纳米中药饮片的应用研究

中国拥有丰富的中药资源 随着科学的发展 中医药日益受到广泛的重视 在为人类健康服务 的同时 市场也越来越大 到 20 世纪末 每年 天然植物药在世界的市场份额已达到 270 亿美元 而我国占其中的份额尚不足 5 大部分都被韩 国 日本 德国占有 而使用的原料绝大多数却 是从中国廉价购得 众所周知 中药难以打入国际市场的一个重 要原因便是中药剂型过于老化 单一 犹太国际 的主脑人物洛克菲勒要求 世贸组织 中凡属其 麾下的成员国禁止买卖中成药 欧盟首先响应 制定了 传统药品法案 该法案规定 对欧 盟市场出口药品的生产厂家必须通过欧盟的 药 品生产质量管理准则 GMP 出口药品的质量 必须符合欧盟药典标准 欧盟的进口商必须办理 药品进口许可证 等等条款 该法案的出台 不 仅在近期封杀了中国的中药 从长远分析 中国 将要为此付出惨痛的机会成本并蒙受长期的经济 损失 由此产生的不良影响不单是在欧洲 而且 还将波及到世界其他国家 如美国政府也马上跟 风 计划在今年开始禁止中国的中药进口 因此 中药现代化的重点应充分重视加工现代化 标准 的国际化使中药面向世界 纳米中药饮片为中药国际化创造了前所未 有的机会 饮片 就是单味药材 每味饮片就象兵团 中的一个士兵 都有其自己的特殊作用 传统的 中药饮片是中药材的切制炮制品 供药厂 医院 医生配方使用 经过近代的药学专家的努力 常 用的几百种饮片的成分 药效 检测方案及标准 基本清楚 这些与国际上天然植物研究基本是一 致的 使纳米中药饮片以其成份清楚 加工精细 而快速替代被限制的中药出口 并形成新的闪亮 经济增长点 这就需将现代高新技术引入到中药 制备当中 科技部 1996 年提出了中药现代化政 策 2002 年颁布 中药现代化发展钢要 有力 地推动了中药现代化的发展进程 China enjoys abundant herbal medicinal resources Along with the development of science and technology and their wide use in serving the health of people Chinese traditional medicine has attracted ever increasing attention and its market has become larger and larger Up to the end of the 20th century the trading volume of natural plant medicines amounts to 27 billion US Dollars each year However the share captured by our country is less than 5 and a large share is occupied by South Korea Japan and Germany but the most part of the raw materials of them are purchased from China at an low price It is well known that an important reason for Chinese traditional medicines difficult to enter the international market is the so excessive aging and singularity of medicinal dosage forms that Rockefeller a dominant figure in the Judas International has instructed all his members in the World Trade Organization not purchase Chinese patent medicines The European Union was the first to make a positive response and has formulated an Act on traditional medicines This act specified that All the manufacturers of medicines to be exported to the EU market should have passed GMP and the quality of exported medicine should conform to the EU pharmacopoeia standard and the importers of the EU should have medicine import license The publication of the act not only has blocked the export of Chinese traditional medicines in the short term but from a long term point of view China will also pay considerable opportunity costs and suffer from long term economic losses In addition the bad influence generated thereof will not only be reflected in Europe but also will spread to other countries throughout the world The United States will follow suit planning to forbid the import of Chinese traditional medicines from China this year Therefore the modernization of Chinese traditional medicines should be focused on the processing in accordance with international standards The appearance of medical nano herbal pieces prepared for decoction has created a rare opportunity for the internationalization of Chinese traditional medicines Herbal pieces prepared for decoction are of single ingredient medicinal materials and have their specific functions The traditional herbal pieces are all cut and processed products of Chinese medicinal materials and are to be supplied to hospitals and drug stores for formulating a prescription Through great efforts of medical experts the components medical effects test schedules and standards are basically clear and are in conformity with the international studies on natural plants This makes it possible for nano herbal pieces to substitute quickly the forbidden ones with their clear components and precise production process However this needs the introduction of high new technology into the preparation of Chinese traditional medicines In 1996 the Ministry of Science and Technology put forward a policy on Chinese traditional medicines and in 2002 promulgated which strongly promoted the development Chinese traditional medicine modernization The appearance of medical nano herbal pieces has created a rare opportunity for the internationalization of Chinese 纳米中药饮片的应用研究 曲 源 曲 莱 曲少忠 王宝华 Applicable study on medical nano herbal pieces Qu Yuan Qu lai Qu Shaozhong Wang Baohua 纳米技术为传统中药产业的改造创造了前所未有 的机会 纳米中药以其独到的高溶解度 高吸收 度 高吸附力度 高生物利用度 高透入力度的 速效 高效 长效及靶向治疗等特点 展现中药 产业现代化光辉前景 纳米中药饮片特点 纳米中药饮片特点 1 是全天然 全成份 保持原有本质 2 常温或低温下用物理粉碎法制备的纳米 颗粒 3 颗粒尺寸 95 分布在 100 500nm 之间 达到全破壁 4 采用了现代纳米固体分散技术 大幅度 提高中药溶出度而具有速效特性 充分提高生物 利用度 5 可采用现代的纳米包合技术 使其成为 可缓释中药 而具有长效特征 6 采用微乳 脂质体 毫微胶粒载体作用 使其具有定向分布的靶向特征 7 以溶出度来决定使用量并压制成常用剂 量的饮片 8 以 X 线广角衍射图谱 指纹图谱 作识 别标签及国际通行证 9 卫生标准方面达到可直接服用的标准 既可泡成汤剂 又可如同片剂一样用水送服 既 可配方 又可单独使用 一 纳米中药饮片全天然 全成分本质一 纳米中药饮片全天然 全成分本质 每味中药饮片内含物质群是个很复杂的问题 譬如人参是化学成分研究时间最长 研究资料积 累最多的一个品种 其文献记载可追溯到 1854 年 Sarriquex s 在 Ann Chem Pharm 杂志上关于人 参喹酮的报导 一百多年来 特别是近三十年来 不断有新的成分被发现 现在已知的内含皂甙有 三十多种 挥发油二十九种 氨基酸十五种 矿 物质二十九种 糖类十六种 有机酸十一种以及 酯类 生物碱 维生素 甾醇和多种酶等物质 而且还不断有新的发现 所以中医一直不认同麻 黄素等于麻黄 甘草酸等于甘草 黄连素等于黄 连 齐墩果酸等于牛膝 德 法联合开发的银杏叶提取物 EG6761 是 一个典范 他们在研究中发现银杏叶提取物的作 用是提取物所得物质群的整体作用结果 德 法 整体 正是这样一种混合物保证了其治疗作用 traditional medicines and the nano herbal pieces with their high solubility digestion absorption adsorption and penetration and target orientated effect as well as their quick high and long term drug action have opened a bright prospect for the modernization of Chinese traditional medicine industry Medical nano herbal pieces are characterized by 1 The preservation of their original natural quality and full components 2 Their nano particles prepared by physical crush under normal or low temperature 3 Their full wall broken with the size of 95 particles distributed between 100 500nm 4 The adoption of modern nano solid dispersion technology that can greatly increase the digestion of Chinese traditional medicines and thus their biologic utilization rate and speed of effectiveness 5 The possibility of adopting nano envelope technology to make them slowly release medicine featured by long term effect 6 The possibility of adopting micro milk lipoplast millimicro and idiosome carrier action to make them characterized by target oriented distribution 7 Their dosage to be determined by digestion or compressed into pieces of common dosage 8 With X ray wide angle diffraction pattern finger print pattern as identification label and international passport 9 Up to the health standard of direct taking either steeped into decoction or admitted directly with water just as tablets and either prescribed or taken independently 1 The intrinsic quality of medical nano herbal pieces full nature and full components The problem of matter clusters of each ingredient of medical herbal pieces is very complicated Taking Radix Ginseng for example the time spent on the study about its components is the longest and the materials accumulated about it are the most numerous The literature about it can be traced to the report on panaquilon written by Sarriquex s and published on the magazine Ann Chem Pharm For a century and especially in resent 30 years new components of Radix Ginseng have been continuously discovered Now it is known Radix Ginseng contains 30 kinds of saponin 29 kinds of naphtha 15 kinds of amino acid 29 kinds of mineral substance 16 kinds of carbohydrate and 11 kinds of organic acid as well as ester alkaloid vitamin sterine and enzyme Doctors of traditional Chinese medicine therefore always don t agree that ephedrine is equal to ephedra Radix Glycyrrhizae equal to Radix Glycyrrhizae acid berberine equal to Rhizoma Coptidis and oleanolic acid equal to Achyranthes root Another example is Semen Ginkgo extractive EG6761 developed jointly by Germany and France In studies they have found that the effect of the extractive is the integral effect of matter clusters of the extractive A person in charge of technology of the Germany and France Group said the extractive EG6761 should be regarded as a whole and it is just the mixture that guarantees the medical effect of Semen Ginkgo They have conducted the study for a long time and have found that if the lactone and flavone contained in the mixture are separated none of them has the integral effect of the extractive And this is in conformity with our 他们进行了长期的研究 把混合物所含内酯和黄 酮相互分离 则都不具备全部提取物整体的功效 在这一点上 和我们对中药的疗效是物质群整体 的功效这样的认识是一致的 又如 贯叶连翘用 于治疗抑郁症 从德国传到美国 使该产品成为 一九九八年美国草药市场令人注目的热点 美国 采用指标成分金丝桃素含量作为质量控制标准 但是 近年一些研究发现此成分无抗抑郁作用 目前还不能断定哪些是杂质 哪些是有效成分 每味药材都是如此 就此而言 研究清楚每味中 药内含成分很不现实 这就要求 在尚不清楚全 体化学成分的情况下 应保持其原有全天然 全 成分的本质 而纳米中药饮片不会有提取不全之 虞 是全天然 全成分的最佳制备方法 二 纳米中药饮片的制备二 纳米中药饮片的制备 1 采用常温或低温 对于动物类中药饮片与不含发挥油的饮片 可采用常温进行纳米粉碎 对于一些含发挥油的 中药饮片 可采用低温状态下粉碎 这样既保证 了植物类 动物类不至于焦化 碳化 挥发油挥 发 从而可以保留中药的活性成分 使其生物活 性物质不被破坏 保证药物疗效的发挥 2 粒径应控制在 100 500nm 之间 我们多年研究认为 纳米中药粉体平均粒径 不应小于 100nm 在 100 500nm 之间最好 此区 间植物不但破壁 其内的细胞也已经打碎 其物 理细化过程已经完成 仍以胃肠溶解吸收为主 可达到营养及药物成分的充分吸收作用 如果完 全追求 100 纳米以下 则增加其不稳定因素及产 生毒副作用的风险 纳米植物加工目的是为了提 高其高吸收度 而以其生产新的改性材料 则言 之尚早 3 结合固体分散技术以提高饮片出解度 从理论上讲 动植物纳米化使其颗粒变小 表面面积增大与胃肠中溶解媒接触更多 更容易 被溶解吸收 但有些中药纳米化后表面电荷增多 表现出易团聚性 分散性差 相溶性差 部分含 粘液性质细胞的中药 经破壁后则表现出极大的 粘稠性和极差的分散性 所以纳米中药饮片需结 合现代的固体分散技术 固体分散技术最初是被用于提高难溶性药物 的生物利用度 后来研究表明 水溶性药物也可 understanding that the curative effect of Chinese traditional medicines is the integral efficacy of matter clusters Still another example is Thorough Fructus Forsythiae for the treatment of depression which have been transferred from Germany to the United States and was a hot point attracting the attention of many people in the US herbal medicine market in 1998 In the United States the contents of hypericin have been adopted as a quality control standard but it has been discovered that this component is not effective in anti depression and up to now it is not possible to confirm which components are impurities and which components are effective This situation is applicable to every ingredient and it is not practical to find out the contents of all the herbal medicines This means that before all the chemical contents of a herbal medicine are made clear it is better to maintain the full original nature and contents of the herbal medicine and Chinese traditional medicine nano herbal pieces are the best full nature and full content products extracted with the best preparation method 2 Preparation of medical herbal nano pieces 1 Adopting normal or low temperature For the preparation of Chinese herbal pieces extracted from animals and that not containing naphtha the raw materials shall be crushed to nano size under normal temperature and for that containing naphths the raw materials shall be crushed under low temperature so as to prevent the animal and plant from coking and carbonization and the naphtha from volatilization and preserve the activity and curative effect of Chinese traditional medicines 2 Controlling the size of particles between 100 500nm What is the actual size of nano particles Through our study for many years we think that the size should not be less than 100nm in average and it would be best to be 100 500nm In this range the wall of plant is not only broken the cell in the plant is smashed as well For digestion and absorption of the stomach and intestines the course of physical fining is already completed and the nutrition and medical contents can be sufficiently absorbed If it is less than 100nm the instability and noxious side effect of the medicine will be increased The nano plant processing is aimed at increasing absorption and as to produce new modified materials it is premature to say 3 Increasing the release and solubility of medicines with solid dispersing technology In terms of theory reducing the size of particles of animals and plants will increase the total surface area of them and thus the contact area between the particles and the dissolvent of the stomach and intestines and make the medicine much more easy to dissolve out and being absorbed However some Chinese traditional medicines after crushed into nano size will have more electric charge on their particles manifested as easy to coacervate and poor in dispensability and inter solubility while some medicines containing mucous cells show extreme large mucosity and extreme poor dispensability Therefore it needs to adopt modern solid dispersing technology for the preparation of medical nano pieces The solid dispersing technology was primarily applied to increasing the biological availability of medicines that are difficult to dissolve but later it was found the technology is also applicable to water soluble medicines and now it has been already applied to the preparation of Chinese traditional medicine Qinghaosu 使用固体分散技术 而且水溶性和难溶性药物都 可采用固体分散技术 该技术已在中药青蒿素制 剂中应用 实际上 固体分散制备过程简单 产品质量易控 制 固体分散技术的工程放大和产业化过程均比 较简单 药材的理化性质和生物利用度在此过程 中不会发生明显变化 因此在解决难溶性药物生 物利用度方面 固体分散技术具有明显优势 并 迅速得到了发展 在中药饮片现代化过程中 固 体分散技术应加以推广应用 并力求产业化 4 利用包合技术突出饮片缓释长效特征 包合技术所采用的载体材料主要是环糊精 是一种纳米尺度的药物载体 研究表明 环糊精 的分子具有筒状结构 筒状结构内部可以包结多 种药物分子 环糊精药物包合物可以提高难溶性 药物的溶解度 降低药物刺激性 特别是中药易 挥发性成分经包合后 可明显提高保留率 增加 贮存过程中药物的稳定性 将中药有效成分包合到环糊精分子内已有一 定数量的文献报道 涉及到的药物有紫苏叶挥发 油 细辛挥发油 蟾酥 薄荷 人参提取物 无 花果提取物 冰片等 随着环糊精衍生物的出现 包合技术在制剂中的研究范围将更加广泛 既可 增加难溶性药物的溶解度和稳定性 又可以作为 水溶性药物的缓释载体 包合技术中的包药方法主要有重结晶法 研 磨法 喷雾干燥法 冷冻干燥法等 这些方法均 可以工程放大 以补正速溶 速效 速排泄的纳 米中药饮片的不足 持续保证适宜血药浓度 三 纳米中药饮片载体技术产生靶向特性三 纳米中药饮片载体技术产生靶向特性 纳米中药饮片结合微乳 脂质体 毫微胶粒 载体 形成靶向给药的特性 微乳 毫微胶粒与 脂质体作为药物的载体 可以延长药物作用时间 增加药物在体内外的稳定性 降低药物的毒性 同时可使药物具有定向分布的靶向特性 微乳作为药物的载体 可以增加难溶性药物 的溶解度 提高水溶性药物的稳定性 此外 微 乳还可作为缓释给药系统 靶向给药系统 脂质体包封合成药物的研究报道甚多 在中 药制剂中的研究文献也逐年增多 这是脂质体研 究的一个新动向 将脂质体技术引入到中药制剂领域 可以明 In fact the preparation course with solid dispersing technology and its enlargement and industrialization is very simple and the product quality is easy to control In this course the physico chemical nature and biological availability of medicinal materials will have no significant change Therefore the solid dispersing technology enjoys significant advantage in respect of increasing the biological availability of the medicines that are difficult to dissolve and has gained rapid development In the course of modernization of Chinese traditional medicines the application of this technology should be popularized and industrialized 4 Projecting the feature of slow releasing and long term effect with the nano envelope technology The material used in envelope technology is mainly cyclodextrin a nano size medical carrier Study shows the cyclodextrin is a cylindrical structure and in the structure various medicinal molecules are enveloped The medicinal substances enveloped in the cyclodextrin can increase the solubility of the medicines difficult to dissolve and lower the irritation of medicines and especially after volatile contents in the medicines being enveloped the medicinal substances can be best preserved and thus increase the stability of Chinese traditional medicines during storage There are many reports about enveloping effective contents of Chinese traditional medicines in cyclodextrin molecules and the medicines involved include Folium Perillae naphtha Herba Asari naphtha Venenum Bufonis Herba Menthae Radix Ginseng extractive Receptaculum Fici Caricae extractive and Borneolum Syntheticum etc With the appearance of cyclodextrin ramification the envelope technology has been studied in a much wider scope It can increase the dissolubility and stability of the medicines difficult to dissolve and the preparations can be used as the slow releasing carrier of water soluble medicines The medicine envelope methods mainly include recrystallization method grinding method spray drying method and freeze drying method All these method can be expanded in engineering to make good the shortage of Chinese herbal pieces in terms of quick dissolution quick effect and quick discharge and maintaining proper concentration of medicine in the blood 3 Target oriented feature of nano herbal pieces Medical nano herbal pieces in combination with micro milk lipoplast millimicro and idiosome carriers shall have the feature of target oriented administration Micro milk idiosome and lipoplast millimicro as medicinal carriers can prolong the effective time increase the stability lower the toxicity of medicines and at the same time make medicines have a target oriented feature of directional distribution The micro milk as a medicinal carrier can increase the solubility of the medicines difficult to dissolve and improve the stability of water soluble medicines In addition it can play a part in slowly releasing medicine and target oriented administration There are many studies and reports about the envelope of synthetic medicines by idiosome and also about the envelope of herbal medicines This is a new trend in the study of idiosome The introduction of idiosome into the preparation of herbal medicines can significantly increase the treatment indices and make some medicines with high toxicity such as Hecaofen and camptothecin much more safer in the treatment 显提高中药对疾病的治疗指数 可使一些毒性较 大的药物如鹤草酚 喜树碱等在治疗疾病时更安 全 在中药现代化过程中 脂质体技术将为中药 在治疗疑难疾病如心血管疾病 癌症等方面提供 更广阔的思路 四 纳米中药饮片其使用量四 纳米中药饮片其使用量 溶出度检测是一种控制固体制剂质量的体外 检测方法 1967 年由美国率先推出 现已成为 制剂工业质量控制的重要衡量指标 在检验上 可用于执行法定标准 在生产中可用于贯彻生产 的要求 在临床领域 可用于新药的研制 处方 筛选和工艺改进等 总之 溶出度检测能比较客 观地反映固体制剂的内在质量 它已经发展成为 制药工业必须的质量控制项目之一 生物利用度检测是在人或动物服药后 通过 对血或尿中药物浓度的测定来反映药物在体内被 吸收利用的程度 进而推断疗效的方法 从理论 上讲 药物的体内测验或临床研究才是评价制剂 的最根本和最可靠的方法 但是由于生物利用度 检测工作量极大 成本高 从药品生产的质量控 制角度来看 不可能都采用费时 费钱 费精力 的测试生物利用度的方法 因此需要借助于体外 溶出度检测结果来确定体内生物利用度 但多数 情况下溶出度与体内生物利用度是相关的 而溶 出度的体外检测较生物利用度检测简单易行 它 不失为一个经济有效的手段 这也是各国药典收 载这一检验项目的意图之一 纳米中药饮片由于完全破壁 晶体几乎全部 析出 与切制饮片 普通粉碎 超细粉碎的晶体 析出量有显著提高 在解决了分散问题之后 测 出溶出度 可以计算出与传统中药饮片用量比例 但是传统丸散膏丹的用量并不都能达到有效的血 药浓度 有很多制剂的用量是应根据胃的负担量 制定的 所以纳米中药饮片的用量应根据国际通 行的溶出量结合传统用药比例来制定科学的使用 量 五 纳米中药饮片的全成分检测五 纳米中药饮片的全成分检测 X 射线射线 衍射指纹图谱衍射指纹图谱 安全有效的目的 另外 中药质量控制方法 在考虑全成分和系列环节的基础上 还要充分考 虑国际惯例 使制定的方法容易被国际医药界所 接受 建立对纳米中药饮片的质量控制体系必须 立足于中药的特色 纳米中药饮片的整体作用特 点决定了纳米中药不同于西药 纳米中药饮片的 of diseases In the course of modernization of herbal medicines idiosome technology will provide a new idea for the treatment of diseases that are difficult to treat such as cardiovascular disease and cancer with herbal medicines 4 Dosage of nano herbal pieces Digestion test is an in vitro test method for the control of solid preparations After its appearance in the United States in 1967 the method has become an important measurement index in the quality control of preparation industry It can be used for th