COMPLEXATION STUDIES OF THE PROTON PUMP INHIBITORS WITH
NATURAL AND MODIFIED CYCLODEXTRINS
L. Marzocchi1, A. Rossi1, J.R. Moyano2, R. Bettini1, A. Gazzaniga3, F. Giordano1
1
Pharmaceutical Department, Faculty of Pharmacy, University of Parma, Italy
2
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Spain
3
Institute for Pharmaceutical Chemistry , University of Milan, Italy
The class of drugs commonly referred to as the proton pump inhibitors (PPIs) is used in the
systemic treatment of many pathologies related to a hypersecretion of gastric acid. By covalently
binding certain critical cystein residues, present in the extracellular luminal domain of the proton
pump protein, the PPIs block the conformational reassessments responsible for the protein’s
pumping action, and thus inhibit the extrusion of protons into the lumen of the stomach 1,2.
However, an initial protonation of the PPI prodrug molecule itself is necessary. The
pharmacological potential of these compounds is currently harnessed in gastro-resistant oral
formulations which guarantee them a systemic effect and a localised protonation in the secretory
canalicula of the gastric mucosa. Whereas localised protonation triggers off biological activity in
vivo, the same series of events leads to their decomposition in vitro, making these compounds
difficult to manage during drug formulation.
The sole desire for greater stability and the welcomed prospect of better bioavailability make
PPIs perfect candidates for complexation with cyclodextrins3. These compounds (omeprazole and
derivatives) share the common chemical structure of a benzimidazole moiety linked, via a
methylensulfinyl bridge, to a pyridine ring and, theoretically, both of these aromatic moieties are
able to interact with the cyclodextrin cavity.
As part of a more ample research project4-6, the possibility of obtaining inclusion complexes
of native and modified cyclodextrins (–cyclodextrin, hydroxypropyl––cyclodextrin and the
sodium salt of sulfobutylether –cyclodextrin) with various PPIs , via kneading and freeze-drying
has been evaluated. Differential Scanning Calorimetry, Fourier Transform Infrared Spectroscopy,
and X-ray Diffractrometry on powder were used to characterise the resulting solid phases.
Furthermore, 1H NMR spectroscopy was chosen as the analytical technique to follow the
supramolecular interactions residing at the heart of inclusion complex formation in solution; the
continuous variations (Job’s Plot) and the phase-solubility7 methods were adopted to determine the
stoichiometry of the resulting complexes.
References
1. Besancon, M.; Simon, A.; Sachs, G. et al. Sites of Reaction of the Gastric H+,K+-ATPase with Extracytoplasmic
Thiol Reagents. J. Biol. Chem., 1997, 22, 438.
2. Sachs, G.; Shin, J.M.; Briving, C. et al. The Pharmacology of the Gastric Acid Pump: the H+,K+-ATPase. Ann. Rev.
Pharmacol. Toxicol., 1995, 35, 277.
3. Szejtli, J. In Cyclodextrin Technology. Davies, J.E.D. Ed.; Kluwer Acad. Pub., Dordrecht-Boston-London, 1998.
4. Arias, M.J.; Muñoz, P.; Moyano, J.R.; Ginés, J.M.; Novak, Cs. Thermal Studies of Different Omeprazole/-CD CoGround Systems. J. Thermal Anal., 1998, 51, 973.
5.
Arias, M.J.; Moyano, J.R.; Muñoz, P.; Ginés, J.M.; Justo, A.; Giordano, F. Study of Omeprazole/-Cyclodextrin
Complexation in the Solid State. Drug Dev. Ind. Pharm., 2000, 26, 253.
6.
Marzocchi; L.; Moyano, J.R; Rossi, A. ; Muñoz, P.; Arias, M.J; Giordano, F. Current Status of ATP-ase Proton
Pump Inhibitor Complexation with Cyclodextrins. Biolog. J. Armenia, 2001, 176.
7.
Higuchi, T; Connors, K.A. Adv. Anal. Chem. Instr. 1965, 4, 117.