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Toward Biopredictive Dissolution for Enteric Coated Dosage Forms.
Mol Pharm. 2016 06 06; 13(6):1927-36.MP

Abstract

The aim of this work was to develop a phosphate buffer based dissolution method for enteric-coated formulations with improved biopredictivity for fasted conditions. Two commercially available enteric-coated aspirin products were used as model formulations (Aspirin Protect 300 mg, and Walgreens Aspirin 325 mg). The disintegration performance of these products in a physiological 8 mM pH 6.5 bicarbonate buffer (representing the conditions in the proximal small intestine) was used as a standard to optimize the employed phosphate buffer molarity. To account for the fact that a pH and buffer molarity gradient exists along the small intestine, the introduction of such a gradient was proposed for products with prolonged lag times (when it leads to a release lower than 75% in the first hour post acid stage) in the proposed buffer. This would allow the method also to predict the performance of later-disintegrating products. Dissolution performance using the accordingly developed method was compared to that observed when using two well-established dissolution methods: the United States Pharmacopeia (USP) method and blank fasted state simulated intestinal fluid (FaSSIF). The resulting dissolution profiles were convoluted using GastroPlus software to obtain predicted pharmacokinetic profiles. A pharmacokinetic study on healthy human volunteers was performed to evaluate the predictions made by the different dissolution setups. The novel method provided the best prediction, by a relatively wide margin, for the difference between the lag times of the two tested formulations, indicating its being able to predict the post gastric emptying onset of drug release with reasonable accuracy. Both the new and the blank FaSSIF methods showed potential for establishing in vitro-in vivo correlation (IVIVC) concerning the prediction of Cmax and AUC0-24 (prediction errors not more than 20%). However, these predictions are strongly affected by the highly variable first pass metabolism necessitating the evaluation of an absorption rate metric that is more independent of the first-pass effect. The Cmax/AUC0-24 ratio was selected for this purpose. Regarding this metric's predictions, the new method provided very good prediction of the two products' performances relative to each other (only 1.05% prediction error in this regard), while its predictions for the individual products' values in absolute terms were borderline, narrowly missing the regulatory 20% prediction error limits (21.51% for Aspirin Protect and 22.58% for Walgreens Aspirin). The blank FaSSIF-based method provided good Cmax/AUC0-24 ratio prediction, in absolute terms, for Aspirin Protect (9.05% prediction error), but its prediction for Walgreens Aspirin (33.97% prediction error) was overwhelmingly poor. Thus it gave practically the same average but much higher maximum prediction errors compared to the new method, and it was strongly overdiscriminating as for predicting their performances relative to one another. The USP method, despite not being overdiscriminating, provided poor predictions of the individual products' Cmax/AUC0-24 ratios. This indicates that, overall, the new method is of improved biopredictivity compared to established methods.

Authors+Show Affiliations

Institute of Pharmacy and Biochemistry, Johannes Gutenberg University Mainz , Staudinger Weg 5, 55099 Mainz, Germany.Department of Pharmaceutical Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.Institute of Pharmacy and Biochemistry, Johannes Gutenberg University Mainz , Staudinger Weg 5, 55099 Mainz, Germany.

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27139040

Citation

Al-Gousous, J, et al. "Toward Biopredictive Dissolution for Enteric Coated Dosage Forms." Molecular Pharmaceutics, vol. 13, no. 6, 2016, pp. 1927-36.
Al-Gousous J, Amidon GL, Langguth P. Toward Biopredictive Dissolution for Enteric Coated Dosage Forms. Mol Pharm. 2016;13(6):1927-36.
Al-Gousous, J., Amidon, G. L., & Langguth, P. (2016). Toward Biopredictive Dissolution for Enteric Coated Dosage Forms. Molecular Pharmaceutics, 13(6), 1927-36. https://doi.org/10.1021/acs.molpharmaceut.6b00077
Al-Gousous J, Amidon GL, Langguth P. Toward Biopredictive Dissolution for Enteric Coated Dosage Forms. Mol Pharm. 2016 06 6;13(6):1927-36. PubMed PMID: 27139040.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Toward Biopredictive Dissolution for Enteric Coated Dosage Forms. AU - Al-Gousous,J, AU - Amidon,G L, AU - Langguth,P, Y1 - 2016/05/10/ PY - 2016/5/4/entrez PY - 2016/5/4/pubmed PY - 2017/10/20/medline KW - IVIVC KW - aspirin KW - biopredictive dissolution KW - enteric coating KW - pharmacokinetics SP - 1927 EP - 36 JF - Molecular pharmaceutics JO - Mol Pharm VL - 13 IS - 6 N2 - The aim of this work was to develop a phosphate buffer based dissolution method for enteric-coated formulations with improved biopredictivity for fasted conditions. Two commercially available enteric-coated aspirin products were used as model formulations (Aspirin Protect 300 mg, and Walgreens Aspirin 325 mg). The disintegration performance of these products in a physiological 8 mM pH 6.5 bicarbonate buffer (representing the conditions in the proximal small intestine) was used as a standard to optimize the employed phosphate buffer molarity. To account for the fact that a pH and buffer molarity gradient exists along the small intestine, the introduction of such a gradient was proposed for products with prolonged lag times (when it leads to a release lower than 75% in the first hour post acid stage) in the proposed buffer. This would allow the method also to predict the performance of later-disintegrating products. Dissolution performance using the accordingly developed method was compared to that observed when using two well-established dissolution methods: the United States Pharmacopeia (USP) method and blank fasted state simulated intestinal fluid (FaSSIF). The resulting dissolution profiles were convoluted using GastroPlus software to obtain predicted pharmacokinetic profiles. A pharmacokinetic study on healthy human volunteers was performed to evaluate the predictions made by the different dissolution setups. The novel method provided the best prediction, by a relatively wide margin, for the difference between the lag times of the two tested formulations, indicating its being able to predict the post gastric emptying onset of drug release with reasonable accuracy. Both the new and the blank FaSSIF methods showed potential for establishing in vitro-in vivo correlation (IVIVC) concerning the prediction of Cmax and AUC0-24 (prediction errors not more than 20%). However, these predictions are strongly affected by the highly variable first pass metabolism necessitating the evaluation of an absorption rate metric that is more independent of the first-pass effect. The Cmax/AUC0-24 ratio was selected for this purpose. Regarding this metric's predictions, the new method provided very good prediction of the two products' performances relative to each other (only 1.05% prediction error in this regard), while its predictions for the individual products' values in absolute terms were borderline, narrowly missing the regulatory 20% prediction error limits (21.51% for Aspirin Protect and 22.58% for Walgreens Aspirin). The blank FaSSIF-based method provided good Cmax/AUC0-24 ratio prediction, in absolute terms, for Aspirin Protect (9.05% prediction error), but its prediction for Walgreens Aspirin (33.97% prediction error) was overwhelmingly poor. Thus it gave practically the same average but much higher maximum prediction errors compared to the new method, and it was strongly overdiscriminating as for predicting their performances relative to one another. The USP method, despite not being overdiscriminating, provided poor predictions of the individual products' Cmax/AUC0-24 ratios. This indicates that, overall, the new method is of improved biopredictivity compared to established methods. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/27139040/Toward_Biopredictive_Dissolution_for_Enteric_Coated_Dosage_Forms_ L2 - https://doi.org/10.1021/acs.molpharmaceut.6b00077 DB - PRIME DP - Unbound Medicine ER -