Evaluating the solubility of compounds intended for intramammary infusion based upon tests conducted across a range of milk matrices.

The ability to evaluate drug solubility in milk and milk-related products has relevance both to human and veterinary medicine. Model compounds explored in a previous investigation focused on drug solubility assessments when delivered in milk-associated vehicles for administration to human patients. In the current investigation, we focus on the solubility of drugs intended for delivery via intramammary infusion to cattle. Because there are logistic challenges typically associated with obtaining raw milk samples for these tests, there is a need to determine potential alternative media as a substitute for raw bovine milk. Given the complexity of the milk matrix, aqueous media do not reflect the range of factors that could impact these solubility assessments. This led to the current effort to explore the magnitude of differences that might occur when substituting raw bovine milk with off-the-shelf milk products such as whole milk, skim milk, or reconstituted whole milk powder. We considered conclusions based upon the solubility assessments derived from the use of the model compounds studied in our previous report and compared them to conclusions obtained when testing two drugs with differing physicochemical characteristics that are approved for administration via bovine intramammary infusion: cephapirin benzathine and cephapirin sodium. Based upon these results, we recommend that whole milk or reconstituted whole milk can substitute for bovine raw milk for the solubility assessment of compounds intended for administration via intramammary infusion. However, unlike the human drug situation, these tests should be conducted at 38°C.

Dose Uniformity of Loteprednol Etabonate (Submicron) Ophthalmic Gel 0.38% Compared with Prednisolone Acetate Ophthalmic Suspension 1.

INTRODUCTION: Loteprednol etabonate (submicron) ophthalmic gel 0.38% (LE SM gel 0.38%) is a corticosteroid formulation designed to retain the nonsettling characteristics of loteprednol etabonate ophthalmic gel 0.5%, but with reduced drug particle size to improve ocular penetration, allowing for reduced dosing frequency. This study compared the dose uniformity of LE SM gel 0.38% with branded and generic prednisolone acetate (PA) 1% suspensions under simulated in-use dosing conditions. METHODS: Drug concentrations in drops of LE SM gel 0.38% and PA 1% suspensions, expressed from bottles that were shaken or not shaken, were determined during 2 weeks of simulated on-label dosing (LE SM gel 0.38%: three times daily; PA suspensions: four times daily). Sedimentation of drug particles was assessed for each product using dispersion analysis. RESULTS: The mean (SD) percent declared drug concentration of LE SM gel 0.38% over 2 weeks was 103.2% (1.3%) when the drug was dispensed from shaken bottles and 103.3% (1.5%) when dispensed from unshaken bottles. However, for branded and generic PA suspensions, mean (SD) percent declared concentrations were 102.2% (1.4%) and 98.3% (2.9%), respectively, when dispensed from shaken bottles; and 89.2% (18.6%) and 78.3% (13.5%), respectively, when dispensed from unshaken bottles. Dispersion analysis showed that drug particles in LE SM gel 0.38% remained fully suspended under accelerated sedimentation conditions, whereas both branded and generic PA suspension drug particles settled out of suspension. CONCLUSIONS: LE SM gel 0.38% delivered the drug consistently at the declared concentration over the entire 2 weeks of simulated in-use dosing conditions, regardless of whether the drug was dispensed from shaken or unshaken bottles. However, both branded and generic PA suspensions required the bottle to be shaken to provide a consistent drug concentration.

Development of a non-settling gel formulation of 0.5% loteprednol etabonate for anti-inflammatory use as an ophthalmic drop.

The eye has protective barriers (ie, the conjunctival and corneal membranes) and defense mechanisms (ie, reflex tearing, blinking, lacrimal drainage) which present challenges to topical drug delivery. Topical ocular corticosteroids are commonly used in the treatment of anterior segment diseases and inflammation associated with ocular surgery, and manufacturers continually strive to improve their characteristics. We describe the development of a novel ophthalmic gel formulation of loteprednol etabonate (LE), a C-20 ester-based corticosteroid with an established safety profile, in the treatment of ocular inflammatory conditions. The new LE gel formulation is non-settling, eliminating the need to shake the product to resuspend the drug, has a pH close to that of tears, and a low preservative concentration. The rheological characteristics of LE gel are such that the formulation is instilled as a drop and transitions to a fluid upon instillation in the eye, yet retains sufficient viscosity to prolong ocular surface retention. The new formulation provides consistent, uniform dosing as evidenced by dose extrusion studies, while pharmacokinetic studies in rabbits demonstrated rapid and sustained exposure to LE in ocular tissues following instillation of LE gel. Finally, results from two clinical studies of LE gel in the treatment of postoperative inflammation and pain following cataract surgery indicate that it was safe and effective. Most patients reported no unpleasant drop sensation upon instillation, and reports of blurred vision were rare.

Safety of repeated topical ocular administration of a polycarbophil-based formulation in several models of ocular surgery in rabbits.

PURPOSE: To evaluate the safety of the polycarbophil-based formulation Durasite in rabbits when administered chronically to intact eyes and acutely to eyes compromised by a corneal epithelial defect, penetrating corneal incision, or laser in situ keratomileusis (LASIK) flap. The rheological properties were evaluated to characterize the behavior of the formulation on the ocular surface. SETTING: Bausch & Lomb, Rochester, New York, USA. DESIGN: Experimental study. METHODS: Intact eyes of albino rabbits received polycarbophil (0.6% or 1.3%) 3 times a day for 1 year. The compromised models using polycarbophil 0.9% were an epithelial defect, penetrating corneal incision, or LASIK flap. Eyes with the epithelial defects were dosed 10 times for 24 hours and then 2 times a day for 2 days, and the defect was monitored with fluorescein. The incision or LASIK eyes were dosed 4 times a day for 11 days starting the day before surgery, with 1 drop just before the surgical procedure. The eyes were examined microscopically. The rheological properties were evaluated using a controlled-stress rheometer with a synthetic tear fluid. RESULTS: No adverse ocular or systemic effects were observed with polycarbophil after chronic administration. In the compromised models, there were no adverse effects of the polycarbophil. There was no evidence of an anterior chamber reaction or qualitative effects on the corneal endothelium. Rheologically, the polycarbophil-based formulation behaved as a sheer-thinning fluid under physical conditions similar to the ocular surface. CONCLUSION: Results suggest that the polycarbophil-based formulation, like other shear-thinning formulations, is safe to use in topical ophthalmic pharmaceutical products indicated for chronic use and for treatment of conditions with compromise of the ocular surface.