Toward Successful Cyclodextrin Based Solubility-Enabling Formulations for Oral Delivery of Lipophilic Drugs: Solubility-Permeability Trade-Off, Biorelevant Dissolution, and the Unstirred Water Layer

Molecular Pharmaceutics
Noa Fine-ShamirArik Dahan

Abstract

The purpose of this work was to investigate key factors dictating the success/failure of cyclodextrin-based solubility-enabling formulations for oral delivery of low-solubility drugs. We have studied the solubility, the permeability, and the solubility-permeability interplay, of the highly lipophilic drug danazol, formulated with different levels (8.5, 10, 20, and 30%) of the commonly used hydroxypropyl-β-cyclodextrin (HPβCD), accounting for the biorelevant solubilization of the drug along the gastrointestinal tract (GIT), the unstirred water layer (UWL) adjacent to the GI membrane, and the overall absorption. HPβCD significantly increased danazol solubility, and decreased the drugs' permeability, in a concentration-dependent manner. These Peff results were in good correlation (R2 = 0.977) to literature rat AUC data of the same formulations. Unlike vehicle without HPβCD, formulations containing 8.5% HPβCD and above were shown to successfully dissolve the drug dose during the entire biorelevant dissolution experiment. We conclude that CD-based solubility-enabling formulations should contain the minimal amount of CD sufficient to dissolve the drug dose throughout the GIT, and not more than that; excess CD does not provide solubil...Continue Reading

References

Apr 25, 2003·Journal of Pharmaceutical Sciences·Venkatramana M Rao, Valentino J Stella
Nov 22, 2005·Expert Opinion on Drug Delivery·Thorsteinn LoftssonTomi Järvinen
Mar 3, 2007·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Arik Dahan, Amnon Hoffman
Jul 3, 2007·Advanced Drug Delivery Reviews·Marcus E Brewster, Thorsteinn Loftsson
May 24, 2008·Journal of Controlled Release : Official Journal of the Controlled Release Society·Arik Dahan, Amnon Hoffman
Jun 30, 2009·Physical Chemistry Chemical Physics : PCCP·René HolmPeter Westh
Sep 3, 2009·Biotechnology and Bioengineering·Ece Dilber GamsizRebecca Lyn Carrier
Mar 6, 2012·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Avital BeigArik Dahan
Mar 31, 2012·International Journal of Pharmaceutics·Christos C LioliosGregory B Sivolapenko
Apr 25, 2012·Molecular Pharmaceutics·Arik DahanGordon L Amidon
May 15, 2012·Biopharmaceutics & Drug Disposition·Ryusuke TakanoShinji Yamashita
Aug 1, 2012·Biopharmaceutics & Drug Disposition·Deanna M MudieGregory E Amidon
Apr 16, 2013·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Stephen Timothy BuckleyMartin Brandl
Jun 19, 2013·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Avital BeigArik Dahan
Jan 6, 2015·Expert Opinion on Drug Delivery·Irina CherniakovAmnon Hoffman
May 17, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Yasuhiro TsumeGordon L Amidon
May 26, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Bart HensPatrick Augustijns
May 27, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Avital BeigArik Dahan
Jan 19, 2016·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·René HolmPeter Westh
Mar 2, 2016·Advanced Drug Delivery Reviews·Christel A S BergströmChristopher J H Porter
Mar 13, 2016·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Niels Erik OlesenRené Holm
Apr 3, 2016·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Yong ChenYogeshvar N Kalia
Apr 6, 2016·AAPS PharmSciTech·J Carolina VisserHenderik W Frijlink
May 1, 2016·Advanced Drug Delivery Reviews·Arik DahanJonathan M Miller
Aug 5, 2016·Expert Opinion on Drug Delivery·Sophia Yui Kau FongMartin Brandl

❮ Previous
Next ❯

Citations

May 16, 2017·International Journal of Pharmaceutics·Isabel Lozoya-AgulloArik Dahan
Jan 4, 2019·Current Pharmaceutical Design·Fakhara SabirNaveed Ahmed
Jul 25, 2019·Current Drug Targets·Nidhi NainwalVikas Anand Saharan
Feb 19, 2020·British Journal of Clinical Pharmacology·Sara AsimusDavid Keeling
Jan 30, 2018·PLoS Computational Biology·Rahila RahimovaLaurent Chaloin
Oct 16, 2018·Medicinal Research Reviews·Milica MarkovicArik Dahan
Jun 21, 2020·Biomolecules·Mikołaj MizeraJudyta Cielecka-Piontek
Oct 19, 2017·The Journal of Physical Chemistry. B·Josh V VermaasMichael F Crowley
Jun 30, 2018·Molecular Pharmaceutics·Enikő BorbásZsombor K Nagy

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.