Cyclodextrin-stabilised ion-pair complexes enhance drug lung uptake via the polyamine transporter
Zarif M. Sofian1, Julie T. W. Wang1, Yuan L1, Paul Royall1, Ben Forbes1, David J. Barlow1, Clive Page 1,2, Khuloud T. Al-Jamal1, Stuart Jones1 & Faiza Benaouda1
1School of Cancer and Pharmaceutical Science, King’s College London, 150 Stamford Street, London, SE1 9NH
2Sackler Institute of Pulmonary Pharmacology, King’s College London, 150 Stamford Street, London, SE 1 9NH
Ion-pairs comprised of a drug (theophylline) and an active transporter substrate (spermine) have been shown in previous work to modulate drug transport into pulmonary cells via the polyamine transport system (PTS). However, the rapid ion-pair breakdown after dose administration (~2 min post dose application) resulted in the transport effects being short-lived. The aim of this work was to investigate if the formation of an ion-pair cyclodextrin inclusion complex could physically stabilise the theophylline-spermine ion-pair and prolong its enhanced uptake in the lung. The theophylline-spermine ion-pair formation was confirmed using Fourier transform infrared spectroscopy and the 1:1 ion-pair/cyclodextrin complex formation was characterised using NMR and 3-D modelling. In vitro, using A549 cells, the uptake of theophylline was increased 1.8-fold when it was formulated as the ion-pair compared to theophylline alone, but this effect decreased with time due to ion-pair dissociation. Complexation of the ion-pairs with cyclodextrins increased the ion-pair’s lifetime and enabled the ~2-fold cell uptake enhancement to be maintained over 20 min. When the cyclodextrin-stabilised ion-pair complex was administered in vivo (as a bolus intravenous injection), the theophylline lung concentration was 2.5-fold higher compared to theophylline alone, but the distribution of the complex in other tissues remained unchanged. The in vitro and in vivo data together suggested that a cyclodextrin stabilised theophylline-spermine ion-pair complex could use the PTS to target delivery to the lung after intravenous infusion, an effect that could be beneficial in the treatment of acute respiratory crisis.