论文标题:大豆异黄酮固体分散体片的制备及其药代动力学的初步研究
论文作者
论文导师 郑国华；孙代华,论文学位 硕士,论文专业 中药学
论文单位 湖北中医学院,点击次数 822,论文页数 88页File Size4738K
2007-05-18论文网 http://www.lw23.com/lunwen_132717/
soy-isoflavone;; solid dispersion;; pvpk30;; dissolution in vitro;; bioavailability
大豆异黄酮主要来源于豆科植物的荚豆类，以大豆中的含量较高，且主要分布于大豆种子的子叶和胚轴中，种皮中含量极少。目前发现的大豆异黄酮共有12种，分为结合型的糖苷和游离型的苷元2类，包括9种异黄酮糖苷和3种相应的糖苷配基(即游离异黄酮)。 大豆异黄酮是大豆生物活性物中最有医疗价值的活性成分，具有雌激素样作用，包括抗肿瘤、抗氧化、心血管保护和改善骨质疏松等作用，能够缓解和减轻女性更年期不适症状，因此其极具研究开发价值。但由于大豆异黄酮本身难溶于水，其生物利用度很低，这对于它的临床应用带来了一定的难度。而固体分散体是增加难溶性药物的生物利用度的常用方法之一，其主要是使难溶性药物在水溶性载体中处于高度分散状态，一般而言，药物在固体分散体中的粒径为0.001～0.1μm，分散状态以分子状态、亚稳定态及无定形态或胶体状态多见。载体对药物润湿性、抑晶性保证了难溶性药物的快速溶出，药物的生物利用度也得到了相应的提高。通常固体分散体的制备方法有溶剂法，熔融法，溶剂-熔融法等，常用的水溶性载体有聚乙二醇类，聚乙烯吡咯烷酮类，泊洛沙姆，有机酸，糖类等。本研究的目的就是利用固体分散的方法设计一种口服有效的大豆异黄酮制剂以提高其生物利用度。 本研究制备了大豆异黄酮固体分散体，考察了不同的载体(PEG4000，PEG6000，P010xamer188，PVPk30)，不同的制备方法(熔融法，溶剂法)对异黄酮的溶出速率的影响，并且对溶出数据进行weibull方程曲线拟合，比较溶出参数，得出以聚乙烯吡咯烷酮k30(PVPk30)为载体，采用溶剂法制备固体分散体的溶出速率最好。并进一步考察了不同比例的pvpk30用量对异黄酮的溶出速率的影响，得出pvpk30：药物=9：1时，异黄酮的溶出速率最快。大豆异黄酮固体分散体的差示热扫描(DTA)分析结果显示大豆异黄酮以无定型状态分散在pvpk30中。固体分散体、物理混合物及纯大豆异黄酮的溶出速率比较结果显示大豆异黄酮固体分散体的溶出速率最好。 大豆异黄酮原料药及其固体分散体的影响因素试验中，大豆异黄酮原料药在高温，高湿，强光条件下，外观，含量，溶出度均未见明显变化，大豆异黄酮固体分散体在高温，强光条件下，外观，含量，溶出度均未见明显变化，在高湿条件下，外观发生了显著的变化，表现为严重的吸湿性，含量和溶出度未见有明显变化。 大豆异黄酮固体分散体片的制备研究中，由于大豆异黄酮固体分散体中的pvpk30含量较大，pvpk30本身的水溶性较好，不利于湿法制粒，且pvpk30是优良的干燥黏合剂，从而选择了全粉末直接压片法制备。以大豆异黄酮固体分散体片的崩解时限和溶出速率为考察指标，采用混料均匀设计法进行处方设计，偏最小二乘回归分析法对均匀设计试验进行建模分析，预测结果与处方验证结果一致，得出的大豆异黄酮固体分散体片(0.5g)最佳处方为大豆异黄酮固体分散体0.18g，预胶化淀粉0.26g，CMSNa0.03g，微粉硅胶0.03g．制备的大豆异黄酮固体分散体片外观完整光洁，色泽均匀，通过紫外分光光度法对其总异黄酮进行了含量控制，通过高效液相色谱法对其主要成分染料木苷进行了含量测定。 大豆异黄酮固体分散体片与其普通片的体外溶出度比较结果表明固体分散体片的溶出度明显高于普通片。6个月的加速试验表明，大豆异黄酮固体分散体片的溶出度有所下降，但依然保持在80％以上。 大豆异黄酮固体分散体片与其普通片的大鼠体内药代动力学试验中，考察了固体分散体片与普通片所含的大豆异黄酮的血液中代谢产物染料木苷元的药物浓度随时间的变化情况，药动学软件DAS的拟合参数表明，固体分散体片在大鼠血液中的大豆异黄酮代谢产物染料木苷元的达峰时间(Tmax)快，达峰浓度(Cmax)高，生物利用度高。 因此，本实验通过固体分散技术制备的大豆异黄酮固体分散体片达到了提高生物利用度的目的。
Soy-isoflavone mainly reside in fabaceous pod, has a high contents in soy bean, distributed in seed leaf and hypocotyls of soybean seed, has a less contents in testa. Now, 12 kinds of Soy-isoflavone has been found, included 9 kinds of soy-isoflavone glycoside and 3 kinds of corresponded aglycone. Soy-isoflavone is the active component of the most medical treatment value in the soybean biological actives, which has estrogen function, including anti-tumor, antioxygen, heart-blood vessel protection, improving bone rarefaction and relieve the indisposition symptom of female climacteric state. so, it has the high value of studying and developing. But, as soy-isoflavone is indissolvable in water, has very low bioavailability, which bring some difficults for its clinical application. Howerer, solid dispersion is one of the technologies of increasing the bioavailability of indissolvable drug, which force drug being at high disperdion state, Generally, drug particle diameter in solid dispersions was 0.001～0.1um, mainly dispersed condition was molecularity, metastable amorphism and colloidal state. Carries" wettability, restrain crystallinity to drug assured drug"s quickly dissolution, the bioavailability of drug has corresponding increase, usually, the preparative method of solid dispersion was solvent co-evaporation, fusion method, and solvent-fusion method. The common water solubility carries was peg, pvp, poloxamer, organic acid, and saccharide. The purpose of this study is designing an effective oral administration preparation by using solid dispersion technology to increase the bioavailability of soy-isoflavone. Soy-isoflavone solid dispersion was prepared in the study, the influence of different carriers (peg4000,peg6000,poloxamer188,pvpk30) and preparative method(solvent co-evaporation, fusion method) to the dissolution rate of soy-isoflavone was considered, moreover, the dissolution data was been taken curve fitting by weibull equations, and comparing their dissolution parameters, and concluded that the dissolution rate of soy-isoflavone was highest when using pvpk30 as carriers and applying dissolvent co-evaporation method. The influence of different amount of carriers to the dissolution rate of soy-isofiavone was further considered, as a result, the dissolution rate of soy-isoflavone was highest when pvpk30: drug=9:1. The diferential thermal analysis (DTA) test show that soy-isoflavone is dispered in pvpk30 in amorphism. Comparing solid dispersion with physical mixture and pure soy-isoflavone was showed that the dissolution rate of soy-isoflavone solid dispersion was highest. In the influencing factor experiments of soy-isoflavone and its solid dispersion, at the condition of high temperature, high moist and highlight, the appearance, content and dissolution of soy-isoflavone has no marked change, at the condition of high temperature and highlight, the appearance, content and dissolution of soy-isoflavone solid dispersion has no marked change, at the condition of high moist, the appearance of soy-isoflavone solid dispersion has marked change, showing severe hydroscopicity, contents and dissolution has no marked change. During the study of preparing soy-isoflavone solid dispersion tablet, disintegration time and dissolution rate of soy-isoflavone solid dispersion tablet was considered as inspection items, tempering uniformity design method was applied to optimize preparation prescription, partial least square method regression analysis was used to modeling for the data of uniformity design, the calculate results was consistent with the experiment validation results, and concluded that the optimizing prescription of soy-isoflavone solid dispersion tablet was Soy-isoflavone solid dispersion 0.18g, Amylum Pregelatinisatum 0.26g, CMSNa 0.03g, Gum Acacia 0.03g. The tablets of soy-isoflavone solid dispersion has good appearance, the contents of total isoflavone in tablet was detected by UV, and the contents of genistin was detected by HPLC. The comparation of dissolution rate between the soy-isoflavone solid dispersion tablet and its normal tablet was showed that the dissolution rate of soy-isoflavone solid dispersion tablet was higher than its normal tablet. six months" accelerated test show that the dissolution of soy-isoflavone solid dispersion tablet has some extent decline, but the final dissolution was still kept above 80%. During the study of pharmacokinetics of soy-isoflavone solid dispersion tablet and its normal tablet in rats, the time-variation curve of the concentration of Genistein which was the metabolic product of soy-isoflavone in blood was described, the fitting parameter of the pharmacokinetics software(DAS) show that the rats administered soy-isoflavone solid dispersion tablet was found in their blood the Genistein"s Tmax was faster, Cmax was higher, and bioavailability was higher. As a result, soy-isoflavone solid dispersion tablet in the study reach its purpose of increasing bioavailability.
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