Sufentanil-2‐Hydroxypropyl‐β‐Cyclodextrin Inclusion Complex for pain Treatment: Physicochemical, Cytotoxicity, and Pharmacological Evaluation

Sufentanil (SUF) is a synthetic analgesic opioid widely used for the management of acute and chronic pain. This drug was complexed with 2‐hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) and the physicochemical characterization, in vitro/ex vivo toxicity assays, and pharmacological evaluation were performed. Differential scanning calorimetry, Fourier transform infrared spectroscopy (FTIR) analysis, and X‐ray powder diffraction showed the formation and the morphology of the complex. Nuclear magnetic resonance afforded data regarding inclusion complex stoichiometry (1:1) with an association binding constant (Ka) value of 515.2 ± 1.2 M−1 between SUF and HP‐β‐CD. Complexation with HP‐β‐CD protected SUF from light exposure and increased its photostability. Release kinetics revealed a decrease in SUF release rate (Krel = 7.05 ± 0.52 and 5.61 ± 0.39 min−1/2 for SUF-HP‐β‐CD and SUF, respectively) and reduced hemolytic or myotoxic effects after complexation. Time course of tail‐flick test showed that the duration of analgesia induced by SUF (150.0 ± 34.6 min) was significantly increased (p < 0.001) after complexation with HP‐β‐CD (355.7 ± 47.2 min) when injected at the same dose (1 μg kg−1), prolonging the duration of analgesia after intramuscular administration and representing an alternative on the development of effective and safe drug‐delivery system for opioid analgesics.