Investigation Of Preparation And Pharmacokinetics For Hydroxycamptothecin Liposome

Hydroxycamptothecin (HCPT), a potent antitumor drug, is one of the DNA topoisomerase I inhibitors. It showed high antitumor activity in vitro and in vivo. HCPT injection used clinically has some disadvantages including short half-life and imperfect tissues distribution, so the full therapeutic potential of HCPT has not yet been achieved. Thus, in this study we intend to prepare the HCPT liposome (L-HCPT) to improve its pharmacokinetics characters such as half-life and tissues distribution and enhance antitumor activity.In order to control the quality of L-HCPT, the methods for determination of HCPT quantity by HPLC and for determination of entrapment efficiency of L-HCPT by sephadex gel filtration chromatography-HPLC were established, which could determine HCPT quantity and entrapment efficiency accurately.According to the entrapment efficiency, various factors were studied. The main variables were the Ch/PC ratio (A), HCPT/(Ch+PC) ratio (B) and HCPT solution/ chloroform ratio (C). The uniform experimental design was chosen to optimize the condition of preparation L-HCPT. The analysis showed (A) 1:2, (B) 1:100, (C) 1:4, which were the optimal formulation. Under the optimal formulation, HCPT was encapsulated 52.79%.The diameter of L-HCPT was mensurated by laser particle analyzer, and morphological characteristic of L-HCPT was observed by transmission electron microscope. The stability of L-HCPT was valuated with the indexes of appearance, diameter, entrapment efficiency and preoxidation value in 4. 25 . 40 for 3 month. The results showed that thefreeze-dried L-HCPT stored in 4 would keep L-HCPT structure stably.The pharmacokinetic parameters and tissues distribution of market HCPT injection (M-HCPT) or L-HCPT were studied after intravenous administration M-HCPT or L-HCPT to rabbits and rats, respectively. HCPT concentration in plasma and tissues was determined by HPLC. Comparing with M-HCPT, it showed higher plasma concentration levels, longer elimination half life, larger area under the curve values and lower clearance, smaller central compartment volume of L-HCPT(P < 0.05); and larger area under the curve values in liver, spleen, heart and lung (P < 0.05). The results of pharmacokinetics and tissues distribution showed that L-HCPT had better tissues targeting and slow-release effect than M-HCPT.