一贯煎定时释药缓释微丸的研制
摘要
一贯煎,为清代名医魏之琇所创,出于《续名医类案·心胃痛门》。该方由北沙参、麦冬、地黄、当归、枸杞子、川楝六味药材组成,具有滋阴疏肝的功效,用于肝肾阴虚驻症,临床主要用于治疗慢性乙型肝炎、肝硬化、慢性肝炎等症。一贯煎目前临床上还以传统汤剂方式给药,为了提高药物生物利用度,减少给药次数,采用现代科学技术手段对其进行制剂研究是很必要的。目前口服缓释固体制剂主要是通过膜控来实现的,而对于多数中药来说,都是由其中许多成分协同作用而达到治疗效果的;如果制备中药口服缓释制剂,简单的膜控不可能使其中各种成分同速率释放出来。故本文研制了一贯煎定时释药缓释微丸,即对载药丸芯包双层衣,分别为内层溶胀层和外层水不溶的控释层,水缓慢透过外层而引起内层溶胀,至一定程度后致使外层膜破裂而触发药物完全的、同时、迅速的释放,通过控制控释层衣膜厚度调节水的渗透速度制备具有3 h和6 h时滞的两种包衣微丸,将丸芯和两种包衣微丸按比例混合装入硬胶囊,可同时达到缓释和同时释药的目的。
本文采用TLC鉴别方法,对制剂中地黄、当归、枸杞子、北沙参及川楝子五味药材进行鉴别,并选用君药地黄中的梓醇和臣药当归中的阿魏酸为指标性成分,采用HPLC法建立了两种指标性成分的含量测定方法,释放度测定方法。以上方法可靠,重现性好,为制剂研究和质量控制奠定了较好的基础。
根据半仿生提取理论,以指标性成分梓醇和阿魏酸含量及干浸膏为指标,用均匀设计优选出一贯煎方药半仿生提取的最佳提取工艺条件;采用正交试验设计方法,优化醇沉工艺,可有效去除中药中常见的杂质;提取精制工艺条件可靠,重现性好。验证实验证明对于一贯煎方药,半仿生提取法优于水提法,半仿生提取醇沉法优于水提醇沉法。
药效学试验表明制得的一贯煎提取物对CCl_4致大鼠肝损伤有明显降低转氨酶、保护肝细胞的作用。
采用挤出滚圆法制备一贯煎载药丸芯,通过处方筛选和工艺优化使目标丸芯30 min累计释药85%以上,收率约为78.2%,微丸外观圆整。用流化床悬浮包衣法对一贯煎微丸进行溶胀层和控释层的包衣,以低取代羟丙基纤维素为溶胀层包衣材料,使增重20%,以乙基纤维素为控释层包衣材料,制备控释层增重分别为0%、20%和24%的包衣微丸均匀混合,装入硬胶囊得一贯煎定时释药缓释制剂;对其进行释放度测定,一贯煎定时释药缓释微丸中梓醇和阿魏酸体外释放的f_2值为78.2,释放度无显著性差异,并具有明显缓释特征。
Yiguanjian was set up by the famous doctor Wei Zhixiu in Qing Dynasty, quoted from the book named Xu Ming Yi Lei An·Xin Wei Tong Men. This prescription is made of six medicines including Coastal Glehnia Root、Dwarf Lilyturf Root Tuber, Aahesive Rehmannia Root Tuber, Chinese Angelica, Barbury Wolfberry Fruit and Szechwan Chinaberry Fruit, which owns protective effect to liver and can be used to cure liver ailment. Clinically, it is mainly used to treat chronic hepatitis B, hepatocirrhosis, chronic hepatitis and so on. Yiguanjian is currently administrated in the form of traditional decoctions clinically. It is necessary to study the preparation using the modern technology in order to improve the bioavailability and decrease the times of drug administration. Therefore, this paper is focused on studying Yinguanjian sustained-release pellets of time-controlled release; it means to coat the drug-loading pill core with double decks, that is the inner swelling layer and the outer controlled layer. The water gradually permeated the outer layer in order to swell the inner layer. When the inner layer swelled to some extent, the outer layer would break which could trigger the drug completely, simultaneously releasing. By controlling the thickness of the controlling-release layer, we could regulate the rate of water permeating. Thus we could prepare two kinds of coated pellet that the time lag is 3 and 6 hours, respectively. By mixing the pellet core and the kinds of coated pellet at some ratio, the preparation could achieve the aim of sustained releasing and simultaneous releasing.
This paper introduced the method of TLC, which was used to identify the fivemedicine materials: Aahesive Rehmannia Root Tuber, Radix Angelicae Sinensis, Barbury Wolfberry Fruit, Coastal Glehnia Root and Szechwan Chinaberry Fruit in the preparation. The Catalpol of Aahesive Rehmannia Root Tuber and the Ferulic of Radix Angelicae Sinensis were selected as the standard substance whose measuring method was set. A HPLC method was applied to measure the releasing degree. This method is credible with good fidelity, which was the good basis for the preparation study and the quality control.
According to the theory of semi-bionic extracting, using the amount of indicative substance-Catalpol and Ferulic and dry-extravts as the standard, we selected out the best semi-bionic extracting technics' conditions of Yiguanjian. Applying orthogonal design test, we optimize the technics of alcohol precipitation method which could effectively remove the ordinary impurity of the medicine. The condition of the extracting and optima technics is credible with good recurrence. The experiment proved that the semi-bionic extracting method is better than the water extracting method and the alcohol precipitation of semi-bionic extracting method is better than the alcohol precipitation of water extracting method.
The experiment of pharmic identified that the extracting of Yiguanjian applying optimized and refined technics had the obvious effect of reducing GPT, GOT and protective effect to liver with broad safe scope.
Prepare Yiguanjian drug-loading pellets using extrusion-spheronization. By filtering the prescription and optimizing the technics, the yield of the target pellet is 78.2% and the appearance of the pellet is round and full. A fluid-bed spray processor was adopted for the coating of the buffer pellets. Using low-substituted hydroxypropyl cellulose (L-HPC) as the main coating material of the inner swelling layer increasing the weight of inner coating layer by 20% and 15%. It can achieve the effect of time-controlled release by controlling the thickness of the outer coating membrane wth surelease as the coating solution of the outer swelling layer. Yiguanjian sustained-release capsules were developed by encapsulating the three kinds of coated pellets whose coating load were 0%, 20% and 24% at equivalent ratio. Investigating the drug release the f_2 of Catalpol and Ferulic acid in Yiguanjian sustained-release pellets is 78.2. The release had no significant release, while the characteristics of sustained release could be obviously seen.
本文采用TLC鉴别方法,对制剂中地黄、当归、枸杞子、北沙参及川楝子五味药材进行鉴别,并选用君药地黄中的梓醇和臣药当归中的阿魏酸为指标性成分,采用HPLC法建立了两种指标性成分的含量测定方法,释放度测定方法。以上方法可靠,重现性好,为制剂研究和质量控制奠定了较好的基础。
根据半仿生提取理论,以指标性成分梓醇和阿魏酸含量及干浸膏为指标,用均匀设计优选出一贯煎方药半仿生提取的最佳提取工艺条件;采用正交试验设计方法,优化醇沉工艺,可有效去除中药中常见的杂质;提取精制工艺条件可靠,重现性好。验证实验证明对于一贯煎方药,半仿生提取法优于水提法,半仿生提取醇沉法优于水提醇沉法。
药效学试验表明制得的一贯煎提取物对CCl_4致大鼠肝损伤有明显降低转氨酶、保护肝细胞的作用。
采用挤出滚圆法制备一贯煎载药丸芯,通过处方筛选和工艺优化使目标丸芯30 min累计释药85%以上,收率约为78.2%,微丸外观圆整。用流化床悬浮包衣法对一贯煎微丸进行溶胀层和控释层的包衣,以低取代羟丙基纤维素为溶胀层包衣材料,使增重20%,以乙基纤维素为控释层包衣材料,制备控释层增重分别为0%、20%和24%的包衣微丸均匀混合,装入硬胶囊得一贯煎定时释药缓释制剂;对其进行释放度测定,一贯煎定时释药缓释微丸中梓醇和阿魏酸体外释放的f_2值为78.2,释放度无显著性差异,并具有明显缓释特征。
Yiguanjian was set up by the famous doctor Wei Zhixiu in Qing Dynasty, quoted from the book named Xu Ming Yi Lei An·Xin Wei Tong Men. This prescription is made of six medicines including Coastal Glehnia Root、Dwarf Lilyturf Root Tuber, Aahesive Rehmannia Root Tuber, Chinese Angelica, Barbury Wolfberry Fruit and Szechwan Chinaberry Fruit, which owns protective effect to liver and can be used to cure liver ailment. Clinically, it is mainly used to treat chronic hepatitis B, hepatocirrhosis, chronic hepatitis and so on. Yiguanjian is currently administrated in the form of traditional decoctions clinically. It is necessary to study the preparation using the modern technology in order to improve the bioavailability and decrease the times of drug administration. Therefore, this paper is focused on studying Yinguanjian sustained-release pellets of time-controlled release; it means to coat the drug-loading pill core with double decks, that is the inner swelling layer and the outer controlled layer. The water gradually permeated the outer layer in order to swell the inner layer. When the inner layer swelled to some extent, the outer layer would break which could trigger the drug completely, simultaneously releasing. By controlling the thickness of the controlling-release layer, we could regulate the rate of water permeating. Thus we could prepare two kinds of coated pellet that the time lag is 3 and 6 hours, respectively. By mixing the pellet core and the kinds of coated pellet at some ratio, the preparation could achieve the aim of sustained releasing and simultaneous releasing.
This paper introduced the method of TLC, which was used to identify the fivemedicine materials: Aahesive Rehmannia Root Tuber, Radix Angelicae Sinensis, Barbury Wolfberry Fruit, Coastal Glehnia Root and Szechwan Chinaberry Fruit in the preparation. The Catalpol of Aahesive Rehmannia Root Tuber and the Ferulic of Radix Angelicae Sinensis were selected as the standard substance whose measuring method was set. A HPLC method was applied to measure the releasing degree. This method is credible with good fidelity, which was the good basis for the preparation study and the quality control.
According to the theory of semi-bionic extracting, using the amount of indicative substance-Catalpol and Ferulic and dry-extravts as the standard, we selected out the best semi-bionic extracting technics' conditions of Yiguanjian. Applying orthogonal design test, we optimize the technics of alcohol precipitation method which could effectively remove the ordinary impurity of the medicine. The condition of the extracting and optima technics is credible with good recurrence. The experiment proved that the semi-bionic extracting method is better than the water extracting method and the alcohol precipitation of semi-bionic extracting method is better than the alcohol precipitation of water extracting method.
The experiment of pharmic identified that the extracting of Yiguanjian applying optimized and refined technics had the obvious effect of reducing GPT, GOT and protective effect to liver with broad safe scope.
Prepare Yiguanjian drug-loading pellets using extrusion-spheronization. By filtering the prescription and optimizing the technics, the yield of the target pellet is 78.2% and the appearance of the pellet is round and full. A fluid-bed spray processor was adopted for the coating of the buffer pellets. Using low-substituted hydroxypropyl cellulose (L-HPC) as the main coating material of the inner swelling layer increasing the weight of inner coating layer by 20% and 15%. It can achieve the effect of time-controlled release by controlling the thickness of the outer coating membrane wth surelease as the coating solution of the outer swelling layer. Yiguanjian sustained-release capsules were developed by encapsulating the three kinds of coated pellets whose coating load were 0%, 20% and 24% at equivalent ratio. Investigating the drug release the f_2 of Catalpol and Ferulic acid in Yiguanjian sustained-release pellets is 78.2. The release had no significant release, while the characteristics of sustained release could be obviously seen.
引文
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