Synergistic effect of miscible cellulose-based microparticles and pH modulators on the bioavailability of a weakly basic drug and its metabolites

This study aimed to evaluate the miscibility of cellulose derivatives to improve the release rate and stability of microparticles containing the weakly basic drug itraconazole (ITZ). We also investigated the effect of some organic acids on the microenvironmental pH (pHm) and the release rate of ITZ from the cellulose-based mi-croparticles. The synergistic effect of cellulose-based microparticles and pHm modulators on the bioavailability of ITZ compared with the reference product was investigated in a rabbit model. Differential scanning calorimetry and Fourier-transform infrared spectroscopy (FTIR) analysis showed that ITZ, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose phthalate were miscible at a ratio of 1.5:3:1 (w/w/w), and the stability of the microparticles was maintained for 6 months under accelerated conditions. In addition, X-ray diffraction, FTIR, and scanning electron microscopy were used to characterize the properties of the microparticles. Through the titration technique and determination of pHm, the combination of fumaric acid and maleic acid (1:2, w/w) was found to be the most effective pHm modulator for microparticles. The integration of cellulose-based micropar-ticles and pHm modulators showed a synergistic effect on the flux and relative bioavailability of ITZ and its active metabolite OH-ITZ (182.60 % and 217.67 %, respectively) when compared with the reference product.

Automated summary

This study evaluated the miscibility of cellulose derivatives to enhance the release rate and stability of microparticles containing a weakly basic drug, itraconazole (ITZ). The effect of organic acids on the microenvironmental pH (pHm) and ITZ release was also investigated. In a rabbit model, the synergistic effect of cellulose-based microparticles and pHm modulators on ITZ bioavailability was compared with the reference product. The results showed that ITZ, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose phthalate exhibited miscibility and the stability of microparticles was maintained for 6 months. Integration of cellulose-based microparticles and pHm modulators significantly increased the flux and relative bioavailability of ITZ and its active metabolite OH-ITZ.