硫普罗宁金属药物的合成及其治疗肝炎的研究
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摘要
肝炎（Hepatitis）是肝脏的炎症，即肝脏受到损害，肝功能出现异常的肝脏炎症性疾病的统称。肝炎的治疗一直是临床中一个比较棘手的问题。硫普罗宁（MPG）是一种新型含游离巯基的甘氨酸衍生物，目前已作为改善肝功能的药物广泛应用于临床，该药物能有效地治疗各类急、慢性肝炎、酒精性肝炎、药物性肝炎及有关症状，具有保护肝细胞，促进肝细胞再生的作用，同时该药也能有效降低放疗、化疗的毒副作用，同时也有一定的解毒作用。
由于硫普罗宁呈强酸性（其pH约1.6），现有的制剂多是加辅料（医用碳酸氢钠）将其配为中性应用于临床。但是经过研究发现硫普罗宁在水相中中和到中性的过程中很容易分解产生副产物，致使产品的纯度下降，这必定会影响该产品的安全性和有效性。已有文献报道临床上使用硫普罗宁后产生不良反应的病例，例如过敏、恶心、胸闷、腮腺肿胀，有的甚至产生休克的现象。因此目前临床上直接用的硫普罗宁制剂均有潜在的问题，即在中和为中性的过程中不稳定而发生分解。尽管临床上已经显示出很多的不良反应，但是受限于硫普罗宁钠合成工艺的难度，一直没有合适的工艺制备出符合药用的硫普罗宁钠。
我们根据硫普罗宁的特性，设计、合成出符合药用的中性的硫普罗宁金属药物，直接用于临床，使用方便，降低毒性，提高疗效。钠、钾、锌作为人体必备的微量元素，具有重要的生物学功能。本课题以硫普罗宁为主体，将钠、钾、锌通过化学方法与其结合，生成盐或配合物。根据母体和金属的药理学作用，达到降低毒性或协同治疗的功效。尽管有文献报道了硫普罗宁钠水合物的制备方法，用2-乙基己醇钠与硫普罗宁在异丁醇中反应，加水析出产物。但是该方法产率低，产品纯度低，不易于工业化生产。本文主要探讨了硫普罗宁钠、钾、锌等金属药物的合成方法。这些方法具有产品收率高，纯度好，成本低，操作简便，易于工业化生产等特点。并通过理化常数测定，运用元素分析、核磁共振氢谱（1H-NMR）、核磁共振碳谱（13C-NMR）、质谱（MS）、红外光谱、紫外光谱和粉末X-射线衍射等分析手段，对所做的各种硫普罗宁金属药物进行了结构确证。
本论文重点对硫普罗宁钠原料药进行了药理、毒理、药效学的研究，结果表明：改造后的硫普罗宁钠、硫普罗宁锌和硫普罗宁钾与硫普罗宁相比，具有稳定性好，毒副作用低，疗效好的特点。
为了尽快投入临床使用，我们首先对硫普罗宁钠进行了全方位研究。将原料药制适宜临床使用的注射剂、片剂和胶囊剂。硫普罗宁金属药物与硫普罗宁具有相同的药理作用，由于硫普罗宁在小肠内吸收，所以我们将其制成肠溶片，采用耐酸包衣，并对配方进行反复筛选，考察了释放度，溶出度，从中选出最佳方案。此外，我们也做了制剂的质量研究，并制定了切实可行的质量标准。
结合硫普罗宁钠的制备工艺和制剂的质量研究，我们按照国家药品监督管理局对新药的研究要求，完成了各项研究资料。现已经取得硫普罗宁钠原料药（国药准字H20090039，河南省联谊制药有限公司），注射剂（国药准字H20090038，河南省新谊药业股份有限公司），片剂和胶囊的国家新药证书和生产批件，且申报中国发明专利并获得授权。
硫普罗宁锌、硫普罗宁钾目前正在按照国家药品监督管理局对新药的研究要求，做各项研究，拟将其开发成疗效高、毒性低、使用方便的治疗肝病的新药。
Hepatitis is caused by the inflammation of liver. It’s a kind of liver inflammation diseasewith the symptom of injured liver and hepatic dysfunction. The therapy of hepatitis has alwaysbeen a serious clinical problem. Tiopronin is a new drug, which has been widely used in clinicas the medicine for improving liver function. It can effectively cure chronic hepatitis, alcoholichepatitis and other relevant symptoms. It can protect hepatic cells and be taken as protectingagents of the radiotherapy and chemotherapy and be used as the antidote of heavy mental.
Tiopronin was a strong acid.(pH1.6). It was used in clinic together with sodium carbonate.However, it has been discovered that tiopronin is easily decomposed in buffer solution whenneutralized by soudium carbonate. It is also reported that tiopronin has cause some adversereaction in many clinical cases, such as allergy, nausea, chest tightness, parotid gland swellingand even shock. So it still remains a clinical problem that tiopronin can be easily decomposedin the process of neutralization, which may influence curative effects. But due the difficultsynthestic process, no appropriate sodium tiopronium was put into use.
On the basis of structue of tiopronin, we design and synthesize metal-based tiopronin durgsfor clinical use. Sodium, potassium and zinc are essential trace elements for human body,which have an important biological function. We use chemical methods to combine tioproninwith sodium, potassium and zinc, to prepare salts and organometallic compounds. Accordingto the pharmacology function of matrix and metal, collaborative therapy is achieved andtoxicity is reduced. It have been reported that sodium tiopronin hydrate can be prepared by2-ethyl hexanol sodium and tiopronin in isobutanol solution, then the product is separated byadding water. However, this method has disadvantages of lower yields and complex operation.We mainly find the processes for preparing sodium tiopronin, potassium tiopronin and zinctiopronin. These new methods have the higher yields, better products, simpler operation, lowercost and can be simply put into industrial operation. And the research of pharmacology andtoxicology indicated that comparing with tiopronin, modified sodium tiopronin, potassiumtiopronin and zinc tiopronin have better stability and low side-effect in clinic.Through the determination of its physical and chemical constants, organic analysis,1H-NMR,13C-NMR,Mass Spectrum (MS), Infrared Spectrum (IR), Ultra Spectrum (UV), power X-ray Diffraction(XRD), et al., the structure of metal-based drug of MPG is verified.
The pharmacology and toxicology of sodium tiopronin were studied. We then carry on thecomprehensive analysis of sodium tiopronin for clinical use. We manage to make crude druginto injections, tablets and capsules. Because of the similar pharmacological effects of sodiumtiopronin and tiopronin, we prepared enteric-coated tablets, which are coated by anti-acid film.We have tried different formulations, made a study of release percent and dissolution percentof the tablets and finally optimized the radio. We make a further study of quality research todetermine the quality of NaMPG tablets and have set feasible quality standard.
According to the requirement of SFDA, we have accomplished the research of NaMPGcombining its preparation process and quality research. Now we have get Chinese NewMedicine Certificate and Product License of NaMPG. and its injections. We have applied forChinese patent of invention and successfully get authorized.
At present, we are doing all kinds of research of zinc tiopronin and potassium tiopronin tocollective scientific data. We will apply for the Chinese new medicine certificate of zinctiopronin and potassium tiopronin and try to develop new drugs for hepatic disease.
由于硫普罗宁呈强酸性（其pH约1.6），现有的制剂多是加辅料（医用碳酸氢钠）将其配为中性应用于临床。但是经过研究发现硫普罗宁在水相中中和到中性的过程中很容易分解产生副产物，致使产品的纯度下降，这必定会影响该产品的安全性和有效性。已有文献报道临床上使用硫普罗宁后产生不良反应的病例，例如过敏、恶心、胸闷、腮腺肿胀，有的甚至产生休克的现象。因此目前临床上直接用的硫普罗宁制剂均有潜在的问题，即在中和为中性的过程中不稳定而发生分解。尽管临床上已经显示出很多的不良反应，但是受限于硫普罗宁钠合成工艺的难度，一直没有合适的工艺制备出符合药用的硫普罗宁钠。
我们根据硫普罗宁的特性，设计、合成出符合药用的中性的硫普罗宁金属药物，直接用于临床，使用方便，降低毒性，提高疗效。钠、钾、锌作为人体必备的微量元素，具有重要的生物学功能。本课题以硫普罗宁为主体，将钠、钾、锌通过化学方法与其结合，生成盐或配合物。根据母体和金属的药理学作用，达到降低毒性或协同治疗的功效。尽管有文献报道了硫普罗宁钠水合物的制备方法，用2-乙基己醇钠与硫普罗宁在异丁醇中反应，加水析出产物。但是该方法产率低，产品纯度低，不易于工业化生产。本文主要探讨了硫普罗宁钠、钾、锌等金属药物的合成方法。这些方法具有产品收率高，纯度好，成本低，操作简便，易于工业化生产等特点。并通过理化常数测定，运用元素分析、核磁共振氢谱（1H-NMR）、核磁共振碳谱（13C-NMR）、质谱（MS）、红外光谱、紫外光谱和粉末X-射线衍射等分析手段，对所做的各种硫普罗宁金属药物进行了结构确证。
本论文重点对硫普罗宁钠原料药进行了药理、毒理、药效学的研究，结果表明：改造后的硫普罗宁钠、硫普罗宁锌和硫普罗宁钾与硫普罗宁相比，具有稳定性好，毒副作用低，疗效好的特点。
为了尽快投入临床使用，我们首先对硫普罗宁钠进行了全方位研究。将原料药制适宜临床使用的注射剂、片剂和胶囊剂。硫普罗宁金属药物与硫普罗宁具有相同的药理作用，由于硫普罗宁在小肠内吸收，所以我们将其制成肠溶片，采用耐酸包衣，并对配方进行反复筛选，考察了释放度，溶出度，从中选出最佳方案。此外，我们也做了制剂的质量研究，并制定了切实可行的质量标准。
结合硫普罗宁钠的制备工艺和制剂的质量研究，我们按照国家药品监督管理局对新药的研究要求，完成了各项研究资料。现已经取得硫普罗宁钠原料药（国药准字H20090039，河南省联谊制药有限公司），注射剂（国药准字H20090038，河南省新谊药业股份有限公司），片剂和胶囊的国家新药证书和生产批件，且申报中国发明专利并获得授权。
硫普罗宁锌、硫普罗宁钾目前正在按照国家药品监督管理局对新药的研究要求，做各项研究，拟将其开发成疗效高、毒性低、使用方便的治疗肝病的新药。
Hepatitis is caused by the inflammation of liver. It’s a kind of liver inflammation diseasewith the symptom of injured liver and hepatic dysfunction. The therapy of hepatitis has alwaysbeen a serious clinical problem. Tiopronin is a new drug, which has been widely used in clinicas the medicine for improving liver function. It can effectively cure chronic hepatitis, alcoholichepatitis and other relevant symptoms. It can protect hepatic cells and be taken as protectingagents of the radiotherapy and chemotherapy and be used as the antidote of heavy mental.
Tiopronin was a strong acid.(pH1.6). It was used in clinic together with sodium carbonate.However, it has been discovered that tiopronin is easily decomposed in buffer solution whenneutralized by soudium carbonate. It is also reported that tiopronin has cause some adversereaction in many clinical cases, such as allergy, nausea, chest tightness, parotid gland swellingand even shock. So it still remains a clinical problem that tiopronin can be easily decomposedin the process of neutralization, which may influence curative effects. But due the difficultsynthestic process, no appropriate sodium tiopronium was put into use.
On the basis of structue of tiopronin, we design and synthesize metal-based tiopronin durgsfor clinical use. Sodium, potassium and zinc are essential trace elements for human body,which have an important biological function. We use chemical methods to combine tioproninwith sodium, potassium and zinc, to prepare salts and organometallic compounds. Accordingto the pharmacology function of matrix and metal, collaborative therapy is achieved andtoxicity is reduced. It have been reported that sodium tiopronin hydrate can be prepared by2-ethyl hexanol sodium and tiopronin in isobutanol solution, then the product is separated byadding water. However, this method has disadvantages of lower yields and complex operation.We mainly find the processes for preparing sodium tiopronin, potassium tiopronin and zinctiopronin. These new methods have the higher yields, better products, simpler operation, lowercost and can be simply put into industrial operation. And the research of pharmacology andtoxicology indicated that comparing with tiopronin, modified sodium tiopronin, potassiumtiopronin and zinc tiopronin have better stability and low side-effect in clinic.Through the determination of its physical and chemical constants, organic analysis,1H-NMR,13C-NMR,Mass Spectrum (MS), Infrared Spectrum (IR), Ultra Spectrum (UV), power X-ray Diffraction(XRD), et al., the structure of metal-based drug of MPG is verified.
The pharmacology and toxicology of sodium tiopronin were studied. We then carry on thecomprehensive analysis of sodium tiopronin for clinical use. We manage to make crude druginto injections, tablets and capsules. Because of the similar pharmacological effects of sodiumtiopronin and tiopronin, we prepared enteric-coated tablets, which are coated by anti-acid film.We have tried different formulations, made a study of release percent and dissolution percentof the tablets and finally optimized the radio. We make a further study of quality research todetermine the quality of NaMPG tablets and have set feasible quality standard.
According to the requirement of SFDA, we have accomplished the research of NaMPGcombining its preparation process and quality research. Now we have get Chinese NewMedicine Certificate and Product License of NaMPG. and its injections. We have applied forChinese patent of invention and successfully get authorized.
At present, we are doing all kinds of research of zinc tiopronin and potassium tiopronin tocollective scientific data. We will apply for the Chinese new medicine certificate of zinctiopronin and potassium tiopronin and try to develop new drugs for hepatic disease.
引文
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