A hydrophobic ion-pairing (HIP) concept considering the high dissociation property of alendronate was used as a strategy to improve the bioavailability of alendronate. Alendronate, which has a negative charge, was ion-paired with organic cations, such as tetraheptylammonium bromide (THAB) or tetrabutylammonium iodide (TBAI), to confer hydrophobicity to alendronate, and increase its intestinal permeability. Solutions containing various concentrations (0.5 to 100 mM) of organic cations were combined with an alendronate solution (5 mM) at molar ratios from 0.1:1 to 20:1 under various pHs (pH 2.2, 6.3 and 10.3). Alendronate exhibited high hydrophobicity when coupled with THAB at a molar ratio of 1:10 in pH 2.2. On the other hand, HIP complexes between alendronate and TBAI showed the maximum hydrophobicity at the same molar ratio at pH 10.3. The zeta potentials of alendronate from the aqueous layer of the HIP complex between alendronate and THAB or TBAI increased gradually with increasing alendronate to THAB molar ratio at pH 2.2 or pH 10.3, respectively. This is the first report of the production of hydrophobic ion-paired alendronate.

This study examined a novel alendronate formulation that was developed to overcome the shortcomings of alendronate, such as its low bioavailability and gastric adverse effects. Alendronate microparticles were prepared using mucoadhesive polymers such as chitosan for improving the intestinal cellular absorption of alendronate and also using a gastric-resistant polymer such as Eudragit L100-55 for reducing the gastric inflammation of alendronate. Alendronate microparticles including chitosan showed a threefold increase in alendronate uptake (6.92 ± 0.27%) in Caco-2 cells when compared with the uptake of alendronate solution (2.38 ± 0.27%) into Caco-2 cells. Most interestingly, alendronate microparticles including chitosan showed 2.80 x 10⁻⁶ cm/s of an apparent permeability coefficient across Caco-2 cells and caused a significant 42.4% enhancement compared with that of alendronate solution across Caco-2 cells. The morphology of the Caco-2 cells treated with alendronate microparticles including chitosan was similar to that of the untreated cells and alendronate microparticles exhibited a negative effect to propodium iodide with some annexin-V fluorescence isothiocyante positive effect. It was proposed that the novel alendronate microparticles could possess the potential of an increased intestinal absorption and fewer adverse effects of alendronate.