In Vitro-In Vivo Predictive Dissolution-Permeation-Absorption Dynamics of Highly Permeable Drug Extended-Release Tablets via Drug Dissolution/Absorption Simulating System and pH Alteration
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Each of dissolution and permeation may be a rate-limiting factor in the absorption of oral drug delivery. But the current dissolution test rarely took into consideration of the permeation property. Drug dissolution/absorption simulating system (DDASS) valuably gave an insight into the combination of drug dissolution and permeation processes happening in human gastrointestinal tract. The simulated gastric/intestinal fluid of DDASS was improved in this study to realize the influence of dynamic pH change on the complete oral dosage form. To assess the effectiveness of DDASS, six high-permeability drugs were chosen as model drugs, including theophylline (pKa1 = 3.50, pKa2 = 8.60), diclofenac (pKa = 4.15), isosorbide 5-mononitrate (pKa = 7.00), sinomenine (pKa = 7.98), alfuzosin (pKa = 8.13), and metoprolol (pKa = 9.70). A general elution and permeation relationship of their commercially available extended-release tablets was assessed as well as the relationship between the cumulative permeation and the apparent permeability. The correlations between DDASS elution and USP apparatus 2 (USP2) dissolution and also between DDASS permeation and beagle dog absorption were developed to estimate the predictability of DDASS. As a result, the common elution-dissolution relationship was established regardless of some variance in the characteristic behavior between DDASS and USP2 for drugs dependent on the pH for dissolution. Level A in vitro-in vivo correlation between DDASS permeation and dog absorption was developed for drugs with different pKa. The improved DDASS will be a promising tool to provide a screening method on the predictive dissolution-permeation-absorption dynamics of solid drug dosage forms in the early-phase formulation development.
KEY WORDSdrug dissolution/absorption simulating system (DDASS) dynamic pH change extended-release tablets in vitro-in vivo correlation (IVIVC) USP apparatus 2 (USP 2)
active pharmaceutical ingredient
biopharmaceutical classification system
drug dissolution/absorption simulating system
in vitro-in vivo correlation
USP apparatus 2
This study was supported by the grants from Key Support Projects of Tianjin Science and Technology (No. 16YFZCSY00440), Natural Science Foundation of China (No. 81303141), Integrative Chinese Medicine Research Project of Tianjin Municipal Commission Health and Family Planning (No. 2017144), and Program for Changjiang Scholars and Innovative Research Team in University (No. IRT_14R41).
Compliance with Ethical Standards
The study was performed in accordance with the Principles of Laboratory Animal Care (NIH No. 8523) and was approved by the Ethical Review Committee of Tianjin University of Traditional Chinese Medicine.
Conflict of Interest
The authors declare that they have no conflict of interest.
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