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Prediction of oral absorption of cinnarizine--a highly supersaturating poorly soluble weak base with borderline permeability.
Eur J Pharm Biopharm. 2014 Nov; 88(3):795-806.EJ

Abstract

Two important driving forces for oral absorption of active pharmaceutical ingredients are drug dissolution and permeability in the gastrointestinal tract. Poorly soluble weak bases typically exhibit high solubility under fasted gastric conditions. However, the solubility of such drugs usually decreases drastically in the fasted small intestine, constraining drug absorption. Since there is a discrepancy in solubility between the fasted state stomach and intestine, it is crucial to examine the influence of dissolution, supersaturation and precipitation on the oral absorption of poorly soluble weak bases during and after fasted state gastric emptying. Cinnarizine is a poorly soluble weak base with borderline permeability, exhibiting supersaturation and precipitation under simulated fasted state gastric emptying conditions. Interestingly, supersaturation and precipitation of cinnarizine under fed state conditions is not expected to occur, since the drug shows good solubility in fed state biorelevant media and exhibits a positive food effect in pharmacokinetic studies. The present work is aimed at investigating the dissolution, supersaturation and precipitation behavior of marketed cinnarizine tablets under fasted and fed state conditions using biorelevant dissolution and transfer methods. In order to predict the in vivo performance of these cinnarizine formulations, the in vitro results were then coupled with different physiologically based pharmacokinetic (PBPK) models, which considered either only dissolution or a combination of dissolution, supersaturation and precipitation kinetics. The results of the in silico predictions were then compared with in vivo observations. The study revealed that under fasting conditions, plasma profiles could be accurately predicted only when supersaturation and precipitation as well as dissolution were taken into account. It was concluded that for poorly soluble weak bases with moderate permeability, supersaturation and precipitation during fasted state gastric emptying may have an essential influence on oral drug absorption and thus on in vivo drug performance.

Authors+Show Affiliations

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.Hennig Arzneimittel GmbH & Co KG, Flörsheim am Main, Germany.Hennig Arzneimittel GmbH & Co KG, Flörsheim am Main, Germany.Hennig Arzneimittel GmbH & Co KG, Flörsheim am Main, Germany.Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address: dressman@em.uni-frankfurt.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25195981

Citation

Berlin, Mark, et al. "Prediction of Oral Absorption of Cinnarizine--a Highly Supersaturating Poorly Soluble Weak Base With Borderline Permeability." European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, vol. 88, no. 3, 2014, pp. 795-806.
Berlin M, Przyklenk KH, Richtberg A, et al. Prediction of oral absorption of cinnarizine--a highly supersaturating poorly soluble weak base with borderline permeability. Eur J Pharm Biopharm. 2014;88(3):795-806.
Berlin, M., Przyklenk, K. H., Richtberg, A., Baumann, W., & Dressman, J. B. (2014). Prediction of oral absorption of cinnarizine--a highly supersaturating poorly soluble weak base with borderline permeability. European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, 88(3), 795-806. https://doi.org/10.1016/j.ejpb.2014.08.011
Berlin M, et al. Prediction of Oral Absorption of Cinnarizine--a Highly Supersaturating Poorly Soluble Weak Base With Borderline Permeability. Eur J Pharm Biopharm. 2014;88(3):795-806. PubMed PMID: 25195981.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prediction of oral absorption of cinnarizine--a highly supersaturating poorly soluble weak base with borderline permeability. AU - Berlin,Mark, AU - Przyklenk,Karl-Heinz, AU - Richtberg,Annette, AU - Baumann,Wolfgang, AU - Dressman,Jennifer B, Y1 - 2014/09/06/ PY - 2014/06/06/received PY - 2014/08/14/revised PY - 2014/08/20/accepted PY - 2014/9/9/entrez PY - 2014/9/10/pubmed PY - 2015/8/5/medline KW - Absorption KW - Cinnarizine KW - Dissolution KW - Permeability KW - Physiologically based pharmacokinetic model KW - Precipitation KW - Supersaturation SP - 795 EP - 806 JF - European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V JO - Eur J Pharm Biopharm VL - 88 IS - 3 N2 - Two important driving forces for oral absorption of active pharmaceutical ingredients are drug dissolution and permeability in the gastrointestinal tract. Poorly soluble weak bases typically exhibit high solubility under fasted gastric conditions. However, the solubility of such drugs usually decreases drastically in the fasted small intestine, constraining drug absorption. Since there is a discrepancy in solubility between the fasted state stomach and intestine, it is crucial to examine the influence of dissolution, supersaturation and precipitation on the oral absorption of poorly soluble weak bases during and after fasted state gastric emptying. Cinnarizine is a poorly soluble weak base with borderline permeability, exhibiting supersaturation and precipitation under simulated fasted state gastric emptying conditions. Interestingly, supersaturation and precipitation of cinnarizine under fed state conditions is not expected to occur, since the drug shows good solubility in fed state biorelevant media and exhibits a positive food effect in pharmacokinetic studies. The present work is aimed at investigating the dissolution, supersaturation and precipitation behavior of marketed cinnarizine tablets under fasted and fed state conditions using biorelevant dissolution and transfer methods. In order to predict the in vivo performance of these cinnarizine formulations, the in vitro results were then coupled with different physiologically based pharmacokinetic (PBPK) models, which considered either only dissolution or a combination of dissolution, supersaturation and precipitation kinetics. The results of the in silico predictions were then compared with in vivo observations. The study revealed that under fasting conditions, plasma profiles could be accurately predicted only when supersaturation and precipitation as well as dissolution were taken into account. It was concluded that for poorly soluble weak bases with moderate permeability, supersaturation and precipitation during fasted state gastric emptying may have an essential influence on oral drug absorption and thus on in vivo drug performance. SN - 1873-3441 UR - https://www.unboundmedicine.com/medline/citation/25195981/Prediction_of_oral_absorption_of_cinnarizine__a_highly_supersaturating_poorly_soluble_weak_base_with_borderline_permeability_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0939-6411(14)00265-3 DB - PRIME DP - Unbound Medicine ER -