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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)
10.1021/MA60074A029
Molecular Interpretation of the Glass Transition Temperature of Polymer-Diluent Systems
T. Chow (1980)
10.1016/0378-5173(92)90301-H
Interaction between dipyridamole and Eudragit S
D. Beten (1992)
Handbook of Pharmaceutical Excipients
R. C. Rowe (1994)
10.1056/NEJM199512073332204
A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection.
M. Markowitz (1995)
10.1097/00002030-199704000-00001
Saquinavir pharmacokinetics alone and in combination with nelfinavir in HIV‐infected patients
Concepta Merry (1997)
10.1097/00002030-199715000-00001
Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV‐infected patients
Concepta Merry (1997)
10.1046/J.1365-2125.1997.00644.X
Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir.
V. Eagling (1997)
10.1021/JS980029P
Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions.
C. Decker (1998)
10.1016/S0140-6736(97)04161-5
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)
10.1211/0022357991772277
Improving the Oral Bioavailability of Albendazole in Rabbits by the Solid Dispersion Technique
N. Kohri (1999)
10.1097/00002030-199910010-00001
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)
10.1097/00002030-199910220-00011
The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring.
G. Gatti (1999)
10.1017/S0885715600010757
Quantitation of crystallinity in substantially amorphous pharmaceuticals and study of crystallization kinetics by X-ray powder diffractometry
Rahul K. Surana (2000)
10.1016/S0939-6411(99)00070-3
Gastric pH profiles of beagle dogs and their use as an alternative to human testing.
Masayuki Akimoto (2000)
10.1002/JPS.1054
Physicochemical considerations in the preparation of amorphous ritonavir-poly(ethylene glycol) 8000 solid dispersions.
D. Law (2001)
10.1007/s11095-004-1185-3
pH-Dependent Dissolution in Vitro and Absorption in Vivo of Weakly Basic Drugs: Development of a Canine Model
R. Zhou (2004)
10.1002/JPS.10566
Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations.
D. Law (2004)
Statistical approaches to establishing bioequivalence
L. Jing (2004)
10.1023/A:1016292416526
Molecular Mobility of Amorphous Pharmaceutical Solids Below Their Glass Transition Temperatures
Bruno C. Hancock (2004)
10.1023/A:1016353705970
Comparison of Canine and Human Gastrointestinal Physiology
J. Dressman (2004)
10.1111/J.1365-2125.2005.02455.X
Population pharmacokinetics of lopinavir in combination with ritonavir in HIV-1-infected patients.
K. Crommentuyn (2005)
10.1248/BPB.28.130
Effect of chronic administration of ritonavir on function of cytochrome P450 3A and P-glycoprotein in rats.
M. Kageyama (2005)
10.1007/s11095-006-9034-1
Use of Surfactants as Plasticizers in Preparing Solid Dispersions of Poorly Soluble API: Stability Testing of Selected Solid Dispersions
A. Ghebremeskel (2006)
10.1002/JPS.21068
PAMPA--critical factors for better predictions of absorption.
A. Avdeef (2007)
10.1016/J.IJPHARM.2006.08.047
Evaluation of the USP dissolution test method A for enteric-coated articles by planar laser-induced fluorescence.
D. Miller (2007)
10.1158/1078-0432.CCR-07-0346
Influence of CYP3A4 Inhibition on the Steady-State Pharmacokinetics of Imatinib
N. V. van Erp (2007)
10.1007/s11095-007-9434-x
Bioequivalence Approaches for Highly Variable Drugs and Drug Products
Sam H. Haidar (2007)
10.1002/JPS.20633
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)
10.1016/J.MATLET.2008.02.008
Prediction of glass transition temperatures: Binary blends and copolymers
W. Brostow (2008)
10.1080/03639040801929273
Enhanced In Vivo Absorption of Itraconazole via Stabilization of Supersaturation Following Acidic-to-Neutral pH Transition
D. Miller (2008)
10.1002/jps.21352
Characterization of amorphous API:Polymer mixtures using X-ray powder diffraction.
A. Newman (2008)
10.1021/mp8000793
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)
10.1080/10601330902905887
Dissolution of poorly water-soluble drugs in biphasic media using USP 4 and fiber optic system
S. Vangani (2009)
10.1007/s11095-009-9852-z
Utility of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) for Initiation and Maintenance of Drug Supersaturation in the GI Milieu
W. Curatolo (2009)
10.1002/jps.21602
Fed and fasted gastric pH and gastric residence time in conscious beagle dogs.
Kazuko Sagawa (2009)
10.1208/s12249-010-9431-y
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)
10.1016/j.ejpb.2009.09.007
Fusion production of solid dispersions containing a heat-sensitive active ingredient by hot melt extrusion and Kinetisol dispersing.
James C Dinunzio (2010)
10.1002/jps.22197
A classification system to assess the crystallization tendency of organic molecules from undercooled melts.
Jared A. Baird (2010)
10.1016/j.ejps.2010.02.003
Formation of nano/micro-dispersions with improved dissolution properties upon dispersion of ritonavir melt extrudate in aqueous media.
I. Tho (2010)
10.1016/j.ejpb.2010.05.006
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)
10.1021/mp100114a
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)
10.1016/j.jpba.2010.06.004
LC-MS/MS studies of ritonavir and its forced degradation products.
R. N. Rao (2010)
10.3109/03639041003652973
Production of advanced solid dispersions for enhanced bioavailability of itraconazole using KinetiSol® Dispersing
James C Dinunzio (2010)
10.1002/jps.22486
Development of a canine model to enable the preclinical assessment of pH-dependent absorption of test compounds.
R. M. Fancher (2011)
10.1016/j.ijpharm.2011.08.007
Thermal processing of a poorly water-soluble drug substance exhibiting a high melting point: the utility of KinetiSol® Dispersing.
Justin R. Hughey (2011)
10.1002/jps.22669
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)
10.1002/jps.23032
Solid-state NMR characterization of high-loading solid solutions of API and excipients formed by electrospinning.
Blair K Brettmann (2012)
10.1111/j.2042-7158.2012.01523.x
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)
10.1021/mp400278j
Inhibitory effect of hydroxypropyl methylcellulose acetate succinate on drug recrystallization from a supersaturated solution assessed using nuclear magnetic resonance measurements.
K. Ueda (2013)
10.1016/j.ijpharm.2012.11.026
Evaluation of gastrointestinal drug supersaturation and precipitation: strategies and issues.
Jan Bevernage (2013)
10.1021/mp400165b
Hot melt extrusion for amorphous solid dispersions: temperature and moisture activated drug-polymer interactions for enhanced stability.
Ashish L. Sarode (2013)
10.1111/jphp.12183
Interactions between drugs and polymers influencing hot melt extrusion
Y. Li (2014)
10.1021/mp400498n
Investigating miscibility and molecular mobility of nifedipine-PVP amorphous solid dispersions using solid-state NMR spectroscopy.
Xiaoda Yuan (2014)
10.1016/j.ejps.2013.12.015
In vivo predictive mini-scale dissolution for weak bases: Advantages of pH-shift in combination with an absorptive compartment.
K. J. Frank (2014)
10.1016/j.ejps.2013.09.018
Use of the pentagastrin dog model to explore the food effects on formulations in early drug development.
P. Zane (2014)
10.1053/j.gastro.2014.04.045
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)
10.1016/j.ejpb.2013.10.005
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)
10.1021/mp500692a
Investigation of drug-excipient interactions in lapatinib amorphous solid dispersions using solid-state NMR spectroscopy.
Yang Song (2015)
10.1208/s12249-015-0393-y
Challenges and Strategies in Thermal Processing of Amorphous Solid Dispersions: A Review
Justin S. LaFountaine (2015)
10.1586/17474124.2015.1032938
Ritonavir-boosted protease inhibitor based therapy: a new strategy in chronic hepatitis C therapy
Samuel W Brayer (2015)
10.1016/j.ejps.2016.02.002
Investigation of a suitable in vitro dissolution test for itraconazole-based solid dispersions.
J. Thiry (2016)
10.1111/jphp.12478
Bioavailability enhancement of a BCS IV compound via an amorphous combination product containing ritonavir
D. Miller (2016)
10.1016/j.ejpb.2016.01.018
Enabling thermal processing of ritonavir-polyvinyl alcohol amorphous solid dispersions by KinetiSol® Dispersing.
Justin S. Lafountaine (2016)
10.1021/ACS.MOLPHARMACEUT.6B00613
Investigation and Mathematical Description of the Real Driving Force of Passive Transport of Drug Molecules from Supersaturated Solutions.
E. Borbás (2016)
10.1093/ANNONC/MDW368.42
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)
10.1021/acs.molpharmaceut.7b00338
Impact of Drug-Rich Colloids of Itraconazole and HPMCAS on Membrane Flux in Vitro and Oral Bioavailability in Rats.
Aaron M. Stewart (2017)
10.1016/j.xphs.2016.07.031
Predicting the Crystallization Propensity of Drug-Like Molecules.
Bruno C. Hancock (2017)
10.1021/acs.molpharmaceut.7b00740
Absorptive Dissolution Testing of Supersaturating Systems: Impact of Absorptive Sink Conditions on Solution Phase Behavior and Mass Transport.
Siddhi S Hate (2017)
10.1208/s12249-018-1007-2
Expanding the Application and Formulation Space of Amorphous Solid Dispersions with KinetiSol®: a Review
Daniel J Ellenberger (2018)



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