Abstract
Purpose :
The quality of an ophthalmic suspension is crucial to its clinical effectiveness and understanding formulation attributes is important for successful product development. This study aims to demonstrate the effect of physicochemical properties including solubility, pKa (for ionizable molecules), and particle size with morphology/shape on in situ drug dissolution rate (e.g. release within tear following topical instillation). Such descriptors and relationships of simulated in vitro release tests (IVRT) can be used as input parameters for predictive optimization of sensitive product design parameters impacting drug absorption and disposition from complex topical ophthalmic suspensions.
Methods :
DDDPlus™ and Ocular Compartmental Absorption & Transit (OCAT) v3, a module in GastroPlus™ (Simulations Plus, Inc.) were used to simulate drug dissolution (vs IVRT) and biodistribution (vs rabbit pharmacokinetics, PK) in aqueous humor (AH) and iris ciliary body (ICB) as target compartments. Measured or empirically estimated input parameters for drugs found in commercial topical ophthalmic suspensions were obtained from experimental literature. The simulation results were compared to IVRT, and then used for global optimization of physiologically based PK models. All referenced data were extracted from original publications using GetData Graph Digitizer®.
Results :
DDDPlus™ simulations enabled fabrication of dissolution profiles similar to experimentally determined ones from IVRT. Between sets of dissolution predictions variations on mixing rate (e.g. blinking), USP simulated tear fluid (STF) composition, and molecular structure based vs. physicochemical property support files use were successfully evaluated. Without sensitive parameter identification and optimization DDDPlus™ tended to underpredict dissolution of studied drug particle examples. OCAT v3 simulated ocular exposures produced expected results and trends in rabbit AH and ICB from topical ophthalmic suspensions.
Conclusions :
DDDPlus™ can serve as an initial assessment tool to build in vitro correlations with STF dissolution models, which can subsequently be relayed to OCAT v3 for ocular pharmacokinetic predictions. This is a novel tool being developed and promoted by the FDA for in silico approaches for establishment of bioequivalence in complex drug products, such as topical ophthalmic suspensions.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.