Development of novel tenofovir disoproxil phosphate salt with stability enhancement and bioequivalence to the commercial tenofovir disoproxil fumarate salt in rats and beagle dogs.

Tenofovir disoproxil (TD) is very unstable in the solid state under storage conditions. Moreover, tenofovir disoproxil fumarate (TDF), a commercial salt, is chemically unstable in alkaline solution. In this study, a novel tenofovir disoproxil phosphate (TDP), with stability enhancement and bioequivalence to commercial TDF in rats and beagle dogs, has been developed as an alternative. The TDP and its tablets were easily manufactured, and its physicochemical properties, such as morphology, crystallinity, solubility, lipophilicity and stability were investigated and compared to TD and TDF. Its dissolution and pharmacokinetics were investigated in rats and beagle dogs in comparison to TD and TDF. TDP appeared as an irregularly-shaped crystalline powder with a rough surface, like TDF. However, TDP significantly improved the solubility (7.4 ± 1.3 vs. 28.6 ± 1.0 mg/ml), hydrophilicity (Log P, 0.58 ± 0.03 vs. 0.47 ± 0.04), and aqueous stability (drug concentration over 12 h at pH 6.8 84.0 ± 2.0% vs. 88.2 ± 1.5%) of TD compared to TDF. The TDP gave no significant different plasma concentrations, AUC and C _max compared to TDF in rats (AUC, 1242.1 ± 584.9 vs. 825.9 ± 79.5 h·ng/ml; C _max , 154.8 ± 25.4 vs. 210.9 ± 70.3 ng/ml). Moreover, the TDP-loaded tablets were stable for at least six months and provided similar dissolution and bioequivalence to the TDF-loaded commercial product in beagle dogs (AUC, 26,832.7 ± 4093.0 vs. 26,605.3 ± 2530.1 h·ng/ml; C _max , 4364.0 ± 2061.9 vs. 4186.3 ± 2616.5 ng/ml). Therefore, as an alternative salt, the TDP would be a recommendable candidate with stability enhancement and bioequivalence to the commercial TDF.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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