Study On The Preparation Of Chrysophanol-Hydroxypropyl-β-Cyclodextr In Inclusion Complex And Its Pharmacokinetics

Chrysophanol(Chry) is an effective monomer in Polygonaceae plantssuch as rhubarb, Polygonum cuspidatum, Polygonum multiflorum, whichbelongs to anthraquinone compounds and has antibacterial action,hemostasis, anticancer effect, relieving a cough, diuretic and otherpharmacological effects. According to the literatures, chrysophanol caneliminate free radicals and has obvious anti-aging and the promotion oflearning and memory. Chrysophanol is fat-soluble compound and soluble inmethanol, ethanol, acetone and other organic solvents. As chrysophanolhas a very small solubility in water and its bioavailability is not high, itsclinical application is limited. Therefore, inclusion technology ofchrysophanol was studied in the subject in order to broaden the applicationscope of chrysophanol and provide alternative formulation for clinicalapplication of drug. Inclusion technique can greatly improve the solubilityof insoluble drug, which is widely used in formulations research ofinsoluble drugs. In this paper, using hydroxypropyl-β-cyclodextrin (HP-β-CD) as the inclusion material, chrysophanol was made into inclusion complex by the best preparation method and technics to increaseits solubility in water, and the stability and dissolution in vitro ofchrysophanol inclusion complex were examined. The pharmacokineticcharacteristics of chrysophanol inclusion complex were studied in animalsas well . All the parameters can provide the basis for the development ofchrysophanol inclusion complex injections. The inclusion ratio and recovery of chrysophanol inclusion complexwere adopted as the observation criteria and the optimal preparationmethod was decided by comparing the inclusion effect of stirring method,grinding method and supersonic method in the same technics conditions.The technology conditions of preparation were screened by the orthogonaltest. The multiple factors including weight ratio of chrysophanol andHP-β-CD, concentration of solvent, time and temperature were investigated in the inclusion process to optimize the preparation conditions ofChry-HP-β-CD. The inclusion complex was identified by ultraviolet and visible spectrophotometry(UV-vis), thin-layer chromatography(TLC) andphase solubility. The result showed that the optimumpreparation conditionsfor inclusion were established as follows: the weight ratio of chrysophanoland hydroxyphrophy-β-cyclodextrin was 1:60, concentration of ethanol was 50%, temperature was 30℃and timewas 2h. The inclusion ratio ofChry-HP-β-CD was 64.11%. The phase solubility curve was AL type. Whenthe quality fraction of HP-β-CD was 20%, the solubility of chrysophanol increased 102.66 times.Study on the stability and dissolution in vitro: The chrysophanolwas compared with the chrysophanol inclusion complex to study both lightstability, thermal stability and wet stability. The dissolution in vitro wasresearched by dynamic dialysis technology to observe the release propertiesof Chry-HP-β-CD. The result showed that the stability of Chry-HP-β-CD was increased more significantly than that of chrysophanol under the hightemperature, high humidity and light conditions. Chry-HP-β-CD had good performance in vitro dissolution showing a degree of sustained-releasecharacteristics.Study on pharmacokinetics in animals: Two kinds of animal wereused to investigate the pharmacokinetics of chrysophanol preparetion. Therabbits were injected intravenously chrysophanol or Chry-HP-β-CD, and then plasma drug content was measured at different time points andStudy on the preparation methods and technics of chrysophanolhydroxypropyl-β-cyclodextrin inclusion complex(Chry-HP-β-CD): pharmacokinetic parameters and the compartment model were analyzed.The mice were injected chrysophanol or Chry-HP-β-CD in tail vein and some tissues such as plasma, heart, liver, brain, spleen, lung, kidney ofmice were taken at different time points to determine the content ofchrysophanol and study tissue distribution characteristics of chrysophanoland Chry-HP-β-CD in mice. The result showed that the pharmacokinetics of chrysophanol and Chry-HP-β-CD were two-compartment models in rabbits. The average half-life for elimination phase (t1/2β) of both was9.093h and 13.075h respectively . It was speculated that the eliminationprocess of Chry-HP-β-CD was slightly slower than that of chrysophanol. Two-sample t-test was used to statistically analyze the content ofchrysophanol and Chry-HP-β-CD in various tissues of mice. Through comparing chrysophanol and Chry-HP-β-CD with intravenous injection in mice, the content of chrysophanol in the blood, liver and brain had asignificant difference(p<0.05).In summary, the optimized technology conditions are stable and simpleand have the high inclusion rate. HP-β-CD is fit to include chrysophanol and the solubilization effect is significant. Chry-HP-β-CD significantly improved the stability and in vitro dissolution of drugs. Chry-HP-β-CD is two-compartment pharmacokinetic model in rabbits. Chry-HP-β-CD can significantly improve the content of drugs in brains of mice.