(M1130-03-14) Development and Characterization of Preservative Free Ocular Formulation

Purpose: The purpose of the investigation is to develop and characterize an ocular formulation intended for reducing the side effects associated with preservative which is one of the ingredients of the formulation.

Methods: Preparation of Composition - The inactive ingredients (sodium phosphate monobasic and sodium phosphate dibasic) of the product composition are transferred to a container. The solvent vehicle is added to the container and subjected to mixing condition. Upon formation of a clear solution, the active ingredients, Brimonidine Tartrate and Timolol Maleate are added. Again, the solution is subjected to mixing for formation of a uniform solution. Now, pH adjustments are made using hydrochloric acid and sodium hydroxide. Followed  by this, volume adjustments are made. This solution is subjected to sterile filtration using 0.22 micron filter in clean room. The sterile solution is filled into ophthalmic squeeze dispensers (OSD) bottles (5 mL and 10 mL). The OSD bottles are loaded into stability chambers for storage conditions: 25°C/60% RH, 25°C/40% RH, 40°C/75% RH. The samples are withdrawn at definite time points to investigate the effect of OSD bottle (device components) on product composition at the storage conditions.  Analytical Characterization - The product composition is subjected to analytical characterization of critical attributes such as for assay, impurities, pH and osmolarity. The assay and impurity profiling (or related substances) are determined using high pressure liquid chromatography (HPLC) methods. In addition, other attributes are also investigated which are as follows: Density, Viscosity, Refractive index, Fill volume, Recoverable volume, % weight loss, Drop size (volume and weight), Elemental impurities, Residual solvents. All the measurements are performed on calibrated instruments using validated methods. The data points are subjected to statistical analysis.

Results: From the data, it can be observed that the OSD containers are compatible with product formulation at the storage conditions. The assay limits of active ingredients: Brimonidine Tartrate and Timolol Maleate are within the USP limits of 90-110%. And the level of impurities (related substances) remained within the qualification threshold limits (not more than 1.0%). The level of threshold limits are based on maximum allowable dose of eye drops. The pH of the composition is 7.0 which is within the specification (pH limits: 6.5 - 7.3). And the osmolality of formulations is in the range: 260 - 350 mOsm/kg. Other parameters are comparable to reference specifications and complied to specification limits.

Conclusion: The product composition is stable at room temperature condition and accelerated conditions. The device components of ophthalmic squeeze dispenser (OSD) are compatible with product composition. Hence, the preservative free composition can be stored and dispensed using novel OSD device.

References: Switch from BAK-preserved to preservative-free latanoprost decreases anterior chamber flare in POAG patients. Ph A Kestelyn, Ph G Kestelyn, D De Bacquer, A M Stevens. Int Ophthalmol . 2019 Jan;39(1):105-109.

Acknowledgements: Intera Healthcare acknowledges the support of Biotechnology Industry Research Assisted Council (BIRAC), Government of India for supporting the research. The authors declare no conflict of interests.