Solubilization of tropicamide by poloxamers: physicochemical data and activity data in rabbits and humans

Abstract

A series of polyoxyethylene-polyoxypropylene (POE/POP) block copolymers (Poloxamers, or Pluronics) were evaluated as solubilizers for tropicamide, a poorly water-soluble mydriatic/cycloplegic drug. The selected Pluronics were L64, P65 and F68 (POP weight 1750, POE weight 1150, 1650 and 6650, respectively), P75 and F77 (POP weight 2050, POE weight 2100 and 4550, respectively), P84, P85, F87 and F88 (POP weight 2250, POE weight 1950, 2350, 5450 and 9150, respectively) and F127 (POP weight 4000, POE weight 8600). The following studies were carried out: solubility of tropicamide in polymer solutions, partition coefficient of the drug between isopropyl myristate and polymer solutions, critical micelle concentration (CMC) of the polymers, viscosity of the polymeric solutions containing tropicamide, mydriatic activity tests on rabbits and humans, cycloplegic activity tests on humans. The solubility isotherms (25 °C) showed that the saturation solubility of the drug increased linearly with increasing surfactants concentration in the 4.0–20.0 w/v concentration range. In the presence of 20% w/v Pluronics the drug solubility increased substantially, ranging from 1.9 times (F88) to ca. 3.0 times (P85) the solubility in water at the same temperature (0.57 g/100 ml). Analysis of the solubility data indicated that the solubility of tropicamide increased as the oxyethylene content of the surfactants increased, and that the amount of drug solubilized per EO unit decreased with increasing hydrophilicity (increasing OE chain length) of surfactants. Calculation of the relative amount of drug bound to the POE and to the POP portions of the surfactant molecules indicated that binding occurs in part to the hydrophilic (POE) outer mantle, and in part to the hydrophobic, (POP) inner core of the micellar aggregates, with POE/POP binding ratios varying from 1.17 to 3.13, depending on the polymer type. Biological activity tests were carried out with some 15% w/v polymeric solutions (L64, P75, P84, P85 and F87) containing 1.0% w/v tropicamide, and with some 20.0% w/v solutions (P85, F87) containing 1 5 % w/v drug. The results indicate that tropicamide bioavailability, both in rabbits and in humans, was not decreased by micellar Solubilization, and that some Poloxamers can perform satisfactorily as solubilizing vehicles for tropicamide, producing neutral 1.0% and 1.5% drug solutions which are better tolerated and more effective than the standard aqueous eyedrops.