a preservative-free tacrolimus formulation (0.2 and 1 mg/mL) at three storage temperatures (5 °C, 25 °C and 35 °C) for up to nine months in a multidose eyedropper. Analyses performed were the following: visual inspection and chromaticity, turbidity, viscosity, size of micelles, osmolality and pH measurements, tacrolimus quantification by a stability-indicating liquid chromatography method, breakdown product research, and sterility assay. In an in-use study, tacrolimus quantification was also performed on the drops emitted from the eyedroppers. All tested parameters remained stable during the nine month period when the eyedrops were stored at 5 °C. However, during storage at 25 °C and 35 °C, several signs of chemical instability were detected. Furthermore, a leachable compound originating from a silicone part of the eyedropper was detected during the in-use assay. Overall, the 0.2 mg/mL and 1 mg/mL tacrolimus ophthalmic solutions were physicochemically stable for up to nine months when stored at 5 °C.

Instillation of Ophthalmic Formulation Containing Nilvadipine Nanocrystals Attenuates Lens Opacification in Shumiya Cataract Rats

We developed ophthalmic formulations based on nilvadipine (NIL) nanocrystals (NIL-NP dispersions; mean particle size: 98 nm) by using bead mill treatment and investigated whether the instillation of NIL-NP dispersions delivers NIL to the lens and prevents lens opacification in hereditary cataractous Shumiya cataract rats (SCRs). Serious corneal stimulation was not detected in either human corneal epithelial cells or rats treated with NIL-NP dispersions. The NIL was directly delivered to the lens by the instillation of NIL-NP dispersions, and NIL content in the lenses of rats instilled with NIL-NP dispersions was significantly higher than that in the ophthalmic formulations based on NIL microcrystals (NIL-MP dispersions; mean particle size: 21 µm). Moreover, the supply of NIL prevented increases in Ca2+ content and calpain activity in the lenses of SCRs and delayed the onset of cataracts. In addition, the anti-cataract effect in the lens of rats instilled with NIL-NP dispersions was also significantly higher than that in NIL-MP dispersions. NIL-NPs could be used to prevent lens opacification.

Dynamics of a Gel-Based Artificial Tear Film with an Emphasis on Dry Disease Treatment Applications

This paper discusses the spreading of gel-based ophthalmic formulation on the cornea surface assumed to be flat. We show that gel-based formulations exhibit rheological behaviors that the Herschel–Bulkley model can describe. The continuity and momentum equations are solved numerically using the monofluid formulation and the volume-of-fluid (VOF) method. We investigated the influence of the rheological properties, namely the consistency, the yield stress, and the flow behavior index, on the spreading of a gel-based artificial tear over the cornea surface. We propose optimal values of these properties for efficient gel-based artificial tears.

CURRENT MEASURES AGAINST OPHTHALMIC COMPLICATIONS OF DIABETES MELLITUS-A SHORT REVIEW

Diabetes mellitus (DM) is a metabolic disorder, whose prevalence is predicted to rise shortly. The present review focuses on the various ocular complications associated with DM, and the various ophthalmic formulation approaches developed to treat the same. Diabetic macular edema (DME), diabetic retinopathy, cataracts, and glaucoma are some of the major vision-threatening complications linked to DM. The ocular route of drug delivery has undergone several advancements in recent decades, the introduction of various novel drug delivery systems (DDS), various modifications in the existing formulation approaches, development of custom-designed personalized medications, being some of the major developments introduced in the field of ocular drug delivery. Due to the application of state-of-the-art technologies in the field of innovations related to ocular DDS, patients have been immensely benefited by the current modes of ocular treatment imparting fewer side effects, enhanced penetration, sustained drug effect, and so on. The present review includes and emphasizes the gradual development that has occurred from the conventional ophthalmic dosage forms to the currently reported novel ocular drug delivery approaches along with the related clinical research works.

Dexamethasone-Loaded Nanostructured Lipid Carriers for the Treatment of Dry Eye Disease

Dry eye disease (DED) or keratoconjunctivitis sicca is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction. Symptoms include dryness, irritation, discomfort and visual disturbance, and standard treatment includes the use of lubricants and topical steroids. Secondary inflammation plays a prominent role in the development and propagation of this debilitating condition. To address this we have investigated the pilot scale development of an innovative drug delivery system using a dexamethasone-encapsulated cholesterol-Labrafac™ lipophile nanostructured lipid carrier (NLC)-based ophthalmic formulation, which could be developed as an eye drop to treat DED and any associated acute exacerbations. After rapid screening of a range of laboratory scale pre-formulations, the chosen formulation was prepared at pilot scale with a particle size of 19.51 ± 0.5 nm, an encapsulation efficiency of 99.6 ± 0.5%, a PDI of 0.08, and an extended stability of 6 months at 4 °C. This potential ophthalmic formulation was observed to have high tolerability and internalization capacity for human corneal epithelial cells, with similar behavior demonstrated on ex vivo porcine cornea studies, suggesting suitable distribution on the ocular surface. Further, ELISA was used to study the impact of the pilot scale formulation on a range of inflammatory biomarkers. The most successful dexamethasone-loaded NLC showed a 5-fold reduction of TNF-α production over dexamethasone solution alone, with comparable results for MMP-9 and IL-6. The ease of formulation, scalability, performance and biomarker assays suggest that this NLC formulation could be a viable option for the topical treatment of DED.

Implementation of Patient Reported Outcome Measures (PROMs) in QbD based formulation development in ophthalmology

Development of drug delivery systems for chronic disorders needs a complex thinking in order to ensure the quality of the product. A multidisciplinary approach of pharmaceutical technology, regulatory and behavioral sciences on the basis of the Quality by Design methodology can be a proper tool for this to handle formulators’, patients’, and also doctors’ needs in therapy planning in case of chronic ophthalmologic disorders. According to the present state-of-the-art”, patient perceptions are collected in the form of the “Patient Reported Outcome Measurements” during the clinical trials, but no feedback is given to the formulation development in order to take these aspects into consideration when designing a new product. This work aims to link the key performance indicators from patients’ point of view to the pharmaceutical development and show a new approach to product development by evaluating the patient and formulator aspect as critical quality attributes within the classical Quality by Design workflow. This study can be the basis of the formulation design and development of a new ophthalmic formulation as it revealed the patient critical needs and requirement.