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Generation Of A Weakly Acidic Amorphous Solid Dispersion Of The Weak Base Ritonavir With Equivalent In Vitro And In Vivo Performance To Norvir Tablet
Daniel J Ellenberger, Dave A. Miller, Sandra U. Kucera, Robert O. Williams
Published 2018 · Materials Science, Medicine
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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%.
This paper references
Influence of Diluent and of Copolymer Composition on the Glass Temperature of a Poly-mer System
T. Fox (1956)
Molecular Interpretation of the Glass Transition Temperature of Polymer-Diluent Systems
T. Chow (1980)
Interaction between dipyridamole and Eudragit S
D. Beten (1992)
Handbook of Pharmaceutical Excipients
R. C. Rowe (1994)
A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection.
M. Markowitz (1995)
Saquinavir pharmacokinetics alone and in combination with nelfinavir in HIV‐infected patients
Concepta Merry (1997)
Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV‐infected patients
Concepta Merry (1997)
Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir.
V. Eagling (1997)
Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions.
C. Decker (1998)
Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease
D. W. Cameron (1998)
Randomised placebo-controlled trial of r i t o n a v i r i n a d v an ced HIV- 1 d i s e a s e
DW Cameron (1998)
Improving the Oral Bioavailability of Albendazole in Rabbits by the Solid Dispersion Technique
N. Kohri (1999)
The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals.
R. V. van Heeswijk (1999)
The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring.
G. Gatti (1999)
Quantitation of crystallinity in substantially amorphous pharmaceuticals and study of crystallization kinetics by X-ray powder diffractometry
Rahul K. Surana (2000)
Gastric pH profiles of beagle dogs and their use as an alternative to human testing.
Masayuki Akimoto (2000)
Physicochemical considerations in the preparation of amorphous ritonavir-poly(ethylene glycol) 8000 solid dispersions.
D. Law (2001)
pH-Dependent Dissolution in Vitro and Absorption in Vivo of Weakly Basic Drugs: Development of a Canine Model
R. Zhou (2004)
Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations.
D. Law (2004)
Statistical approaches to establishing bioequivalence
L. Jing (2004)
Molecular Mobility of Amorphous Pharmaceutical Solids Below Their Glass Transition Temperatures
Bruno C. Hancock (2004)
Comparison of Canine and Human Gastrointestinal Physiology
J. Dressman (2004)
Population pharmacokinetics of lopinavir in combination with ritonavir in HIV-1-infected patients.
K. Crommentuyn (2005)
Effect of chronic administration of ritonavir on function of cytochrome P450 3A and P-glycoprotein in rats.
M. Kageyama (2005)
Use of Surfactants as Plasticizers in Preparing Solid Dispersions of Poorly Soluble API: Stability Testing of Selected Solid Dispersions
A. Ghebremeskel (2006)
PAMPA--critical factors for better predictions of absorption.
A. Avdeef (2007)
Evaluation of the USP dissolution test method A for enteric-coated articles by planar laser-induced fluorescence.
D. Miller (2007)
Influence of CYP3A4 Inhibition on the Steady-State Pharmacokinetics of Imatinib
N. V. van Erp (2007)
Bioequivalence Approaches for Highly Variable Drugs and Drug Products
Sam H. Haidar (2007)
A calorimetric investigation of thermodynamic and molecular mobility contributions to the physical stability of two pharmaceutical glasses.
Deliang Zhou (2007)
The effect of cytochrome P 450 metabolism on drug response , interactions , and adverse effects
C Merry (2007)
Prediction of glass transition temperatures: Binary blends and copolymers
W. Brostow (2008)
Enhanced In Vivo Absorption of Itraconazole via Stabilization of Supersaturation Following Acidic-to-Neutral pH Transition
D. Miller (2008)
Characterization of amorphous API:Polymer mixtures using X-ray powder diffraction.
A. Newman (2008)
Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview.
D. R. Friesen (2008)
inventors; Abbott Laboratories, assignee. Solid pharmaceutical dosage formulations
G Berndl (2008)
Dissolution of poorly water-soluble drugs in biphasic media using USP 4 and fiber optic system
S. Vangani (2009)
Utility of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) for Initiation and Maintenance of Drug Supersaturation in the GI Milieu
W. Curatolo (2009)
Fed and fasted gastric pH and gastric residence time in conscious beagle dogs.
Kazuko Sagawa (2009)
Dissolution Enhancement of a Drug Exhibiting Thermal and Acidic Decomposition Characteristics by Fusion Processing: A Comparative Study of Hot Melt Extrusion and KinetiSol® Dispersing
Justin R. Hughey (2010)
Fusion production of solid dispersions containing a heat-sensitive active ingredient by hot melt extrusion and Kinetisol dispersing.
James C Dinunzio (2010)
A classification system to assess the crystallization tendency of organic molecules from undercooled melts.
Jared A. Baird (2010)
Formation of nano/micro-dispersions with improved dissolution properties upon dispersion of ritonavir melt extrudate in aqueous media.
I. Tho (2010)
Predicting in vivo absorption behavior of oral modified release dosage forms containing pH-dependent poorly soluble drugs using a novel pH-adjusted biphasic in vitro dissolution test.
Ulrich Heigoldt (2010)
Application of a biphasic test for characterization of in vitro drug release of immediate release formulations of celecoxib and its relevance to in vivo absorption.
Y. Shi (2010)
LC-MS/MS studies of ritonavir and its forced degradation products.
R. N. Rao (2010)
Production of advanced solid dispersions for enhanced bioavailability of itraconazole using KinetiSol® Dispersing
James C Dinunzio (2010)
Development of a canine model to enable the preclinical assessment of pH-dependent absorption of test compounds.
R. M. Fancher (2011)
Thermal processing of a poorly water-soluble drug substance exhibiting a high melting point: the utility of KinetiSol® Dispersing.
Justin R. Hughey (2011)
Effect of gastric pH on the pharmacokinetics of a BCS class II compound in dogs: utilization of an artificial stomach and duodenum dissolution model and GastroPlus,™ simulations to predict absorption.
Shobha N. Bhattachar (2011)
Solid-state NMR characterization of high-loading solid solutions of API and excipients formed by electrospinning.
Blair K Brettmann (2012)
Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems
Daniel J. Phillips (2012)
inventors; Abbott Laboratories, assignee. Solid pharmaceutical dosage form
J Rosenberg (2012)
Inhibitory effect of hydroxypropyl methylcellulose acetate succinate on drug recrystallization from a supersaturated solution assessed using nuclear magnetic resonance measurements.
K. Ueda (2013)
Evaluation of gastrointestinal drug supersaturation and precipitation: strategies and issues.
Jan Bevernage (2013)
Hot melt extrusion for amorphous solid dispersions: temperature and moisture activated drug-polymer interactions for enhanced stability.
Ashish L. Sarode (2013)
Interactions between drugs and polymers influencing hot melt extrusion
Y. Li (2014)
Investigating miscibility and molecular mobility of nifedipine-PVP amorphous solid dispersions using solid-state NMR spectroscopy.
Xiaoda Yuan (2014)
In vivo predictive mini-scale dissolution for weak bases: Advantages of pH-shift in combination with an absorptive compartment.
K. J. Frank (2014)
Use of the pentagastrin dog model to explore the food effects on formulations in early drug development.
P. Zane (2014)
ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection.
P. Andreone (2014)
Supersaturation, nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs.
Ashish L. Sarode (2014)
Investigation of drug-excipient interactions in lapatinib amorphous solid dispersions using solid-state NMR spectroscopy.
Yang Song (2015)
Challenges and Strategies in Thermal Processing of Amorphous Solid Dispersions: A Review
Justin S. LaFountaine (2015)
Ritonavir-boosted protease inhibitor based therapy: a new strategy in chronic hepatitis C therapy
Samuel W Brayer (2015)
Investigation of a suitable in vitro dissolution test for itraconazole-based solid dispersions.
J. Thiry (2016)
Bioavailability enhancement of a BCS IV compound via an amorphous combination product containing ritonavir
D. Miller (2016)
Enabling thermal processing of ritonavir-polyvinyl alcohol amorphous solid dispersions by KinetiSol® Dispersing.
Justin S. Lafountaine (2016)
Investigation and Mathematical Description of the Real Driving Force of Passive Transport of Drug Molecules from Supersaturated Solutions.
E. Borbás (2016)
A phase I dose-escalation trial of bi-daily (BID) weekly oral docetaxel as ModraDoc006 in combination with ritonavir
V. D. Weger (2016)
inventors; DisperSol Technologies, LLC, assignee. Formulations of deferasirox and methods of making the same
DA Miller (2016)
inventors; Pion Inc., assignee. Apparatus and method for the assessment of concentration profiling and permeability rates
AS Narang (2016)
Impact of Drug-Rich Colloids of Itraconazole and HPMCAS on Membrane Flux in Vitro and Oral Bioavailability in Rats.
Aaron M. Stewart (2017)
Predicting the Crystallization Propensity of Drug-Like Molecules.
Bruno C. Hancock (2017)
Absorptive Dissolution Testing of Supersaturating Systems: Impact of Absorptive Sink Conditions on Solution Phase Behavior and Mass Transport.
Siddhi S Hate (2017)
Expanding the Application and Formulation Space of Amorphous Solid Dispersions with KinetiSol®: a Review
Daniel J Ellenberger (2018)
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Daniel A. Davis (2020)
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S. Arora (2020)
Selective Laser Sintering 3-Dimensional Printing as a Single Step Process to Prepare Amorphous Solid Dispersion Dosage Forms for Improved Solubility and Dissolution rate.
Daniel A. Davis (2020)
Biorelevant two-stage in vitro testing for rDCS classification and in PBPK modelling - Case example ritonavir.
Tom Fiolka (2020)
Innovations in Thermal Processing: Hot-Melt Extrusion and KinetiSol® Dispersing
D. Tan (2020)
The tangential flow absorption model (TFAM) - a novel dissolution method for evaluating the performance of amorphous solid dispersions of poorly water-soluble actives.
Bastian Haering (2020)