Physicochemical properties, NMR spectroscopy and tolerance of inclusion complexes of antazoline and tetracaine with hydroxypropyl-β-cyclodextrin

To improve the tolerance of antazoline and tetracaine ophthalmic solutions, inclusion complexes of the free bases of both drugs with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were prepared. The physicochemical properties of the drug:HP-beta-CD solutions were determined and the inclusion complexes were characterised by H-1 and C-13 NMR spectroscopy. The apparent complex constants were calculated from the phase-solubility diagram and were estimated at 403 M-1 and 1308 M-1 for the antazoline:HP-beta-CD complex and tetracaine:HP-beta-CD complex, respectively. H-1 and C-13 NMR analysis showed that in the 1:1 complexes the total antazoline fraction was present as an inclusion complex, whereas tetracaine was only partly included in spite of a similar phase solubility diagram. NMR spectroscopy also revealed the site of interaction of the drugs with the HP-beta-CD molecule. A solution acceptability test was carried out on volunteers. A relationship between the surface tension of the solutions and the tolerance was observed. (C) 1998 Elsevier Science B.V. All rights reserved.