Interaction Study of an Amorphous Solid Dispersion of Cyclosporin A in Poly-Alpha-Cyclodextrin with Model Membranes by 1H-, 2H-, 31P-NMR and Electron Spin Resonance

The properties of an amorphous solid dispersion of cyclosporine A (ASD) prepared with the copolymer alpha cyclodextrin (POLYA) and cyclosporine A (CYSP) were investigated by 1H-NMR in solution and its membrane interactions were studied by 1H-NMR in small unilamellar vesicles and by 31P 2H NMR in phospholipidic dispersions of DMPC (dimyristoylphosphatidylcholine) in comparison with those of POLYA and CYSP alone. 1H-NMR chemical shift variations showed that CYSP really interacts with POLYA, with possible adduct formation, dispersion in the solid matrix of the POLYA, and also complex formation. A coarse approach to the latter mechanism was tested using the continuous variations method, indicating an apparent 1？:？1 stoichiometry. Calculations gave an apparent association constant of log？Ka = 4.5. A study of the interactions with phospholipidic dispersions of DMPC showed that only limited interactions occurred at the polar head group level (31P). Conversely, by comparison with the expected chain rigidification induced by CYSP, POLYA induced an increase in the fluidity of the layer while ASD formation led to these effects almost being overcome at 298？K. At higher temperature, while the effect of CYSP seems to vanish, a resulting global increase in chain fluidity was found in the presence of ASD. 1. Introduction One challenging task in the manufacturing process is to improve the bioavailability of poorly water-soluble drugs. Thus, in recent decades, numerous potentially bioactive pharmaceutical ingredients (APIs) were found to have only low aqueous solubility. As a result, oral delivery of poorly water-soluble drugs often results in low bioavailability. Poorly water-soluble drugs cannot achieve dissolution and therefore have great difficulty passing through digestive fluid to contact absorbing mucosa and be absorbed. If the drug molecules’ dissolution process is slow, due to inherent physicochemical properties of the molecules or formulation factors, then dissolution may be the rate-limiting step in absorption and will influence drug bioavailability. This is the case with class II drugs, for example, cyclosporine A (CYSP) (according to the drug Biopharmaceutics Classification System (BCS)). Cyclosporin A (CYSP), a hydrophobic cyclic peptide, is widely used as an immunosuppressant drug for transplant therapy [1, 2]. For this specific kind of drug, many enabling technologies are available for the formulator to consider, including lipids, cosolvents, surfactants, nanoparticles, cyclodextrin complexes, and amorphous solid dispersions. The suitability of a