| Curcumin is the main active component in drying rhizome of the plants Curcumae longae L., Curcumae Phaeocaulis, Curcumae Wenyujin which belong to Zingiberaceae. Curcumin which belong to diketone chemical, have many pharmacologic actions which include anti-tumor, anti-oxidant, anti-inflammatory, reduce blood fat. Curcumin is becoming the effective drug for reducing blood fat recently because of its low toxicity and the good effectiveness. But Curcumin have some defects, such as bad water-solubility and liposolubility, can be easily oxidized, weak stability in water, bad absorption, fast Metabolism, poor biological availability. Because of these, use and development of Curcumin become limited.This paper is to prepare Curcumin phytosomes solid dispersion, and finally to make dispersible tablet so as to increase the stability and dissolution rate. First to prepare the Curcumin phytosomes and its solid dispersion and to optimize the condition for prepare. And then to study the physical and chemical characteristics of Curcumin. Meanwhile by adding piperine which is a glucuronidase inhibitors to make up as compound prescription with the purpose to inhibit the Curcumin Metabolism in vivo and to increase biological availability. Preliminary assessment of Curcumin, Curcumin phytosomes, Curcumin phytosomes solid dispersion and its dispersible tablet was done in rabbit in vivo. The whole experiments contain the following parts:1. Optimization and assessment for preparation of Curcumin phytosomes.(1)First to establish the standard for prepare Curcumin phytosomes-that is combination rate.The prerequisite is that ethanol-acetidin azeotrope as reaction solvent and the ratio of Curcumin-phosphatide is stable, and then optimize the condition of the reaction, such as concentration of the reactant, the reaction time and reaction temperature by orthogonal design. Through statistical analysis and confirmatory test, the best reaction condition is as following:ethanol- acetidin azeotrope as reaction solvent, ratio of Curcumin-phosphatide is 0.9:1(w/w), temperature is 55℃, time is 0.5 hour, concentration of Curcumin is 3%(w/v), and the yield of Curcum in phytosomes is 95.35%.(2) Identification of Curcumin phytosomes and its physico-chemical property: the Rf value of Curcumin phytosomes and Curcumin reference substance is the same in the three different developing solvents. That is to say the phytosomes is form from intermolecular force of Curcumin and phosphatide, not by producing a new chemical. DSC was used to inspect of the phase-transition temperature;IR was to Validate the structure; apparent O/W partition coefficient of Curcumin was determined in aqueous solution and noctyl-alcohol by UV. DSC showed that the phase-transition temperature of the phytosomes changed, lower than Curcumin and phosphatide. IR showed that the spectrum of the physical mixed compound was nearly the plus of Curcumin and phosphatide,but the phytosomes changed a lot, which indentified that Curcumin phytosomes has been prepared successfully. In the experiment of determination the apparent O/W partition coefficient of Curcumin, Curcumin phytosomes changed the solubleness in noctyl-alcohol.Apparent O/W partition coefficient of the Curcumin phytosomes was 11.11 times more than crude drug. That was to say phytosomes increase the liposolubility of Curcumin.According to the results, the reason can be speculated that lecithin positive ion and Curcumin negative ion migrate after certain condition, it produce migrate power, the two ions interattract each other and integrate. Thus the Curcumin phytosomes is obtained.2. preparation of Curcumin phytosomes solid dispersion and its physico-chemical property.(1) Preparation of solid dispersionUs ing the following adjuvants:PVPk-30, PEG4000, PEG6000, poloxamer407 and poloxamer188 to prepare solid dispersion respectively, choosing dissolution rate in vivo as index, PVPk-30 was the best disperse adjuvants to prepare Curcumin phytosomes solid dispersion.The experiment was done according the different ratio of drug and adjuvants, different preparing methods. The results shows that dissolution rate in vivo of Curcumin phytosomes solid dispersion increase with the ratio of PVPk-30, but increase rate become slower. Finally, the condition for preparing Curcumin phytosomes solid dispersion is as following:ratio of Curcumin phytosomes and PVPk-30 is 1:2 through grinding method.(2) Identification of solid dispersionBy using IR, DSC to identify Curcumin phytosomes solid dispersion, the rusults showed that Curcumin phytosomes solid dispersion was formed. (3) Dissolution rate Comparison:Curcumin phytosomes solid dispersion has better dissolution rate than Curcumin crude drug and Curcumin phytosomes in 0.1 mol/L Hydrochloric acid solution with 0.2%SDS.That is 9.15 and 2.80 times higher. That means Curcumin phytosomes-PVPk-30 (1:2) solid dispersion have better dissolution than Curcumin phytosomes.3. prescription technics and dissolution in vitro on compound curcumin dispersible tablets.(1) The study on the prescription technics:the superior adjuvant and usage range had been fixed on according to the one-way test, the time when the dispersible tablet was thoroughly via to the 2th griddle. Under the optimization for the prescription of dispersible tablet by L9(34) orthogonal experiment.The final prescription for the dispersible tablet was as follows:curcumi ne phospholipids complex of solid dispersions 36 percentage, piperine 0.25 percentage, microcrystalline cellulose 50 percentage, colloidal silicon dioxide 6 percentage, Cross-linked carboxymethyl cellulose 8 percentage.Due to the sever piquancy of the piperine and the bitterness of the curcumine, the menthol and aspartame had been usd as the flavoring agent in order to keep the dispersible tablet good taste.The dispersible tablet preserved pleasantly cool and sweet when 0.3 percentage of aspartame and 0.3 percentage of menthol had been added, which was very suitable to the aged and the optimum proportion of which had been concerted under the study of one-way test, the oral taste as the indicator. The three batches of dispersible tablets disintegrated, whose weights is 1.0g every tablet, the diameter is 1.5cm, the color is brown and the time when via to the 2th griddle was about 1min, beside of the uniform dispersion, which were up to the preparation general rule of dispersible tablet in china pharmacopoeia,2010 version.(2) The study on dissolution:The dissolution of curcumine in the dispersible tablet was superior to in the common tablet in the hydrochlor ic acid solution of which the concentration was 0.1mol/L and 0.2 percentage SDS was added, by the UV determination.4. The study on the quality standard of compound curcum in dispersible tabletsThe Identification methods of compound curcumin dispersible tablets had been established; the determination of the curcumine and piperine by HPLC had also been concerted as follows:the mobile phase was composed of mixture of citric acid and THF (60:40, v/v), the UV detect ion wavelength was set at 343nm, the method is simple, accurate and repeatable and the method of the related substances of dispers ible tab let had been established according to the method of determination; the request for the dissolution of the dispersible tablet was fixed by the dissolution in vitro of three batches of common tablets, which all conformed to the test standard on the dispersible tablet in china pharmacopoeia,2010 version.5. Study on the primary stability of the dispers ible tablet of curcumine complexThe packing and storage of the dispersible tablet of curcumine complex was fixed on the condition of the bright light, high temperature and sever humility. The result of three month for samples in the daily and speed up test showed that the the dispersible tablet of curcumine complex was stable.6. The pharmacokinetics study in rabbits of compound curcumin dispersible tablets.The method for the detection of curcumine concentration in the plasma by LC-MS and the stability in the plasma was studied. The curcumine concentration in the plasma showed little obvious change for 24h. The rabbits, as the test object, grouped by randomly, was administrated the compound curcumin dispersible tablets, compound curcumine phospholipids complex common tablets, compound curcumine phospholipids complex solid dispersion common tablets and compound curcumine crude drug common tablets respectively. The curcumine concentration of designed time points was determined by LC-MS for the pharmacokinetics study. The result of the pharmacokinetics study showed that when the single dosage was increased by double, the curcumine bioavailability of compound curcumine crude drug common tablet was the least and the relative bioavailability of the compound curcumin dispersible tablets, compound curcumine phospholipids complex common tablets, compound curcumine phospholipids complex solid dispersion common tablets was 474%,132% and 230% respectively. In conclusion, the phosphol ipids complex, sol id dispersion and dispersible tablet could all improve the absorbability of curcumine and achieved the aim of the subject.In summary, on the background of the study on curcumine phosphol ipids complex, some innovation in this paper were as follows:1.The technics of phosphol ipids complex bad broken the restriction of correlative patent:the solvent of the preparation was azeotropic ethanol and Ethyl acetate(3:7) and the ratio of the curcumi ne to Soy lecithi n was 0.8-0.9:1 (W/W) instead of 1:1-1:3 (mol/mol) or the weight ratio of curcumine to phosphatidylcholine was confined in the range of 1-10.2. Dispersible tablet was firstly introduced to further enhance the disso lution of the curcumi ne phosphol ipids complex of solid dispersion in order to improve the bioavai lability of the curcumine.3. The LC-MS method was firstly used for the determi nation of curcumi ne concen-tration in the plasma of rabbits. |
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