Abstract
Purpose: :
An ideal suspension formulation for consistent ophthalmic dosing is one which requires no shaking to resuspend drug particles but is administered as a drop. Loteprednol etabonate ophthalmic gel, 0.5% (LE gel), was designed to exhibit non-settling characteristics yet be expressed as a drop. This study examines the viscoelastic properties which are the basis for this unique behavior.
Methods: :
Yield point values were measured on an AR 2000 Rheometer (TA Instruments) fitted with a vane rotor and cup containing 30 mL undiluted product at 25 oC. Oscillatory rheology was conducted on the AR 2000 using a 40-mm parallel plate apparatus at an oscillatory frequency of 1 rad/s with variable oscillatory stress. Sedimentation behavior was characterized using a LUMiSizer dispersion analyzer (L.U.M. GmbH) at 1000 rpm (116-145 g) for up to 24 hr.
Results: :
Rotational rheology experiments on LE gel spanned the range of 1-100 Pa of shear stress. At high shear stress (100 Pa) viscosity is <0.1 Pa-s. As shear stress decreases viscosity increases. Viscosity approaches infinity near 4 Pa of shear stress indicating this value as the yield point for this formulation. Oscillatory rheology studies confirm the solid-fluid behavior of the product, dependent on shear stress. At low oscillatory stress the elastic modulus, G' (~38 Pa) greatly exceeds the viscous modulus, G" (2 Pa). As oscillatory stress increases, G' decreases and eventually crosses over G" at ~6 Pa, demonstrating the transition from a gel- to a sol-state. The transition from sol at high shear back to gel at low shear occurs rapidly (within ~15 sec). The effect of these rheological properties is seen in sedimentation studies. Sedimentation analysis of LE gel and Lotemax® using the LUMiSizer dispersion analyzer shows that LE gel does not sediment over 24 hr at 1000 rpm. Lotemax is a low viscosity ophthalmic suspension and sediments almost immediately. We have observed visually and confirmed by HPLC analysis that LE gel does not sediment over 16 months under ambient conditions.
Conclusions: :
The rheologic data indicate loteprednol etabonate ophthalmic gel, 0.5%, to be a shear-thinning material with solid-like properties at low shear and fluid-like properties above shear stress of ~6 Pa. This results in a gel at rest which allows no sedimentation of drug particles, and a fluid under applied shear stress such as occurs when the product is expressed through a dropper tip. Because the sol-gel transition occurs quickly, drug particle sedimentation does not occur during the use of the product. By eliminating the need to shake the product, inconsistent patient compliance to shaking instructions will not affect the delivered dose of loteprednol etabonate ophthalmic gel, 0.5%.
Keywords: inflammation • development • corticosteroids