【作者】 李丹；

【导师】 陈大为； 宋洪涛；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2007， 硕士

【摘要】 复方丹参片为中华人民共和国药典2005年版一部收载品种,由丹参、三七、冰片三味药组成。本品可活血通络,散瘀止痛,用于治疗胸痹心痛及冠心病、心绞痛,心肌梗塞等。临床用药广泛,疗效确切,作用温和,未见明显的毒副作用,可长期服用。本文将其改为复方丹参缓释胶囊,研究了处方中丹参及三七的提取纯化工艺,建立了检测内在质量的定量控制方法,在此基础上研究制备了复方丹参缓释胶囊,并对其进行了初步的药效动力学研究,取得了较为理想的结果。本文选择具有较强药理活性的丹酚酸B、丹参素、原儿茶醛、三七总皂苷和冰片作为复方丹参缓释胶囊的指标性成分,建立了HPLC、UV和GC测定含量的质控方法,试验结果表明,上述方法灵敏度高、重现性好、分离度好,较好地满足和适合于复方丹参缓释胶囊的分析测试应用；建立了主要指标性成分丹酚酸B、三七总皂苷和冰片体外溶出度的测定方法,为进一步进行处方及工艺的深入研究提供了有效的分析手段。采用大孔树脂法纯化丹参总酚酸,经过单因素考察及正交试验确立了丹参总酚酸的纯化工艺。大孔树脂柱径高比为1：7,树脂药材比为5：1,以2.5 BV·h-1的流速先用30%乙醇将丹参素和原儿茶醛洗脱完全,再用50%乙醇将丹酚酸B洗脱完全。经过三批小试结果验证三种指标成分的转移率均在80%以上,在固形物中的含量为29.7%,是传统水醇法的2.8倍。采用大孔树脂法纯化三七总皂苷,经过单因素考察确立了三七总皂苷的纯化工艺为大孔树脂柱径高比为1：6,树脂药材比为4：1,以9～12 BV·h-1的流速用70%乙醇洗脱三七总皂苷。结果三七总皂苷的转移率为95.4%,在固形物中的含量为77.2%。采用球磨法将冰片制成冰片β-环糊精包合物,其包合物收率为91.8%,包封率为94.9%。经过纯化后的中间体大大提高了精制程度为进一步制备复方丹参缓释制剂奠定了基础。通过对复方丹参微丸处方因素的考察,确定了复方丹参同步释放微丸的制备处方如下：10%三味药材的精制物；2%SDS；5%CMS-Na；20%泡腾崩解剂和63%MCC,以70%乙醇做粘合剂制软材后采用挤出滚圆的方法制备复方丹参同步释放微丸。微丸中三味药的平均体外溶出累积百分率10min内均可以达到80%以上。三成分之间的f2平均值分别为：冰片与三七总皂苷60.0、冰片与丹酚酸B58.9、三七总皂苷与丹酚酸B87.3。各指标成分的D.E.15平均值分别为：冰片58.5、三七总皂苷63.2、丹酚酸B64.4。三味药基本达到了同步释放。采用流化床、双层膜包衣技术制成系列具有不同释药时滞的定时释药微丸。溶胀层包衣材料选择为3% L-HPC,1%SDS,2% HPMC,其增重为12%；控释层包衣材料选择为2% EC 90%乙醇溶液,2%微粉化滑石粉,0.2%邻苯二甲酸二乙酯,增重分为8%、12%、16%、20%、24%、26%。将其按一定比例混合后装入胶囊制成复方丹参缓释胶囊,从而使理化性质不同的各成分在缓释的同时达到了同步释放。采用比浊法测定血小板聚集率,将其作为药效学指标,通过测定6条家犬两周期随机交叉口服给药自制复方丹参缓释胶囊和市售复方丹参片,对其进行了药效动力学研究。应用非隔室模型法求算了两者的药动学参数。市售复方丹参片T1/2为1.5 h,MRT为4.56 h,自制复方丹参微丸的T1/2为2.4 h,MRT为8.11h,约为复方丹参片的2倍,基本达到了预期的缓释效果。更多还原

【Abstract】 The compound Danshen tablets, listed in the first section of the 2005 s edition of "Pharmacopoeia of the People s Republic of China", was composed of Danshen, panax notoginseng and borneol.This medicine can activating blood and removing stasis, which can cure chest pain, coronary heart disease, angina, myocardial infarction,etc.The tablets, widely used as clinical medicine, have exact curative effect with little side effect and can be used in long term. The compound Danshen tablets were developed into compound Danshen delayed-release capsules in this paper. The process of extraction of radix Salvia miltiorrhizza and radix panax notoginseng was studied and the quantity controlled method was also established. The compound Danshen delayed-release capsules were successfully prepared and the results of pharmacodynamics study were satisfied.Salvia molic acid B, Danshensu, protocatechuic aldehyde, the total panax notogiseng saponins (PNS) and borneol were selected as target ingredients of the compound Danshen delayed-release capsules, the contents of which were determined by means of HPLC, UV and GC methods. The results suggested that the methods above had high sensitivity, good reproducibility and separability which were suitable for the analysis of the compound Danshen delayed-release pellets. The mensuration of dissolution in vitro of Salvia molic acid B, PNS and borneol was established, which provided an effect analysis method for further study.Salviamolic acid was purified by using the macroporous resin and the process of purification was verified by means of single factor experiment design and orthogonal experiment. The ratio of the height to bore of the resin column is 7 to 1,the radio of the resin to the material drug is 5 to 1,and the velocity of the elution is 2.5BV·h-1,30% ethanol can totally elute the Danshensu and protocatechuic aldehyde,then we use 50% ethanol to elute Salvia molic acid B. The three results confirm that the transformation ratio of the three index components are all over 80%,the content in the dried part is 29.7%,which is 2.8 times of the alcohol sedimentation. We used macro reticular resin to purify PNS, by means of single factor experiment design we decide that the process of purification are:the ratio of the height to bore of the resin column is 6 to 1,the radio of the resin to the material drug is 4 to 1, gradient elutive liquid is 50% ethanol and the velocity of the elution is 9～12BV·h-1.The result is:the transformation ratio of PNS is 95.4%, and the content in the dried part is 77.2%. Borneol was made into borneol-β-cyclodextrin inclusion compound by using ball mill. The yield of the inclusion compound was 91.8% and the encapsulating rate is 94.9%. The intermediate purified greatly enhanced the degree of preparation and established the foundation for further preparation of the compound Danshen delayed-release capsules.The prescription of the compound Danshen isochronous fast-release pellets was determined by investigating the formula factor of the compound Danshen pellets. The prescription was consist of 10% purifier of the three medicinal materials,2% SDS, 5% CMS-Na,20% effervescence disintegrating agent and 63% MCC.The method of extrusion-spheronization method was adopted for preparing the compound Danshen isochronous fast-release pellets by using 70% alcohol as adhesive. The average dissolve accumulated amount in vitro of the three medicines in the pellets could come to more than 80% within 10 min. The average f2 of the three components—(borneol and PNS), (borneol and Salvia molic acid B) and (PNS and Salvia molic acid B) was 60.0,58.9 and 87.3 separately. The average D.E.15 of borneol, PNS and salviamolic acid were 58.5,63.2, and 64.4 separately. The three medicines could be released synchronously.A fluid bed spray processor and double-film coating technology were adopted for preparing a series of time-release pellets with different time lags. The coating material of swelling layer was 3% L-HPC,1% SDS with increased weight of 12%. The coating material of controlled layer was 2%EC,90% alcohol solution,2% micronization talc and 0.2% Diethyl phthalate with increased weight of 8%,12%,16%,20%,24%, 26% separately. The compound Danshen delayed-release capsules were made of these materials that were mixed in certain proportion, therefore, the components with different properties could be released synchronously while being sustained released.Use platelet aggregation as the index of pharmacodynamics, which is tested by nephelometery. Six dogs were randomly divided into two groups, which were separately treated with self-made compound Danshen pellets and the compound Danshen tablets on sale for one period and next period change the medicine for each group. Noncompartment model was used to calculate the parameters of pharmarmacokimetics. The results indicate that the T1/2 of the compound Danshen tablets on sale is 1.5 h and MRT is 4.56.The T1/2 of self-made compound Danshen pellets is 2.4 h and the MRT is 8.11 which is about 2 times of the compound Danshen tablets. As a result, the self-made compound Danshen pellets basically achieve the expected delayed releasing effects.更多还原