Complex of 9-nitro-camptothecin in hydroxypropyl-beta-cyclodextrin: in vitro and in vivo evaluation.

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.