The number of the cyclodextrin-containing drug formulations on the market has been continuously growing since the first drug (prostaglandin E1 formulated with α-cyclodextrin) was launched in Japan in 1976. We have collected a list of drugs from various sources available on the internet to find 130 approved pharmaceutical ingredients formulated with either parent cyclodextrins or their hydroxypropyl, sulfobutyl, random methylated or sulfolipo derivatives. We have sorted the drug products according to the cavity size of the cyclodextrins, the administration route and dosage forms.

We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (\(\Delta G_{solv}^{CR}\) = −9.98 kcal·mol\(^{−1}\)), which has a minimal \(\Delta G_{solv}^{OR}\) of −67.01 kcal·mol\(^{−1}\). A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco's Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring introduced inside the amphiphilic cavity of the host molecule. The OR binding affinity was confirmed by a minimal Gibbs free energy of binding (\(\Delta G_{bind}\)) value of −5.57 ± 0.02 kcal·mol\(^{−1}\), an equilibrium binding constant (\(K_{b}\)) of 79.89 ± 2.706 μM, and a ligand efficiency index (\(LE_{lig}\)) of −0.21 ± 0.001. Our current data suggest that in order to improve the clinical applications of midazolam via its complexation with trimethyl-β-cyclodextrin to increase drug's overall aqueous solubility, it is important to concern the different forms and ionization states of this anesthetic. All mean values are indicated with their standard deviations.

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 (P_app). In addition, SEV binding affinity to SBEβCD was confirmed by a minimal Gibbs free energy of binding (ΔG_bind) value of −1.727 ± 0.042 kcal·mol⁻¹ and an average binding constant (K_b) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.