Container-content interactions: ophthalmic drugs and multi dose flasks

Conservative free ophthalmic formulations need to be packaged either as single doses, or using specially designed sterility preserving multi dose eyedroppers. Our objective was to evaluate potential content-container interactions between a device with a silicone sterility preserving membrane and the emitted drops of several ophthalmic solutions.

Latanoprost (0.05 mg/ml) and a micellar solution of cyclosporine (1, 10 and 20 mg/ml) were used as model drugs. Quantification of the active substance in emitted drops (1 to 2 drops per day) from low density polyethylene (LDPE) bottles without any sterility preserving device and from LDPE bottles with a sterility preserving silicone membrane (LDPE-Si) was performed for 14 days (n = 4), using validated HPLC methods.

For latanoprost, concentrations did not vary by more than 10% from the initial concentration in drops emitted from LDPE flasks. In LDPE-Si flasks, a decrease in latanoprost mean concentration was observed for every drop, throughout the 14 day study period, ranging from -22.9% in the first drop to -76.4% in the second drop and -64.9% at day 14. For cyclosporine, concentrations did not vary by more than 10% from the initial concentration in drops emitted from both LDPE and LDPE-Si bottles, for all 3 tested concentrations. However, for 1 mg/ml cyclosporine solutions, concentrations dropped by 7.3% in the third drop when emitted from LDPE-Si bottles, but quickly regained initial levels (-2.1%) thereafter.

LDPE-Si bottles should be avoided for the administration of the tested formulation of latanoprost, as the loss of active substance may cause a sever under-dosing. However, they may be used for tested formulation of ophthalmic cyclosporine. An evaluation of LDPE-Si bottles with other molecules (rifamycin, norfloxacin, timolol) is currently in underway.