ABSTRACT
Transport within human tissue matrices, e.g., the subcutaneous tissue, exhibits some resemblance to chromatographic processes. Here, a porous matrix comprising agarose beads compatible with UV-vis imaging was developed for a parallel piped rectangular flow cell (4 mm light path). Introduction of high-molecular weight dextrans (Mr â¼ 200000 and â¼500000) at 10% (w/v) rendered imaging possible by providing optical clearing of the turbid porous matrix, resulting in improved transmittance as well as resolution (from 400 to 180 µm) at 280 nm, as well as 520 nm. The interplay between diffusive and convective transport at 0 < Pe ≤ 28 was visualized at 280 nm upon injection of dexamethasone suspensions. Real-time UV-vis imaging showed in-flow cell the effect of incorporating ion-exchange resins on the retention of infliximab, lysozyme, and α-lactalbumin. The ion-exchange matrix may serve as a surrogate for polyelectrolytes in the subcutaneous tissue, assessing the potential role of electrostatic interactions of biotherapeutics upon injection. UV-vis imaging of size-exclusion chromatographic matrixes may be of interest in its own right and potentially develop into a characterization tool for injectables.
Subject(s)
Lactalbumin , Subcutaneous Tissue , Humans , Chromatography, Ion Exchange/methodsABSTRACT
Assessing in vivo performance to inform formulation selection and development decisions is an important aspect of drug development. Biopredictive dissolution methodologies for oral dosage forms have been developed to understand in vivo performance, assist in formulation development/optimization, and forecast the outcome of bioequivalence studies by combining them with simulation tools to predict plasma profiles in humans. However, unlike compendial dissolution methodologies, the various biopredictive methodologies have not yet been harmonized or standardized. This manuscript presents the initial phases of an effort to develop best practices and move toward standardization of the biopredictive methodologies through the Product Quality Research Institute (PQRI, https://pqri.org ) entitled "The standardization of in vitro predictive dissolution methodologies and in silico bioequivalence study Working Group." This Working Group (WG) is comprised of participants from 10 pharmaceutical companies and academic institutes. The project will be accomplished in a total of five phases including assessing the performance of dissolution protocols designed by the individual WG members, and then building "best practice" protocols based on the initial dissolution profiles. After refining the "best practice" protocols to produce equivalent dissolution profiles, those will be combined with physiologically based biopharmaceutics models (PBBM) to predict plasma profiles. In this manuscript, the first two of the five phases are reported, namely generating biopredictive dissolution profiles for ibuprofen and dipyridamole and using those dissolution profiles with PBBM to match the clinical plasma profiles. Key experimental parameters are identified, and this knowledge will be applied to build the "best practice" protocol in the next phase.
