In Vitro Dissolution and in Silico Modeling Shortcuts in Bioequivalence Testing

Purpose: To review in vitro testing and simulation platforms that are in current use to predict in vivo performances of generic products as well as other situations to provide evidence for biowaiver and support drug formulations development. Methods: Pubmed and Google Scholar databases were used to review published literature over the past 10 years. The terms used were “simulation AND bioequivalence” and “modeling AND bioequivalence” in the title field of databases, followed by screening, and then reviewing. Results: A total of 22 research papers were reviewed. Computer simulation using software such as GastroPlus™, PK-Sim® and SimCyp® find applications in drug modeling. Considering the wide use of optimization for in silico predictions to fit observed data, a careful review of publications is required to validate the reliability of these platforms. For immediate release (IR) drug products belonging to the Biopharmaceutics Classification System (BCS) classes I and III, difference factor (ƒ1) and similarity factor (ƒ2) are calculated from the in vitro dissolution data of drug formulations to support biowaiver; however, this method can be more discriminatory and may not be useful for all dissolution profiles. Conclusions: Computer simulation platforms need to improve their mechanistic physiologically based pharmacokinetic (PBPK) modeling, and if prospectively validated within a small percentage of error from the observed clinical data, they can be valuable tools in bioequivalence (BE) testing and formulation development.

GRID-system Based on European EGI Standards for Large-scale Calculations Using the Original Accelerated Method of Quantum Chemistry

Based on the analysis of modern tools for creating GRID-type information systems that are part of the European EGI “standard” – UMD repository (including new versions of Globus Toolkit, ARC, dCache, etc.), the applying of GRID systems for computational chemistry is briefly discussed. The GRID system created by the authors combines two clusters with Linux CentOS 7 and is based on software from UMD-4. The relevance and effectiveness of batch processing systems (we use Torque 4.2.10) in quantum chemical calculations is increased for mass calculations of docking complexes (including for drug modeling problems), for which an improved semiempirical method with more efficient approximations was proposed, implemented in the Fortran-95 LSSDOCK software package. For such calculations, new approximation methods have been developed, including for DFT functionals, and their software implementation is carried out. Converters of calculation results by LSSDOCK into a natural for GRID XML-based format CML version 3 are developed. Using the CML format based on dCache software, a single tree of a virtual GRID filesystem distributed between heterogeneous nodes is used to store the results of LSSDOCK calculations.

Modeling the oxidative consumption of curcumin from controlled released poly(beta-amino ester) microparticles in the presence of a free radical generating system

Despite the promise of its therapeutic benefits, curcumin as a free molecule has failed to demonstrate significant clinical success. Arguably, its inherently poor stability and rapid clearance is a significant reason for these negative outcomes. The incorporation of curcumin into the backbone of a crosslinked hydrogel that utilizes poly(beta-amino ester) (PBAE) chemistry can provide a tunable protective network with the ability to release at a controlled rate while improving its therapeutic potential. Kinetics of curcumin conjugated PBAE microparticles controlled release delivery system in the presence of oxidative environments was studied for the first time, where consumption rates of active curcumin and release products were obtained. The constituent amount of curcumin present in solution was improved by incorporating the active into the network in comparison to curcumin as a free drug. Modeling curcumin conjugated PBAE microparticles will provide a design platform to improve translation and overall success in delivering a therapeutic agent that matches levels of oxidative stress.