Complexation of oxethazaine with 2‐hydroxypropyl‐β‐cyclodextrin: increased drug solubility, decreased cytotoxicity and analgesia at inflamed tissues

Objectives Oxethazaine (OXZ) is one of the few local anaesthetics that provides analgesia at low pH, but presents poor solubility, cytotoxicity and no parenteral formulations. To address these issues, we aimed to prepare OXZ host‐guest inclusion complex with hydroxypropyl‐beta‐cyclodextrin (HP‐β‐CD)...

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Published in:Journal of pharmacy and pharmacology 2017-06, Vol.69 (6), p.652-662
Main Authors: Prado, Andressa R., Yokaichiya, Fabiano, Franco, Margareth Kazuyo Kobayashi Dias, Silva, Camila Morais Gonçalves da, Oliveira‐Nascimento, Laura, Franz‐Montan, Michelle, Volpato, Maria C., Cabeça, Luís F., Paula, Eneida
Format: Article
Language:English
Subjects:
2-Hydroxypropyl-beta-cyclodextrin - chemistry
Analgesia - methods
Anesthetics, Local - chemistry
Anesthetics, Local - pharmacology
Animals
BALB 3T3 Cells
bioassay approaches
Calorimetry, Differential Scanning - methods
Cell Line
Cell Survival - drug effects
Chemistry, Pharmaceutical - methods
dosage form design and characterization
Drug Compounding - methods
Ethanolamines - chemistry
Ethanolamines - pharmacology
Inflammation - drug therapy
Magnetic Resonance Spectroscopy - methods
Mice
Microscopy, Electron, Scanning - methods
Pain - drug therapy
Pain Management - methods
pharmaceutical analysis
pharmaceutics and drug delivery
Rats
Rats, Wistar
Solubility
Spectroscopy, Fourier Transform Infrared - methods
X-Ray Diffraction - methods
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Summary:Objectives Oxethazaine (OXZ) is one of the few local anaesthetics that provides analgesia at low pH, but presents poor solubility, cytotoxicity and no parenteral formulations. To address these issues, we aimed to prepare OXZ host‐guest inclusion complex with hydroxypropyl‐beta‐cyclodextrin (HP‐β‐CD). Methods The inclusion complex was formed by co‐solubilization, followed by a job plot analysis to determine stoichiometry of complexation and dialysis equilibrium analysis (based on UV/VIS absorption and fluorescence profiles of OXZ). Complex formation was confirmed by phase‐solubility data, X‐ray, Scanning Electron Microscopy and DOSY‐1H‐NMR experiments. In vitro cytotoxicity was analysed by MTT test in 3T3 fibroblasts. In vivo analgesia was tested by Von Frey test (inflammatory wounds – rats). Key findings Oxethazaine complexed (1 : 1 molar ratio) with HP‐β‐CD, as indicated by loss of OZX crystalline structure (X‐ray) and strong host: guest interaction (NMR, K = 198/M), besides increased solubility. In vitro cell survival improved with the complex (IC50 OXZ = 28.9 μm, OXZ : HP‐β‐CD = 57.8 μm). In addition, the complex (0.1% OXZ) promoted in vivo analgesia for the same time that 2% lidocaine/epinephrine did. Conclusion Our results show that complexation improved physicochemical and biological properties of OXZ, allowing its application to inflamed tissues by parenteral routes.
ISSN:0022-3573
2042-7158
DOI:10.1111/jphp.12703