Physiochemical Properties and Cytotoxicity of a Benzalkonium Chloride-Free, Micellar Emulsion Ophthalmic Formulation of Latanoprost

Arindam Halder, Ajay J Khopade

Formulation Department, Sun Pharmaceutical Industries, Ltd, Tandalja, Vadodara, India

Correspondence: Ajay J Khopade
Sun Pharmaceutical Industries, Ltd., Tandalja, Vadodara 390020, Gujarat, India
Tel +91 22 6645 5645 Ext 1900
Email ajay.khopade@sunpharma.com

Purpose: Prostaglandin derivatives are used widely to reduce intraocular pressure associated with open-angle glaucoma. The most widely used prostaglandin derivative, latanoprost, is available in an ophthalmic solution that is solubilized and preserved with 0.02% benzalkonium chloride (BAK), which has been shown to be cytotoxic to corneal cells. Latanoprost ophthalmic solution with BAK requires specific storage temperatures, which can impact the supply cycle. Here, we describe the production, physicochemical characteristics, and cytotoxicity profile of a micelle formulation that solubilizes latanoprost without the need for BAK.
Methods: The optimum concentration of castor oil with the surfactant polyethylene glycol (15) hydroxystearate was determined, and the mixture stirred. Various surfactants were tested to determine the ideal mixture to form a micelle formulation. Viscosity, zeta potential, surface tension, droplet size, and osmolality of the batches were tested. The cytotoxicity of the micelle formulation was determined in a corneal cell viability assay that compared positive and negative controls, latanoprost without BAK, latanoprost with BAK, and placebo.
Results: A castor oil concentration of 0.15% produced a micelle formulation with a diameter of < 100 nm. This micelle formulation had unique characteristics that were not mimicked when either the surfactant or the oil was changed. The physicochemical characteristics in multiple batches of the micelle formulation did not vary significantly between batches. Long-term and accelerated stability studies showed latanoprost potency remained constant for 24 months at 25°C/75% relative humidity (RH) and at 40°C/25% RH for 6 months.
Conclusion: The micelle formulation technology system is capable of solubilizing latanoprost in an ophthalmic formulation without the need for BAK. The system is stable at room temperature.

Keywords: open angle glaucoma, micelle formulation, benzalkonium chloride, latanoprost