摘要
消化性溃疡主要指发生在胃和十二指肠的慢性溃疡,即胃溃疡和十二指肠溃疡,中医根据其临床症状将其归属于“胃脘痛”的范畴。该病病程较长,反复发作,临床表现复杂,是一种全球性常见的慢性胃肠病。姜百片是一种治疗胃溃疡的复方中药,含高良姜、香附、百合和乌药提取物。本研究中使用的药品为姜百原料药的浸膏粉,棕红色,气微香,味微辣。
本研究成功建立了大、小鼠乙醇胃损伤模型、大鼠水浸应激溃疡模型、大鼠醋酸损伤溃疡模型、大鼠幽门结扎模型、小鼠幽门螺杆菌感染模型及小鼠醋酸疼痛模型,考察了姜百原料药不同剂量对各种急、慢性胃溃疡模型的溃疡指数、胃液量、胃液总酸度、胃蛋白酶活性、抗氧化体系(SOD,MDA)、生长因子(EGF,VEGF)及幽门螺杆菌(Hp)活力等的影响;成功培养了Hp,验证了姜百片组方中高良姜的提取分离纯化物——二苯基庚酮在体外对Hp的抑制作用,并对组方中香附、百合及乌药的提取物进行体外Hp抑菌筛选实验。
结果显示,姜百原料药可以显著降低大鼠乙醇胃损伤模型、大鼠水浸应激溃疡模型、大鼠幽门结扎溃疡模型、大鼠乙酸灼烧溃疡模型的溃疡指数(P＜0.05);可以显著提高小鼠乙醇胃损伤模型组织SOD活力,降低组织MDA含量(P＜0.05);可以显著提高醋酸灼烧模型胃组织EGF和VEGF的水平(P＜0.05);可以显著降低大鼠幽门结扎模型胃蛋白酶活力(P＜0.05);还可以减少小鼠醋酸疼痛模型扭体次数(P＜0.05);姜百原料药对小鼠Hp感染模型胃内细菌具有显著抑制作用(P＜0.05);姜百片中高良姜和乌药的提取物在体外具有抑制Hp的作用。
本实验经过初步探讨分析,认为姜百原料药的胃黏膜保护及胃溃疡的治疗作用主要有两方面的原因:一是姜百原料药可能具有提高组织抗氧化能力及增强组织自身生长及修复能力的作用,其发挥作用的具体机制还有待进一步深入研究;二是姜百片在体内外对Hp具有一定的抑制作用,其作用可能与姜百原料药中高良姜和乌药的提取物有关。
姜百原料药浸膏粉具有较强辛辣味,口服给药用量较大,不适宜制成颗粒剂和胶囊剂,因此选择制成片剂并进行包衣改善嗅味。姜百原料药浸膏粉具有粘性大、易吸湿、遇水后发粘不易分散且流动性变差等特点。因此片剂处方设计以改善吸湿性和崩解时限为重点,通过制粒、选择合适的辅料及原料与辅料的比例、控制压片场所的相对湿度,选择合适的崩解剂及其用量和加入方式、合适的片剂硬度等进行实验,初步确定了姜百片的处方和制剂工艺。
本实验以淀粉、微晶纤维素、糊精、硬脂酸镁、微粉硅胶和交联羧甲基纤维素钠(CC-Na)为考察对象进行筛选,最终选定微晶纤维素为稀释剂,CC-Na为崩解剂,微粉硅胶为润滑剂;对原料与辅料的比例进行筛选,确定原辅料最佳比例6:4;考察CC-Na的不同用量(5%,6%,7%,8%)对崩解时间的影响,确定7%为最佳崩解剂用量;通过比较崩解剂外加,内外加和内加对崩解时间的影响,选择崩解剂加入方为内加;比较片剂硬度(7kg,4kg)对崩解时间的影响,确定压片硬度为4 kg;测定颗粒在不同湿度环境中的吸湿率,绘制吸湿曲线,求得颗粒的临界湿度为68.5%。
初步确定姜百片的处方为:原料药60%,稀释剂(微晶纤维素)30%,崩解剂(CC-Na)7%,润滑剂(微粉硅胶)3%;成型工艺为:姜百片原辅料分别烘干,混合均匀,过80目筛,以70%乙醇润湿,30目筛制粒,然后压片,片重0.4g,硬度4 kg,压片过程环境相对湿度控制在68.5%以下。按照本处方和工艺制得的片剂,外观、硬度、片重差异和崩解时限均符合中国药典2005版片剂质量要求。
Peptic ulcer primarily occurred in the stomach and duodenum,is a common chronic gastrointestinal diseases.According to its clinical symptoms Peptic ulcer is vested in "Stomachache" category in traditional Chinese medicine.JiangBai Tablet is a compound Chinese medicine on gastric ulcer,containing extraction of Galangal, Cyperus rotundus,lily,and Lindera aggregata.The drug used in this study is JiangBai powder,brown-red,aromatic and spicy.
Ethanol-induced gastric ulcer rat model,stress ulcer rat model,pyloric ligation ulcer rat model,acetic acid ulcer rat model,Helicobacter pylori Infection mouse model and Acetic acid achy mouse model were successfully cloned.The protection and therapeutic effects of JiangBai Powder in different doses were investigated on those models.Ulcer index,gastric volume,gastric juice total acidity,pepsin activity, anti-oxidation system(SOD,MDA),growth factor(EGF,VEGF) and Helicobacter pylori(Hp) activity were measured to evaluate the effects;Hp was cultured and the inhibitory effect of the 2-phenyl-heptanone which extracted from galangal on Helicobacter pylori(Hp) in vitro was validated.Antibacterial screening experiments about Galangal,Cyperus rotundus,lily,and Lindera aggregata were carried out too.
The results showed that Jiangbai Powder can significantly reduce the ulcer index (P＜0.05)on ethanol-induced gastric ulcer rat model,stress ulcer rat model,pyloric ligation ulcer rat model and acetic acid ulcer rat model;can significantly improve the SOD activity(P＜0.05)and reduce the MDA content(P＜0.05)of ethanol-induced gastric mouse model;can significantly improve the EGF and VEGF level of gastric tissue on Acetic acid ulcer rat model and the pepsin activity(P＜0.05) of the pyloric ligation rat model;It can also reduce the frequency of the turning trunk reaction on Acetic acid achy mouse model;Jiangbai Powder has inhibitory effect on Hp in vitro and the 2-phenyl-heptanone in vivo,which was extracted from galangal.
The protection and therapeutic mechanism of Jiangbai Powder on gastric ulcer can be summarized as followings:firstly,Jiangbai Powder may enhance tissue regenerate capacity and anti-oxidation,its specific mechanism remains to be further studied; secondly,Jiangbai Powder has a certain Hp inhibitory effect and the extraction form Galangal and Lindera aggregata may be the main reason.
The Jiangbai Powder is inappropriate to be made as capsules or granules for its strong spicy flavor,larger amount of oral administration.Therefore coated tablets were chosen as the suitable dosage form.The moisture absorption and disintegration time were the important problem to solve for the Jiangbai Powder is hygroscopic viscous, poor mobility after water dispersed.So the formulation and tableting procedur were abtained by selecting appropriate accessories,disintegrant and its dosage,rigidity and the best RH%.
This experiment investigated the fluidity,hygroscopicity,disintegration of starch microcrystalline cellulose,dextrin,magnesium stearate,silica powder and croscarmellose sodium(CC-Na),selected microcrystalline cellulose as fillers,CC-Na as disintegrant,aerosol as glidants,the ratio of raw materials and adjuvant was 6:4;studied the impact of different dosage of CC-Na(5%,6%,7%,8%) on dissolution,7%was the best dosage;studied the impact of different adding way of disintegrant on dissolution,chose the within plus way of adjuvant;compared the impact of rigidity(7 kg,4 kg) on dissolution,opted 4 kg as the proper rigidity;Determined the moisture absorption rate of Jiangbai granules in different humidity,drawn moisture absorption curve,obtained that the critical relative humidity(CRH)was 68.5%.
The formulation of the Jiangbai Tablet is 60%of raw materials,30%of fillers (microcrystalline cellules),7%of the disintegrant(croscarmellose sodium,CC-Na) and 3%of glidants(aerosol);Jiangbai powder and adjuvant were dried,mixed evenly, sieved by 80 mesh,wetted with 70%ethanol,granulated with 30 mesh then tabletted, the tablet weight is 0.4 g and rigidity is 4 kg,the CRH is controlled below 68.5%in the tabletting process.Tablets obtained in this way were met the requirements of Ch.P.2005 in appearance,rigidity,tablets weight variation and dissolution.
引文
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