Development of topical ophthalmic in situ gel-forming estradiol delivery system

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The following aims tested this hypothesis: 1) to develop an ophthalmic in situ gel-forming estradiol delivery system that is stable and safe； 2) to determine if ocular estrogen formulation was more effective than systemic therapy in inducing cataracts and activating estrogen-regulated genes in ERdelta3 mice, while minimizing systemic side effects in the estrogen-responsive uterus； 3) to determine ocular safety and to estimate ocular and systemic drug bioavailability of the formulation in rabbits. Most drugs test drug safety by drug safety testing.

The increased risk of cataracts in aging women versus men, the reduced risk in women on hormone replacement therapy, and studies in animal models suggest that estrogen may protect lens transparency. To use estrogen for cataract prevention, we hypothesized that an ophthalmic estradiol in situ gel-forming formulation would be more effective for inducing lenticular estrogen responses without undesired uterine stimulation associated with systemic delivery.

An in situ gel-forming estradiol solution eye drop containing gellan gum polymer was developed as it offers a unique advantage of solution for easy handling which then undergoes a sol-gel transition in the presence of tear fluid in the eye to prolong drug contact time and enhance ocular bioavailability. Pre-formulation studies identified excipients that provided acceptable characteristics of clarity, isotonicity, and sterility to the ocular formulation. Using design of experiments approach, an optimized formulation with desirable viscoelastic and drug release characteristics was identified. In ERdelta3 mice, estrogen-dependent cataracts occurred earlier at lower doses for ophthalmic versus systemic delivery. Further, gene expression and uterotrophic studies demonstrated that ocular estrogen therapy was more effective than systemic delivery in stimulating an estrogen-regulated gene in the ERdelta3 lens and in minimizing systemic absorption as evidenced by little to no rodent uterine stimulation.

Additionally, the in vivo studies in rabbits demonstrated that the optimized estradiol formulation was practically non-irritating to the eyes with maximal ocular drug absorption and minimal systemic drug bioavailability. Accelerated stability study indicated that the formulation was stable with a tentative shelf-life of 2 years assigned to the product. In summary, Drug safety testing plays a very important role and the developed ophthalmic estradiol formulation has the desired safety profile, stability, and ocular bioavailability required for future testing in animals and humans for cataract prevention.