Track: Formulation and Delivery - Chemical - Formulation - Drug Substance Properties
Category: Late Breaking Poster Abstract
Solubility and Stability Enhanced Prednisolone Acetate Solutions
Purpose: Solubility enhanced drug formulations are susceptible to physical instability issues. Dilution with body fluids, pH changes, ionic strength variation, and body temperature can crash out the dissolved drug prior to its absorption. Prednisolone acetate is an adrenocortical steroid, indicated for steroid responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe. As the drug is practically insoluble in water, suspensions are formulated (0.12 and 1.0%), which require up to four times application daily. The purpose of this study is to enhance the solubility of prednisolone acetate using various pharmaceutical vehicles, and evaluate the physical stability of solubilized formulations in artificial tear fluid. Methods: Solubility of Prednisolone acetate was evaluated in purified water, and in presence of various solubility enhancing agents under ambient room temperature. Nonionic surfactants, pH modifiers, cosolvents, and PEGylated lipid excipients, such as polysorbate-80, poloxamers, citric acid, tartaric acid, fumaric acid, ascorbic acid, polyethylene glycol, propylene glycol, PEG-15 hydroxystearates, polyoxyl 40 hydrogenated castor oil and polyoxyl 35 castor oil were used. Vehicles that showed greater solubilizing potential (≥5 mg/mL) were evaluated for their capacity to retain the drug in solution when diluted with artificial tear fluid under 37°C. Various viscosity enhancing polymers and microemulsifiers were used as crystallization inhibitors. Four prototype solution formulations (1.25 to 5 mg/mL prednisolone acetate) containing solubility enhancers and crystallization inhibitors were prepared, and the effect of temperature cycling on their physical stability was evaluated. Results: Solubility of prednisolone acetate in water was 31 μg/mL. Nonionic surfactants, pH modifiers, and PEGylated lipid excipients did not increase the solubility. About 160-fold increase in solubility was observed with polyethylene glycol 400. A clear solution could be obtained at 5 mg/mL concentration. This solution, however, crashed out as irregular shaped crystals when diluted with artificial tear fluid at 1:1 ratio within 15 minutes (Figure 1). Cellulose polymers such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose, and carboxymethyl cellulose could not be dissolved in the polyethylene glycol based prednisolone acetate solution. Povidone (0.5 to 5%) did not inhibit the crystallization behavior of prednisolone solution on dilution. Copovidone (0.5 to 20%), PEG-15 hydroxystearates (0.5 to 20%) and polyoxyl 35 castor oil (0.5 to 30%) showed concentration dependent delay in the crystallization time (Figure 2). Prototype formulations containing 0.5% copovidone or 30% polyoxyl 35 castor oil in polyethylene glycol did not show any physical instability when stressed between ambient and freezing conditions for 5 cycles (Figure 3). Conclusion: Solubility of prednisolone acetate was enhanced by 160-fold, and also the physical stability of solution formulations (0.125, 0.250, and 0.5%) in presence of artificial tear fluid was increased from 15 minutes to 6 hours. These solubility and stability enhanced solutions are, therefore, expected to improve the ocular absorption of prednisolone acetate.