The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

In recent years, cucurbit[7]­uril
(CB[7]) has attracted great attention
in drug delivery. Though the effect of CB[7] in enhancing the solubility
of water insoluble drugs has been validated, the underlying mechanism
remains poorly understood, particularly at a molecular level. This
study is designed to evaluate a CB[7]-based pharmaceutical formulation
to improve solubility and bioavailability of triamterene (a mild potassium-sparing
diuretic). Two polymorphs of triamterene@CB[7] were obtained, and
their crystal structures were determined by single crystal X-ray diffraction.
The CB[7] molecule forms a stable host–guest complex with triamterene
(Ka = 1.69 ± 0.34 × 104 M–1) in aqueous solution (pH = 1.0). The results
of dissolution study demonstrate that the apparent solubility value
of triamterene@CB[7] complex in 0.1 M HCl is 1.6 times as large as
that of triamterene, while free triamterene was released from triamterene@CB[7]
complex in phosphate buffer of pH 6.8. Pharmacokinetic studies in
rats reveal that the AUC0–∞ value of triamterene@CB[7]
complex increases 2.8-fold compared with that of free triamterene,
and t1/2 is prolonged from 1.42 to 2.61
h (P < 0.05) after oral administration. The increased
solubility and oral bioavailability are attributed to the formation
of a hydrophilic capsule composed of two CB[7] molecules, in which
two insoluble triamterene molecules are encapsulated. These results
demonstrate that triamterene@CB[7] complex is a stable and effective
pharmaceutical formulation.