title: The delivery of triamterene by cucurbit[7]uril: synthesis, structures and pharmacokinetics study.
abstract: 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 × 10(4) 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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Ma
authors.forename: Jia-Mei
authors.initials: JM
authors.lastname: Chen
authors.forename: Long
authors.initials: L
authors.lastname: Jiang
authors.forename: Jia
authors.initials: J
authors.lastname: Yao
authors.forename: Tong-Bu
authors.initials: TB
authors.lastname: Lu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D047028:Macrocyclic Compounds / Q000737:chemistry*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014223:Triamterene / Q000737:chemistry* / Q000493:pharmacokinetics*; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction / Q000379:methods; D000099246:Cucurbit(n)urils
chemical_list: D047028:Macrocyclic Compounds; D014223:Triamterene; D014867:Water; D000099246:Cucurbit(n)urils