Novel approaches for improving stability of cysteamine formulations

Cystinosis is a genetic disorder that leads to the formation of cystine crystals in many organs in the body including cornea. Ocular manifestation of this disease is treated by eye drops of cysteamine which can easily oxidize into its disulfide cystamine. The rapid oxidation limits the shelf life as well the duration during which the drug can be used after opening the eye drop bottle. We evaluate two approaches of preventing the oxidation of cysteamine with the goal of increasing the time of use after opening the bottle to one month. The first approach integrates antioxidants such as catalase enzyme and vitamins C and E into the aqueous solution. Results show that catalase is the most effective additive as it decreases the oxidation rate by 58%, which on its own is not sufficient to reach targeted one month stability. The second approach focuses on incorporating diffusion barriers to prevent oxygen from reaching the cysteamine solution. This was accomplished by two methods: formulation of a hydrophobic layer which floats on the surface of the aqueous solution and integration of OMAC (R) oxygen-resistant material into the eye drop bottle. Both methods delay the onset of cysteamine degradation and decrease the rate of degradation. In particular, an eye drop bottle with three layers of OMAC (R) has less than 10% degradation after one month of opening the bottle and withdrawing a drop each day. By integrating all three methods, we designed a system where > 90% of cysteamine remains in the active form for 70 days after opening the bottle. In addition, we examine the use of OMAC (R) as heat-sealed pouches for storage of cysteamine eye drop bottles during packaging to eliminate the need for the current approach of freezing the formulation during shipping. The results show that such heat-sealed pouches would keep cysteamine stable for over one year at ambient conditions.