| Background Medicinal Rhubarb (Rhubarb) is Polygonum (Polygonaceae) rhubarb (Rheum) rhizome and root of perennial herbs, with a hot purge diarrhea, breaking product line stasis, clearing heat function. Rhein (Rhein, RH) is a plant Polygonaceae Rheum, Rheum or medicinal rhubarb is one of the main active ingredient, are hydroxy anthraquinone derivatives, numerous studies demonstrate that their hepatoprotective, anti-fibrosis, reduced sugar, lipid, antioxidant, anti-tumor, anti-inflammatory and other pharmacological effects. Rhein at this stage has become a hot research at home and abroad is the best material for the preparation of health care products can be used for lipid-lowering diet, bowel detoxification, cleaning the environment, prevention of gastric cancer, aging, etc., in the areas of increasingly widespread. However, rhein itself does not dissolve in water, are poorly soluble drugs, therefore,in their study, the need to use pharmaceutical preparations of new technologies, increase its solubility, thereby improving its bioavailability has become an urgent requirement. Therefore, in the course of the study, the use of new technology research and development of drug formulations and new dosage forms Rhein became the focus of experimental ideas first step. And just to make solid dispersion of insoluble drug solubility and dissolution rate increased, so as to improve drug bioavailability purpose, so that drugs play a better pharmacological activity.Therefore,this experiment will be a new technology for solid dispersion of rhein, a soluble polymer polyvinylpyrrolidone (PVP) was prepared solid dispersions of rhein, then its role in hyperlipidemia rats to study its lipid-lowering and antioxidant effects.Objective To improve Rhein insoluble drug abuse do not dissolve in water, application of solid dispersion, water-soluble polymers polyvinylpyrrolidone (PVP) as a carrier, the Rhein solid dispersions prepared to increase its solubility and enhance its bioavailability, so that rhein can better play the pharmacological lipid-lowering and antioxidant effects. To rhein in the clinical application and development of more effective and more stable basis for the new formulation.MethodsBasic Research:Rhein screening solid dispersion prepared the best solution: First choose two water-soluble carrier material PVP, PEG6000 as carrier, three different ratios (1:2,1:4,1:6) of solid dispersions Rhein body were prepared. Through the determination of solubility and dissolution of the determination of the best carrier selected and the best ratio of preparation to determine the Rhein prepared solid dispersions of the best programs and mapping method using infrared (IR) and differential scanning calorimetry method (DSC) Identification of whether the solid dispersion Rhein successfully prepared for the next lay the foundation for in vivo studies. Pharmacokinetics:First, the establishment of a high selectivity, high sensitivity determination of rhein and rhein solid dispersion concentration in rat plasma by high performance liquid chromatography method (HPLC), and the method precision, recovery and stability the determination. A healthy male SPF SD rats (weight 200-250g) as the experimental animals were randomly divided into two groups, one single oral administration of rhein suspension, given the other group was given mixed solid dispersion Rhein suspension, both given the same dose of rhein (50mg/kg), oral administration at different time points after the HPLC method for the determination of rhein concentration in plasma samples.Studies with 3P97 pharmacokinetic compartment model analysis software and its solid dispersion Rhein pharmacokinetic parameters: area under the curve (AUC), maximum plasma concentration (Cmax), half-life (t1 / 2), time to peak (Tmax), and the clearance rate (CL), this analysis of rhein and rhein solid dispersion in rats in vivo pharmacokinetic differences. Pharmacodynamics:A healthy male SPF SD rats (weight 200-250g) as the research object, adaptive feeding week randomized into 5 groups, n = 8, control group, respectively, hyperlipidemia model group, the monomer Rhein group, rhein solid dispersion low dose group and rhein solid dispersions of high-dose group. One single group and rhein rhein solid dispersions of low-dose group, the same acid content of rhubarb. Control group fed normal diet; model group oral administration of fat emulsion made 10ml/kg/d, while oral administration of 1% sodium carboxymethyl cellulose; single group rhein, rhein solid dispersion of low dose group, rhein solid dispersion by oral administration of high dose group, while administration of fat emulsion intervention; monomer Rhein group received 1% CMC suspension dubbed by 25mg/kg/d dose gavage administration; solid dispersion Rhein low dose group received 1% CMC suspension dubbed by single oral administration of rhein content 25mg/kg/d; Rhein high dose group of solid dispersion given 1% CMC suspension dubbed by single oral administration of rhein content 100mg/kg/d. Each group with equal volume of drug concentrations ranging from liquid administered once a day, orally 1h before and after the fasting of water once a week, animal weighing, according to the amount of body weight adjusted dose, for four weeks.The last administration and the fat emulsion, all the animals can not help but water 12h fasting blood serum was separated after the heart, the liver homogenate after the measured serum triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) levels of serum and liver homogenate malondialdehyde (MDA), superoxide dismutase (SOD) activity and glutathione had superoxide dismutase (GSH-PX) activity, liver index, focus on solid dispersions investigated over rhein rhein monomer in the lipid-lowering and antioxidant role of superiority. Organize data using statistical software one-wayANOVA SPSS17.0 ANOVA analysis of data.ResultsResults using infrared spectra (IR) and differential scanning calorimetry method (DSC) test whether rhein successfully prepared solid dispersions. The results show that through the determination of solubility: insoluble solid dispersion of drugs can change the dispersion state of Rhein so highly dispersed in the water-soluble carrier in a significant increase in the solubility of rhein, and the ratio of drug and carrier to 1:4 for the most good solubilization effect.The results showed that in vitro dissolution: two Rhein dissolution of solid dispersion are higher than rhein monomer, indicating that the prepared solid dispersions rhein significantly increase their physical dissolution; and the PVP solid as the carrier Rhein dispersion than in PEG dissolution Rhein as the carrier of solid dispersions, indicating that for the Rhein, the use of PVP as a carrier of water-soluble carrier is better than PEG.Thus, screening out the solid dispersion Rhein best preparation programs: drug and carrier PVP ratio of 1:4 by mass ratio of solvent Rhein prepared solid dispersions.Rhein in under the established detection methods can be separated well and has no obvious impurity peaks. Therefore, this method can determine Rhein specific content. Rhein in the 1.5 ~ 75.0μg / ml has a good linear range; day precision RSD was 0.63%; low, medium and high concentration of recoveries were 98.0%, 98.3%, 99.6%; stability than good. The methods that the accuracy and reproducibility are good. Indicators are consistent with the 2005 version of the drug in vivo detection method Pharmacopoeia requirements.Rat oral solid dispersion Rhein Rhein than monomers in vivo blood concentration after the results: AUC increase of 76.5%, Cmax increased by 75.6%, t1/2 increased from the 2.39 h to 14.8 h, CL 18.78 reduced to 8.8 from the. After that the solid dispersion can improve the bioavailability of rhein, and in vitro dissolution test results.Compared with model group, rhein group, rhein solid dispersion low-dose group and rhein solid dispersion can make the high dose group decreased significantly elevated liver enzymes. That the role of the three groups in turn increased the extent of drug action, of the liver formed a protective effect.The blood lipid indicators, compared with the control group, hyperlipidemia model group TC, TG, LDL-C was significantly higher (P<0.05), while HDL-C values decreased significantly (P<0.05) , in line with the characteristics of hyperlipidemia. Administration after the intervention, the treatment group compared with the model group TC, TG values were significantly decreased (P<0.05), especially in RH-SD low-dose group and RH-SD decline in the high dose group was significantly greater (P<0.05 ); three dose levels of serum HDL-C levels were increased in model group, but the RH-SD high dose group compared with the control group, single RH group and RH-SD compared with the low dose group, RH-SD and RH-SD low-dose high-dose group compared to HDL-C values were not statistically different (P>0.05); In addition to single RH group, the other two solid dispersion treatment group and model group, LDL-C There were significant differences compared (P<0.05), but the single RH group and RH-SD compared to the low dose group LDL-C was not significant (P>0.05).The antioxidant indices, compared with the control group, model group, serum and liver homogenate MDA content, GSH-PX activity increased significantly (P<0.01), while SOD activity was significantly decreased (P<0.01), that hyperlipidemia model in the state, the liver injury in rats. Compared with model group, RH group, RH-SD low-dose group and the RH-SD high-dose group could reduce serum and liver MDA content, GSH-PX activity and increased SOD activity (P<0.05); RH-SD low dose of serum is better than the index with the dose of single RH group (P<0.05), but the MDA content in liver homogenate RH-SD single low-dose group and no significant difference in RH group (P>0.05;RH-SD high-dose group and RH-SD low-dose group in serum and liver homogenate MDA content and SOD,GSH-PX activity significantly different (P <0.05).ConclusionWater-soluble carrier material with PVP, PVP by rhein mass ratio of 1:4 and the ratio of the Rhein prepared solid dispersions were significantly improved dissolution of Rhein, solubility and bioavailability, to overcome the poor water solubility of rhein problems, and increased its absorption and utilization in the body.Solid dispersions with rhein rhein monomer than in rats pharmacokinetic parameters was significantly changed. Solid dispersion in terms of relative monomerAUC,Cmax,t1/2, Tmax increases, CL reduced; for the experimental hyperlipidemic rats, rhein solid dispersion lipid-lowering and antioxidant capacity were markedly enhanced.Tips solid dispersionRhein role in the play displayed some pharmacological dose-effect relationship, and with the traditional chemical drugs compared to lipid-lowering,rhein drug side effects, and the liver may play a protective role. |
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