Studies on the formation of hydrophobic ion-pairing complex of alendronate.
ABSTRACT 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.
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- "In particular, F101 and F112 showed a zeta potential of −7.19 ± 0.46 and 1.76 ± 0.28 mV, respectively. e zeta potential changed to a positive value from −6.98 ± 0.64 to 1.36 ± 0.41 mV with increasing chitosan to alendronate weight ratio from 0.05 to 1, suggesting that alendronate and chitosan can be complexed electrostatically during particle preparation (You et al., 2009). e changes in the solid state of alendronate were assessed using DSC analysis of the alendronate microparticles (Figure 2). "
ABSTRACT: 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.Journal of Drug Targeting 01/2011; 19(1):37-48. DOI:10.3109/10611861003667599 · 2.72 Impact Factor
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ABSTRACT: Alendronate is a poorly absorbed bisphosphonate with an oral bioavailability of 0.7%. In this study, a positively-charged microemulsion was prepared with the aim of improving the bioavailability of alendronate. The positively-charged microemulsion was evaluated for physical stability, cellular uptake and permeability enhancement on Caco-2 monolayers. The bioavailability of alendronate from the microemulsion was compared with the commercially available tablet (Fosmax) for beagle dogs. The 2.0, 0.4 and 0.2% positively-charged microemulsion, stable for 4 h after preparation, promoted alendronate transport across the Caco-2 cells by a factor of 194, 146,and 45.1, respectively, compared with the alendronate solution, though no significant cellular uptake enhancement of alendronate was observed. The permeability enhancement was parallel to the reduction in transendothelial electrical resistance, which indicated the microemulsion modulated the tight junctions and widened the paracellular pathway. In-vivo results showed that the microemulsion gave the highest alendronate plasma concentration at 502 ng/ml (C(max)) after 0.563 h (T(max)), while tablets gave a C(max) of 152 ng/ml after 0.750 h (T(max)). Furthermore, the AUC(0-∞) of alendronate from the microemulsion increased by 2.82-fold when compared with the tablets. Based on the results, the oral bioavailability of alendronate could be significantly improved by the positively-charged microemulsion, which opened the tight junctions and thus increased absorption through the paracellular route.03/2011; 63(3):400-8. DOI:10.1111/j.2042-7158.2010.01229.x
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ABSTRACT: Gemcitabine must be administered at high doses to elicit the required therapeutic response because of its very short plasma half-life due to rapid metabolism. These high doses can have severe adverse effects. In this study, polymeric microparticulate systems of gemcitabine were prepared using chitosan as a mucoadhesive polymer and Eudragit L100-55 as an enteric copolymer. The physicochemical and biopharmaceutical properties of the resulting systems were then evaluated. There was no endothermic peak for gemcitabine in any of the polymeric gemcitabine microparticulate systems, suggesting that gemcitabine was bound to chitosan and Eudragit L100-55 and its crystallinity was changed into an amorphous form. The polymeric gemcitabine microparticulate system showed more than 80% release of gemcitabine in 30 minutes in simulated intestinal fluid. When mucin particles were incubated with gemcitabine polymeric microparticulates, the zeta potential of the mucin particles was increased to 1.57 mV, indicating that the polymeric gemcitabine microparticulates were attached to the mucin particles. Furthermore, the F53 polymeric gemcitabine microparticulates having 150 mg of chitosan showed a 3.8-fold increased uptake of gemcitabine into Caco-2 cells over 72 hours compared with gemcitabine solution alone. Overall, these results suggest that polymeric gemcitabine microparticulate systems could be used as carriers to help oral absorption of gemcitabine.International Journal of Nanomedicine 05/2012; 7:2307-14. DOI:10.2147/IJN.S30465 · 4.20 Impact Factor