1. Toward Successful Cyclodextrin Based Solubility-Enabling Formulations for Oral Delivery of Lipophilic Drugs: Solubility–Permeability Trade-Off, Biorelevant Dissolution, and the Unstirred Water Layer
- Author
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Noa Fine-Shamir, Moran Zur, Jonathan M. Miller, Arik Dahan, Avital Beig, and David Lindley
- Subjects
Absorption (pharmacology) ,Drug ,Chemistry, Pharmaceutical ,media_common.quotation_subject ,Administration, Oral ,Pharmaceutical Science ,02 engineering and technology ,030226 pharmacology & pharmacy ,Excipients ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,medicine ,Solubility ,Dissolution ,media_common ,chemistry.chemical_classification ,Cyclodextrins ,Chromatography ,Intestinal permeability ,Cyclodextrin ,Chemistry ,Danazol ,beta-Cyclodextrins ,021001 nanoscience & nanotechnology ,medicine.disease ,Intestinal Absorption ,Water layer ,Molecular Medicine ,0210 nano-technology ,Drug metabolism - 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...
- Published
- 2017