Approach 1 utilizes more complex strategies for predicting the dissolution/absorption process without providing a significant advantage over approach 2 with regard to accuracy of in vivo predictions.
Several physicochemical parameters are thought to affect in vivo performance of cyclosporine ophthalmic emulsion, including globule size distribution, viscosity profile as a function of applied shear, pH, zeta potential, osmolality, and surface tension. Using a modeling approach, this study predicts cyclosporine ophthalmic emulsion drug bioavailability to the cornea and conjunctiva and tear film breakup time for human subjects as a function of the vehicle physicochemical properties viscosity, surface tension, and osmolality for products that are qualitatively (Q1) and quantitatively (Q2) the same. The change in tear film breakup time from baseline, a potential indirect measure of therapeutic benefit, was predicted to characterize the direct effect of the vehicle on efficacy. Bioavailability predictions showed that while individual predictions were sensitive to variations in corneal and conjunctival permeabilities, geometric mean ratios of the test-to-reference comparisons for formulations that are Q1 and Q2 the same showed little sensitivity. Parameter sensitivity analysis showed that bioavailability and change in tear film breakup time from baseline values were both very sensitive to viscosity, slightly sensitive to surface tension, and insensitive to osmolality. With further improvements, the modeling framework developed for this study may be useful for informing future recommendations of cyclosporine ophthalmic emulsion bioequivalence for potential generic drug products.
The present study was designed to investigate the effect of two plasticizers, i.e., triethyl citrate (TEC) and polyethylene glycol 6000 (PEG 6000) on the in vitro release kinetics of diclofenac sodium from sustained-release pellets. Ammonio methacrylate copolymer type B (Eudragit RS 30 D) is used as the release-retarding polymer. Both plasticizers were used at 10% and 15% (w/w) of Eudragit RS 30 D. Pellets were prepared by powder layering technology and coated with Eudragit RS 30 D by air suspension technique. Thermal properties of drug and drug-loaded beads were studied using differential scanning calorimeter (DSC). DSC thermogram represented the identity of raw materials and exhibited no interaction or complexation between the active and excipients used in the pelletization process. Dissolution study was performed by using USP apparatus 1. No significant difference was observed among the physical properties of the coated pellets of different batches. When dissolution was performed as pure drug, about 8.22% and 90% drug was dissolved at 2 h in 0.1 N HCl and at 30 min in buffer (pH 6.8), respectively. From all formulations, the release of drug in acid media was very negligible (maximum 1.8 +/- 0.08% at 2 h) but in buffer only 12% and 30% drug was released at 10 h from coated pellets containing TEC and PEG 6000, respectively, indicating that Eudragit RS 30 D significantly retards the drug release rate and that drug release was varied according to the type and amount of plasticizers used. The amount of TEC in coating formulation significantly effected drug release (p < 0.001), but the effect of PEG 6000 was not significant. Formulations containing PEG 6000 released more drug (98.35 +/- 2.35%) than TEC (68.01 +/- 1.04%) after 24 h. Different kinetic models like zero order, first order, and Higuchi were used for fitting drug release pattern. Zero order model fitted best for diclofenac release in all formulations. Drug release mechanism was derived with Korsmeyer equation.
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