Preparation And Study Of Hydroxycamptothecin Phytosomes For Intravenous Administration

Hydroxycamptothecin (HCPT), an anticancer drug, has two chemical structure forms-lactone and carboxylic salt. Lots of literatures mentioned that the lactone form exhibited better therapeutic effect and less toxicity. Phytosome was the complex of drug and phospholipids, which formed vesicles spontaneously in water at high drug-lipid mass ratio. The objective of this study is to develop a good and stable injection of lactone HCPT-phytosome for intravenous administration.Tetrahydrofuran was chosen as the complex solvent for HCPT-phytosome preparation. Single factor test and orthogonal design was conducted to obtain the optimized formulation and process parameters. The HCPT-phytosome was characterized by the UV, IR and DSC. HCPT-phytosome was existed in the amorphism state. Solubility of HCPT-phytosome in n-Octyl alcohol and chloroform were determined. The dissolution rate and solubility of HCPT was remarkably elevated by the complex of HCPT and phospholipids. But the HCPT-phytosome was unstable in the organic solvent and generally precipitated during storage.The prescription and process parameters of HCPT-phytosome injection was optimized by the particle size, centrifugation stability and encapsulation efficiency(E.E.). Film disperse method was more suitable to prepare the aqueous dispersion of HCPT-phytosome. High pressure homogenization technique and probe ultrasonic technique were employed and compared. A HCPT-phytosome injection with satisfied drug load capacity (0.5mg/ml) was obtained, the particle size was 117±65nm and the E.E. was 99.4%.Freeze-drying (lyophilization) technique was utilized to prepare freeze-dried HCPT-phytosome injection. Mannitol and fucos were added as cryoprotectant. The particle size, E.E. and pH of the rehydrated product was almostly unchanged. In vitro release of HCPT-phytosome injection was investigated by the dialysis method and exhibited a sustained release profile. The freeze-dried product were stable at the temperature of 25℃±2℃and relative humidity of 60%±10%for 3 months.HPLC method was developed to determine the HCPT concentration in plasma. Pharmacokinetic study of HCPT-phytosome injection and carboxylic HCPT solution were conduct in male rats.3P87 program was used to calculate the pharmacokinetic parameters. Both of them were fit to the two compartment-model. The t1/2,α, t1/2,βand AUC of carboxylic HCPT were 4.608min,30.074min and 128.203μg·min·mL-1, respectively. The t1/2,α, t1/2,βand AUC of HCPT-phytosome injection were 1.208min,45.548min and 104.337μg·min·mL-1, respectively. The MRT0â†'∞of carboxylic HCPT and HCPT-phytosome injection were 17.064min and 61.081min, respectively.