Interaction of fentanyl with various cyclodextrins in aqueous solutions

• Published in: Journal of pharmacy and pharmacology 2016-05, Vol.68 (5), p.588-597
• Main Authors: Ogawa, Noriko, Furuishi, Takayuki, Nagase, Hiromasa, Endo, Tomohiro, Takahashi, Chisato, Yamamoto, Hiromitsu, Kawashima, Yoshiaki, Loftsson, Thorsteinn, Kobayashi, Masaru, Ueda, Haruhisa
• Format: Article
• Language: English
• Subjects: Administration, Buccal; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - chemistry; Aqueous solutions; Carbon-13 Magnetic Resonance Spectroscopy; cyclodextrin; Cyclodextrins - chemistry; Drug Compounding; Excipients - chemistry; Fentanyl - administration & dosage; Fentanyl - chemistry; fentanyl base; fentanyl citrate; Humans; Hydrophobic and Hydrophilic Interactions; inclusion complex; Models, Chemical; NMR; Nuclear magnetic resonance; Proton Magnetic Resonance Spectroscopy; Solubility; Solvents - chemistry; Studies; Water - chemistry
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1111/jphp.12437

Objectives 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. 1H‐ and 13C‐NMR studies and a two‐dimensional rotating frame Overhauser effect spectroscopy (ROESY) study were conducted to confirm inclusion complexes formation. Key findings 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.