An Ion Pairing Approach to Enhance Oral Bioavailability of Alendronate

Aim: Alendronate (AL) is a nitrogen-containing bisphosphonate drug that exhibits limited oral bioavailability due to predominantly hydrophilic molecular properties. To enhance oral absorption of this important osteoporosis drug, a novel ion-pairing strategy using the cationic polymer polyethylenimine (PEI) was explored as an initial step of an alternate oral drug delivery strategy that attempts to prepare polymer-encapsulated ion pair nanoparticles.
Methodology: Electrostatically stabilized AL/PEI association complexes were fabricated by combining AL and PEI solutions prepared in 0.05 M acetate buffer, pH 5.0, at different AL/PEI charge ratios under stirring. The free fraction of AL after complexation with PEI was quantified spectrophotometrically at λ=300 nm using ferric chloride. Particle size distribution and zeta potential of ion pairs formed at different molar AL/PEI ratios were measured by dynamic laser light scattering.
Results: The complexation efficiency of PEI was low until an AL/PEI charge ratio of1:1.7. Increasing PEI concentrations effectively decreased the free fraction of AL implying formation of stable ion pairs between the negatively charged AL and the positively charged polymer. The lowest fraction of free AL was 18.7% measured at an AL/PEI charge ratio of 1:33. The mean hydrodynamic diameter of nanoassemblies decreased with increasing AL/PEI charge ratio reaching a limiting value of 71±1.4 nm at AL/PEI=1:33. Corresponding zeta potential measured for these association complexes was +37±2.8 mV.
Conclusion: AL/PEI charge ratio greater than 1:1.7 facilitates effective formation of electrostatically stabilized ion pairs that carry a significant positive surface charge indicative of substantial colloidal stability in aqueous solution. The small size of AL/PEI complexes fabricated at 1:33 favors these ion pairs for subsequent encapsulation into biocompatible polymers suitable for oral drug delivery.