Abstract
The objective of the present investigation was to study the ability of sulfobutylether-β-cyclodextrin (SBEβCD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBEβCD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (Papp). In addition, SEV binding affinity to SBEβCD was confirmed by a minimal Gibbs free energy of binding (ΔGbind) value of −1.727 ± 0.042 kcal·mol−1 and an average binding constant (Kb) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.
Highlights
Sevoflurane (SEV, fluoromethylhexafluoroisopropyl ether), is an inhalational anesthetic recommended for almost 40 years for induction and maintenance of general anesthesia [1]
In the first phase of the investigations, the SBEβCD and SEV-SBEβCD compounds were investigated by X-ray powder diffractometry and polarized light microscopy to verify the amorphous or crystalline character of the studied compounds
The coarse-grained, porous macroscopic structure of the solid-state lyophilized SEV-SBEβCD complex was observed as semi-uniform with concentric porosity (Figure S1, Supplementary Material)
Summary
Sevoflurane (SEV, fluoromethylhexafluoroisopropyl ether), is an inhalational anesthetic recommended for almost 40 years for induction and maintenance of general anesthesia [1]. There is a rapid increase in the alveolar concentration (FA) of this anesthetic toward the inspired concentration during induction This will impose some difficulties on the SEV bioavailability as a result of the insufficient FA rate, which could be improved via an intravenously injectable formulation of SEV with hydrophilic/amphiphilic cyclodextrins (CDs), including sevoflurane-sulfobutylether-β-cyclodextrin (SBEβCD). SBEβCD is a solubilizing agent for poorly water-soluble compounds used in the formulation of both solid dosage and parenteral forms [5]. It has been previously demonstrated that SBEβCD possesses no cytotoxic effect on heterogeneous human epithelial colorectal adenocarcinoma (Caco-2) cells [9] and has a minimal capacity to solubilize cholesterol and other membrane lipids [10]. We analyzed the interaction of SEV and SBEβCD using the molecular docking technique to predict the SEV binding affinity to cyclodextrin and to define the factors responsible for the drug release kinetics
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