Toxicity of Insulin Administered Chronically to Human Eye In Vivo

Abstract

Insulin administered in eyedrop from with a surfactant agent has been shown to be clinically effective in treating diabetes in animal models. Concentrations of insulin as high as 100 U/ml in saline were shown to produce no detectable clinical toxicity to human eyes in single-dose administration. We sought to investigate the local toxicity of insulin in human eyes during longterm, multidose administration. A prospective, randomized, placebo controlled, double-masked study was conducted involving eight healthy volunteers. Subjects were given 50 pi sterile saline containing 100 U/ml crystalline porcine insulin randomized to one eye and 50 pi placebo (sterile saline) to the fellow eye administered twice daily for 8 weeks. Subjective ocular irritation and visual acuity and objective assessment of the eyelids, conjunctiva, comea, anterior chamber, crystalline lens, pupil size, and intraocular pressure were evaluated. Blood D-glucose levels were monitored to assess glycémie levels. There was no statistically significant difference (p>0.05) observed between insulin-treated and placebo-treated eyes. Eyedrops containing insulin were subjectively as comfortable and objectively as clinically innocuous as sterile saline alone. The results of this study demonstrate that insulin (100 U/ml) in saline is nontoxic to the human eye after long-term, multi-dose exposure. Topical administration of insulin combined with an absorption-promoting agent may be a practical and feasible alternative to multiple daily subcutaneous injections or implanted pump devices currently used in the long-term treatment of diabetes mellitus if a nonirritating absorption-promoting agent can be identified. Further studies are warranted to determine the toxicity and efficacy of these absorption-promoting agents in humans and to develop an eyedrop formulation that maximizes safety, efficacy and compliance in patients with diabetes mellitus.

Effect of Brij-78 on Systemic Delivery of Insulin from an Ocular Device

“…The results from this experiment agree with previous studies [1][2][3][4][5][6][7][8][9][10] in that the systemic absorption of insulin through the eye is facilitated by the surfactant in the formulations. However, the amount of enhancer (20 µg) is much less than in previous studies that required at least 250 µg of enhancer per dose of eyedrop solution.…”

“…The pharmaceutical aspects of these eyedrops, such as the absorption site for insulin, 1 the role of absorption enhancers, [1][2][3][4][5][6][7][8][9][10] and the correlation between its pharmacokinetics and pharmacodynamics, 1,10 have been well established. The latter allows scientists to easily quantitate the release of insulin by monitoring the changes in blood glucose levels.…”

Use of Topical Insulin to Normalize Corneal Epithelial Healing in Diabetes Mellitus

“…Moreover, insulin administered long-term to the human eye at concentrations of up to 100 U/mL for 8 weeks in isotonic sodium chloride solution has been shown not to be toxic. 21 Finally, an additional advantage of using topical ocular administration of insulin in corneal epithelial wound healing of diabetic cases is that it avoids difficulties in converting the dosage needed for the rat to the human based on such factors as surface area, blood volume, and body mass. Thus, the novel findings in the present study showing that topical insulin is efficacious for restoring normal reepithelialization in the rat support the need for clinical trials using this strategy.…”

A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases

“…Generally an absorption enhancer is required for the systemic absorption of insulin delivered by the ocular route. [97][98][99][100][101][102][103][104][105][106][107][108][109][110][111] Lee and coworkers 96 showed that the device could provide a uniform blood glucose reduction over 8 h with the aid of Brij-78 as an absorption enhancer. Furthermore, this group also showed that similar results could be obtained from enhancer-free devices to which acetic acid had been added and removed by evaporation.…”