Generation of a Weakly Acidic Amorphous Solid Dispersion of the Weak Base Ritonavir with Equivalent In Vitro and In Vivo Performance to Norvir Tablet
| Autor: | Dave A. Miller, Sandra U. Kucera, Robert O. Williams, Daniel J. Ellenberger |
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| Rok vydání: | 2018 |
| Předmět: |
Materials science
Magnetic Resonance Spectroscopy Chemistry Pharmaceutical Drug Compounding Pharmaceutical Science 02 engineering and technology Aquatic Science 030226 pharmacology & pharmacy Dosage form Permeability 03 medical and health sciences First pass effect 0302 clinical medicine Differential scanning calorimetry Dogs X-Ray Diffraction Drug Discovery medicine Animals Ecology Evolution Behavior and Systematics Chromatography Ritonavir Ecology Calorimetry Differential Scanning General Medicine HIV Protease Inhibitors Permeation 021001 nanoscience & nanotechnology Bioavailability Amorphous solid 0210 nano-technology Weak base Agronomy and Crop Science Acids medicine.drug Tablets |
| Zdroj: | AAPS PharmSciTech. 19(5) |
| ISSN: | 1530-9932 |
| Popis: | Ritonavir is an anti-viral compound that has also been employed extensively as a CYP3A4 and P-glycoprotein (Pgp) inhibitor to boost the pharmacokinetic performance of compounds that undergo first pass metabolism. For use in combination products, there is a desire to minimize the mass contribution of the ritonavir system to reduce patient pill burden in these combination products. In this study, KinetiSol® processing was utilized to produce an amorphous solid dispersion of ritonavir at two times the drug load of the commercially available form of ritonavir, and the composition was subsequently developed into a tablet dosage form. The amorphous intermediate was demonstrated to be amorphous by X-ray powder diffraction and 13C solid-state nuclear magnetic resonance and an intimately mixed single-phase system by modulated differential scanning calorimetry and 1H T1/1H T1ρ solid-state nuclear magnetic resonance relaxation. In vitro transmembrane flux analysis showed similar permeation rates for the KinetiSol-made tablet and the reference tablet dosage form, Norvir®. In vivo pharmacokinetic comparison between the two dosage forms resulted in equivalent exposure with approximately 20% Cmax reduction for the KinetiSol tablet. These performance gains were realized with a concurrent reduction in dosage form mass of 45%. |
| Databáze: | OpenAIRE |
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