| Objective: The carboplatin-polyD,L-lactide/glycolide microcapsules (CBP-PLGA-MC) were prepared by optimal technological proceture, its acute toxicity, distribution and pharmacokinetics characteristics were investigated with animal experiments.Methods: l.CBP-PLGA-MC were prepared by emulsion-solvent evaporation technique. Various factors related with the drug loading, incorporation efficiency and microparticle size were studied. The uniform experimental design(U15) was chosen to optimize the technology of preparation microcapsules. The particle size, surface morphology, release properties in vitro and stability of the optimized microcapsules were evaluated by optical, electron microscopy, release test in vitro and stability test. 2. 110 mice, weight 18-22g, were divided equally randomized into 11 groups, and 10 mice each group. Different concentration of CBP-PLGA-MC or CBP suspension were administered to mice by i.p. route in order to study the acute toxicity. The volume was injected 0.2ml/10g. The median lethal dose (LD50) of the CBP-PLGA-MC and CBP were calculated. 3. 135 mice, weight 24-26g, were divided equally randomized into 27 groups, and 5 mice each group, which were injected CBP-PLGA-MC or CBP at the dose of 32.5mg/kg in candal vein. At different times after injection, the lung, liver, kidney, spleen and heart were rapidly removed, carboplatin concentration in organs respectively were measured by inductively coupled plasma-atomic emission spectrometry (ICP-AES). 4. 8 rabbits , weight 2.3-2.5kg, with cross-over design were injected CBP-PLGA-MC and CBP at the dose of 143.60mg/m2. The carboplatin concentration in plasma were measure by ICP-AES at different times after injection. Pharmacokinetic characteristics of CBP-PLGA-MC and CBP was analyzed by PKS computer programs.Results: 1. PLGA-MC were prepared by non-aqueous o/o emulsion-solvent evaporation technique with emulsing at 4-5 , then evaporating at 35 for 3 hours. The variables that influence the encapsulation, drug loading and microparticles size were investigated. The analysis showed (1)drug/polymer ratio; (2) polymer concentration;(3)volume ratio of the dispersed and continuous phases, which were the main variables that influence the encapsulation and size of CBP-PLGA-MS. Under the adapted manufacture conditions, carboplatin were encapsulated 74.13 0.56%, the drug loading 6.81 0.04%(w/w), the average diameter of the obtained microcapsules was 14.25 3.52 m(n=3). The CBP-PLGA-MC were spherical with regular surface. The CBP-PLGA-MS have slow-release in phosphate-buffered saline (PH7.4), which accumulated release 63.2%(Td) were 48.97h. CBP-PLGA-MC were stable at 3-5 and 9-17 conditions respectively. 3. The median lethal dose(LD50) of CBP-PLGA-MC and CBP were 293.67 16.02mg/kg and 192.73 16.02mg/kg respectively. LD50 of CBP-PLGA-MC was 1.5 times comparing to carboplatin. 3. The animal experiments with mice showed remarkable accumulation of CBP-PLGA-MC in the lung after injection. During 0.25 to 48 hour, the percent of distribution were contained from 31.97% to 45.59%. On the contrary, the peak value and area under the curve of kidney were decreased to 29% and 62%. comparing to CBP group (p<0.05). 4. The results showed two-compartment model (weigh 1/C*C) was adaptive to describe the pharmacokinetic characteristics of CBP-PLGA-MC and CBP in lung of mice. After i.v. CBP-PLGA-MC and CBP at the equal does, the AUC, Cmax, Tmax, t1/2 , t1/2 , Vd and CL values have significant difference (p<0.05). Three-compartment model (weigh 1/C) was adaptive to describe the pharmacokinetic characteristics of CBP-PLGA-MC and CBP in plasma of rabbits. The AUC, MRT, t1/2 , CL and Cmax values have significant difference (p<0.001).Conclusion: 1. The drug/polymer ratio of CBP-PLGA-MC, the polymer concentration and the volume ratio of the dispersed and continuous phases were mainly influence the encapsulation and microparticles size. 2. Release test in vitro showed the microcapsules have slow-release effect. 3.CBP was encapsuled by PLGA can descent acute toxici...
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