title: Complex of 9-nitro-camptothecin in hydroxypropyl-beta-cyclodextrin: in vitro and in vivo evaluation.
abstract: The effect of a series of cyclodextrins (CDs), especially hydroxypropyl-beta-cyclodextrin (HP-beta-CD), on aqueous solubility and chemical stability of 9-nitro-camptothecin (9-NC), was investigated with an aim of preparing a stable and effective parenteral formulation. The 9-NC/HP-beta-CD complex was obtained in solid form by freeze drying. Then, the pharmacokinetic profiles in rats of aqueous complex were compared to those of free 9-NC solution having an equivalent concentration. The aqueous solubility of 9-NC was increased to 0.52 mg/ml (lower than 5 microg/ml in distilled water, 25 degrees C) by the combination of pH and temperature adjustment. In addition, hydrolysis of 9-NC following pseudo-first-order kinetics was decelerated significantly in physiologic condition in the presence of HP-beta-CD. Comparison of in vivo pharmacokinetic parameters of free 9-NC with the complex indicated that the complex had higher AUC(0-infinity) (439.39 ng h/ml vs. 632.79 ng h/ml for i.m. administration and 385.39 ng h/ml vs. 538.05 ng h/ml for i.v. administration, respectively) and ratio of lactone form. These results demonstrated that 9-NC/HP-beta-CD complex is an attractive parenteral formulation for cancer therapy.
authors.affiliation: School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Jiang
authors.forename: Xianyi
authors.initials: X
authors.lastname: Sha
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Fang
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005612:Freeze Drying; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013696:Temperature; D047392:beta-Cyclodextrins
chemical_list: D000970:Antineoplastic Agents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C079905:rubitecan; D002166:Camptothecin