The effect of cyclodextrins on the aqueous solubility of a new MMP inhibitor: phase solubility, 1 H-NMR spectroscopy and molecular modeling studies, preparation and stability study of nebulizable solutions.

PURPOSE Ro 28-2653 (RO) is a synthetic inhibitor of matrix metalloproteinases (MMPs), which is potentially effective against bronchial remodeling. Given that this molecule has very poor aqueous solu- bility, different cyclodextrins (CDs) have been tested to increase its solubility. The aim of this study was to prepare and to characterize inclusion complexes between RO and CDs, in order to develop nebulizable solutions. METHODS The complex formation was investigated by phase solubility studies. 1 H-NMR spec- troscopy and molecular modeling studies were carried out to elucidate the structure of the inclusion complex between RO and dimethyl-β-CD (DIMEB). Nebuliz- able solutions of RO were developed with CDs and a stability study was performed over 9 months. RESULTS The phase solubility studies showed that β- CD and its derivatives form a 1:2 complex with RO, whereas γ-CD includes RO with a 1:1 stoichiometry and a weak stability constant. T-ROESY spectra showed that DIMEB is able to complex two RO sub- stituents (nitrophenyl and biphenyl groups) with pref- erential orientations, while molecular modeling demonstrated that the configurations observed with 1 H-NMR are energetically favorable, especially owing to H-bond formation between RO and DIMEB. Two CDs were selected to develop nebulizable solutions of RO and the stability study demonstrated that RO deg- radation in solution is strongly dependent on the con- centration of the 1:2 inclusion complex. CONCLUSIONS CDs are able to include RO and to improve its aqueous solubility. The β-CD derivatives can be used to formulate nebulizable solutions of RO, the stability of which depends on the concentration of the 1:2 complex.