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.
OBJECTIVE
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 solubility, 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 spectroscopy and molecular modeling studies were carried out to elucidate the structure of the inclusion complex between RO and dimethyl-beta-CD (DIMEB). Nebulizable solutions of RO were developed with CDs and a stability study was performed over 9 months.


RESULTS
The phase solubility studies showed that beta-CD and its derivatives form a 1:2 complex with RO, whereas gamma-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 substituents (nitrophenyl and biphenyl groups) with preferential 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 degradation in solution is strongly dependent on the concentration of the 1:2 inclusion complex.


CONCLUSIONS
CDs are able to include RO and to improve its aqueous solubility. The beta-CD derivatives can be used to formulate nebulizable solutions of RO, the stability of which depends on the concentration of the 1:2 complex.
Bertholet
Pascal
P
Laboratory of Pharmaceutical Technology, Department of Pharmacy, University of Liège, Belgium. p.bertholet@ulg.ac.be
Gueders
Maud
M
Dive
Georges
G
Albert
Adelin
A
Barillaro
Valery
V
Perly
Bruno
B
Cataldo
Didier
D
Piel
Géraldine
G
Delattre
Luc
L
Evrard
Brigitte
B
D003505:Cyclodextrins / Q000032:analysis / Q000737:chemistry*; D004355:Drug Stability; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D009330:Nebulizers and Vaporizers; D019999:Pharmaceutical Solutions / Q000032:analysis / Q000737:chemistry; D010879:Piperazines / Q000032:analysis / Q000737:chemistry*; D011480:Protease Inhibitors / Q000032:analysis / Q000737:chemistry; D011522:Protons; D011743:Pyrimidines / Q000032:analysis / Q000737:chemistry*; D012995:Solubility / Q000187:drug effects; D014867:Water / Q000737:chemistry
D003505:Cyclodextrins; D061965:Matrix Metalloproteinase Inhibitors; D019999:Pharmaceutical Solutions; D010879:Piperazines; D011480:Protease Inhibitors; D011522:Protons; D011743:Pyrimidines; C453902:Ro 28-2653; D014867:Water