title: Interaction of fentanyl with various cyclodextrins in aqueous solutions.
abstract: OBJECTIVE
  Water-soluble fentanyl citrate salt has been used in sublingual or buccal formulations for the breakthrough pain treatment. However, fentanyl absorption through the lipid mucosal membrane may be improved by enhancing the non-ionic lipophilic fentanyl base solubility. Therefore, the interaction between cyclodextrins (CDs) and fentanyl base has been evaluated to obtain basic information for its application.
  
  
  METHODS
  Parent CDs (α-, β- and γ-CD) as well as α- and β-CD derivatives were used for solubility studies with fentanyl base. Nuclear magnetic resonance (NMR) studies were applied in a system including β-CD or glucosyl-β-CD (G1-β-CD) with fentanyl base or fentanyl citrate. (1) H- and (13) C-NMR studies and a two-dimensional rotating frame Overhauser effect spectroscopy (ROESY) study were conducted to confirm inclusion complexes formation.
  
  
  RESULTS
  Parent CDs displayed BS type phase solubility diagrams; β-CD exhibited a strong interaction with fentanyl base. Hydrophilic β-CD derivatives, such as G1-β-CD, displayed AL type phase diagrams and higher solubilizing effects compared with parent CDs. ROESY study suggested that fentanyl phenyl groups were included in β-CD cavity.
  
  
  CONCLUSIONS
  This study revealed that hydrophilic β-CD derivatives, such as G1-β-CD, could be useful pharmaceutical additives for oral mucosal formulations because of the improved fentanyl base solubility via inclusion complexation.
authors.affiliation: Department of Pharmaceutical Engineering, School of Pharmacy, Aichi Gakuin University, Nagoya, Iceland.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ogawa
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Iceland.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Furuishi
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Iceland.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Iceland.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Endo
authors.affiliation: Department of Pharmaceutical Engineering, School of Pharmacy, Aichi Gakuin University, Nagoya, Iceland.
authors.forename: Chisato
authors.initials: C
authors.lastname: Takahashi
authors.affiliation: Department of Pharmaceutical Engineering, School of Pharmacy, Aichi Gakuin University, Nagoya, Iceland.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Pharmaceutical Engineering, School of Pharmacy, Aichi Gakuin University, Nagoya, Iceland.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawashima
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Thorsteinn
authors.initials: T
authors.lastname: Loftsson
authors.affiliation: Department of Physical Chemistry, Nihon Pharmaceutical University, Saitama, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Physical Chemistry, Nihon Pharmaceutical University, Saitama, Japan.
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Ueda
mesh_terms: D000278:Administration, Buccal; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000737:chemistry*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D003505:Cyclodextrins / Q000737:chemistry*; D004339:Drug Compounding; D005079:Excipients / Q000737:chemistry*; D005283:Fentanyl / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008956:Models, Chemical; D066244:Proton Magnetic Resonance Spectroscopy; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D000701:Analgesics, Opioid; D003505:Cyclodextrins; D005079:Excipients; D012997:Solvents; D014867:Water; D005283:Fentanyl
keywords: cyclodextrin; fentanyl base; fentanyl citrate; inclusion complex; nuclear magnetic resonance