Amorphous PAA-stabilized solid dispersion for enhanced antibacterial activity and bioavailability of trimethoprim

Abstract

The clinical application of trimethoprim (TMP) is limited by the low water solubility, short half-life and low oral bioavailability. Polyacrylic acid-stabilized trimethoprim amorphous solid dispersant (PAA/TMP ASD) are prepared by spray drying technology. The PAA/TMP ASD forms microspheres with diameters from hundreds of nanometers to tens of micrometers. The payload of TMP in the ASD can be regulated by adjusting the feeding ratio. During the continuous 7-day test, the variation range of particle size and Zeta potential is both less than 10%. In gastric juice, the ASD show low cumulative release (13.1% and 30.2%) with an initial explosive phase, whereas in PBS and intestinal fluid, the equilibrium release arrives to 64.3% and 41.5%. At a concentration of 0.097 mg/mL, the in vitro inhibition rate against E. coli can reach more than 98%. The inhibition rate of the biofilm formation is 82% at the concentration of 0.2 mg/mL. The TMP/PAA ASD shortens the peak time from 3.333 to 2.0 h, increases the peak concentration from 1.012 to 1.133 µg/mL, and significantly reduces the absorption half-life from 1.387 to 0.191 h. The TMP/PAA ASD formulation prolongs the elimination half-life from 26.033 to 34.699 h, along with increases AUC and MRT values, and demonstrates higher drug exposure and a longer duration of action in vivo. This work develops an important method to enhance the oral utilization rate of TMP.