Cyclodextrin-based MOFs for oral delivery of fingolimod with enhanced pharmacokinetics.

This study is aimed to improve the pharmacologically important properties of fingolimod – an immunomodulatory drug for multiple sclerosis treatment. Cyclodextrin-based metal-organic frameworks (CD-MOFs) were considered as advanced biocompatible delivery systems, which are able to increase the aqueous solubility, dissolution rate and pharmacokinetics of lipophilic fingolimod. CD-MOFs synthesized on the basis of K+ cations and native α-, β- and γ-cyclodextrins differ in structure and properties. In this work, the influence of surface area, pore dimensions and particle size of CD-MOFs on their capability to fingolimod encapsulation was analyzed for the first time. It was shown that loading of fingolimod into γCD-MOF is more effective compared with αCD-MOF and βCD-MOF. Adsorption of fingolimod on all CD-MOFs under study is a physical process, mechanism of which depends on the CD-MOF porosity. Adsorption of fingolimod on βCD-MOF possessing low surface area is well described by the Langmuir model, whereas the Freundlich model better simulates the fingolimod adsorption on αCD-MOF and γCD-MOF having highly developed surface area. Crystallization of fingolimod in αCD-MOF displaying higher surface area and pore radius was detected; while the drug fully integrates into βCD-MOF and γCD-MOF, causing the disappearance of the drug crystalline phase. Loading in CD-MOF increases the thermal stability of fingolimod. Moreover, in vitro release study showed that dissolution rate of fingolimod loaded into CD-MOFs is considerably increased in phosphate buffer (pH = 6.8). The in vivo experiments showed that bioavailability of orally administrated fingolimod can be improved via encapsulation in γCD-MOF. The obtained results confirm the feasibility of CD-MOFs in design of novel dosage forms of fingolimod for oral administration.