Improvement of the Bioavailability and Anti-hepatic Alveolar Echinococcosis Effect of Albendazole-Isethionate/Hypromellose Acetate Succinate (HPMC-AS) Complex

Abstract

Maximizing the pharmacodynamics of albendazole (ABZ), which is used to treat echinococcoses, is essential for the long-term treatment of echinococcosis patients. ABZ is a weak base whose solubility depends on the pH value of the solvent. After it has been orally administered, its solubility drops sharply from when it is in gastric juices (pH 1.4) to when it is in intestinal juices (pH 6.5) and is subsequently absorbed in the ileum and jejunum. This results in low solubility and poor bioavailability of the drug. In this study, we developed an orally administered albendazole-isethionate (ABZ-HES)/hypromellose acetate succinate (HPMC-AS) complex tablet (T_ABZ-HES-H) with improved solubility and bioavailability. Previous studies demonstrated that ABZ-HES has a higher intrinsic dissolution rate under pH 1.4 than the ABZ free base used in the commercial product Albenda and that HPMC-AS can effectively inhibit ABZ crystallization, which could be due to the hydrophobic interaction between ABZ and HPMC-AS in an aqueous environment. In this study, the dissolution behavior of T_ABZ-HES-Hin vitro was studied by the two-step pH conversion method. Our results demonstrated that the oral bioavailability of T_ABZ-HES-H was approximately 2.6 times higher than that of ABZ. More importantly, in the rat model of secondary hepatic alveolar echinococcosis, the anti-hepatic alveolar echinococcosis effect of T_ABZ-HES-H was 3.4 times higher than that of a commercial product. The improved preparation with salt and polymer has proven to be a feasible method of improving the oral bioavailability and pharmacodynamics of ABZ.

Keywords: HPMC-AS; albendazole-isethionate; anti-hepatic alveolar echinococcosis effect; pharmacokinetics.

FIG 1

Establishment of hepatic AE and lesion structure in model rats.

FIG 2

Physical and chemical properties of ABZ and ABZ-HES. (a) TGA curves for ABZ and ABZ-HES. (b) DSC curves for ABZ and ABZ-HES. (c) FT-IR spectra of ABZ and ABZ-HES. (d) PXRD patterns for ABZ and ABZ-HES.

FIG 3

Chemical structures of ABZ and ABZ-HES. (a) Structural formula and related properties of ABZ. (b) Structural formula of ABZ-HES.

FIG 4

Intrinsic dissolution profiles of ABZ and ABZ-HES (mean ± standard deviation [SD] [n = 3]).

FIG 5

Two-step dissolution profiles of ABZ preparations in pH 1.4 and 6.5 media (mean ± SD [n = 3]).

FIG 6

In vivo drug release behavior of ABZ preparations (mean ± SD [n = 6]). (a) Plasma concentration-time curve for ABZ. (b) Plasma concentration-time curve for ABZ-SO.

FIG 7

Pharmacodynamic study of ABZ preparations in the treatment of secondary hepatic AE in the rat model. Cysts appeared in representative liver tissues (mean ± SD [n = 5]) after 30 days of oral administration of CMC-Na (a), ABZ (b), or TABZ-HES-H (c). The x-y diagram for each group is the size of the lesion in the direction of the x-y axes, and the z diagram is the size of the lesion in the direction of the z axis, all of which are marked in red.

FIG 8

Microstructure of the lesions in the treatment of secondary hepatic AE in the rat model with the ABZ preparation (mean ± SD [n = 5]). (a) Size of the lesions in the model rats after administration, measured by ultrasonography. (b) Typical SEM images of the cysts 30 days after administration.

FIG 9

Schematic diagram of improving the efficacy of ABZ against hepatic AE with a salt/HPMC-AS formulation.