• Evaluation of In Vitro/In Vivo Correlations for Transdermal Delivery Systems by In Vitro Permeation Testing and Human Pharmacokinetic Studies, With and Without a Transient Heat Application

      Shin, Soo Hyeon; Stinchcomb, Audra L.; Hassan, Hazem; 0000-0001-5091-8870 (2018)
      An in vitro model that exhibits in vitro/in vivo correlations (IVIVC) is a powerful tool in biopharmaceutical drug development because it can efficiently predict drug product performance in vivo. While the concept of IVIVC has been utilized mostly for oral dosage forms, demonstrations of IVIVC with in vitro permeation testing (IVPT) for transdermal delivery systems (TDS) are emerging. The objective of this work was to evaluate IVIVC for TDS using two model drugs, nicotine and fentanyl, with different physicochemical characteristics (e.g. log P). Additionally, the effect of heat exposure (42 ± 2 °C) on the rate and extent of TDS drug delivery was evaluated. IVPT studies using excised human skin and in vivo pharmacokinetic (PK) studies in human subjects were conducted under harmonized study conditions and designs to evaluate IVIVC. The correlations were evaluated in multiple ways, including a single point comparison of parameters such as steady-state concentration and heat-induced increase in partial AUCs, as well as a point-to-point correlation (Level A IVIVC). Level A IVIVC was examined using multiple approaches. A strong IVIVC was consistently observed for nicotine TDS in presence and absence of heat, suggesting the utility of IVPT as a tool to evaluate and predict in vivo performance of nicotine TDS. The IVIVC results for fentanyl were relatively weaker, especially when IVIVC for heat effects were examined, with greater in vivo heat effects observed compared to the in vitro heat effects. A separate study evaluating IVIVC for fentanyl TDS without a heat exposure component and utilization of some PK parameters obtained directly from study subjects yielded improved IVIVC results. The findings from the present research work suggest that IVPT data generally shows good predictability of in vivo performance of TDS at normal temperature conditions. However, the usefulness of IVPT for assessing and predicting external factors such as heat, especially for lipophilic drug molecules, may have some limitations that could be further improved.
    • Understanding Curing of Ethylcellulose Film Coating and In Vitro In Vivo Performance of Oral Dosage Forms with Scientific Regulatory Implications on Biowaiver

      Lin, Zhongqiang; Hoag, Stephen W. (2015)
      The aim of this study focus on the extended release formulation on two aspects: the quantification and mechanistic research on pharmaceutical coating curing with a specific focus on how the moisture affect the curing; and in vivo and in vitro release of matrix ER tablets with implications on regulatory biowaiver using marketed products as practical examples. In all cases, it was found that the relative humidity of the environments were more important to reach higher extent of coalescence for EC pseudolatex films and temperature along cannot achieve sufficient polymer coalescence. A quantitative relationship was established that could be used to quantify the extent of coalescence in EC curing to a reasonable accuracy. The NIR spectral data with the tool of chemometrics can enable accurate prediction of physicomechanical properties accurately. Dissolution models demonstrated the release mechanism of EC coated ER multiparticulate was predominately determined by the breaking down of the coating rather than diffusion of drugs through the EC coating layer. Fluoresence anisotropy was found to be useful in the solid system for the first time. By measuring fluorescence anisotropy in the fluorescence labeled EC films can allow real time monitoring of the curing process. To justify biowaiver, it is essential to understand effects of API properties, formulation design, product characteristics, test method and its in vivo relevance. It is therefore concluded that the biowaiver criteria specified in the regulatory guidance should apply only to multiparticulate beaded dosage forms where strengths only differ in the number of beads containing the active moiety.