复方苦参注射液生产过程控制技术和标准研究&利用脂质体技术降低长春瑞滨毒性的探索研究
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摘要
研究1：复方苦参注射液生产过程控制技术和标准研究
复方苦参注射液(FKI)由苦参、白土苓两味中药经提取、精制而成,具有清热利湿、凉血解毒、散结止痛之功效,临床主要用于抗癌,缓解癌痛及出血,提高人体免疫功能等,因其疗效确切,本产品2010年的年销售额突破五亿元,并呈快速增长的趋势。为了深入开展中药大品种的技术升级和产品改造,本文以FKI为研究对象,对其关键生产工艺,如渗漉工艺、醇沉工艺及活性炭脱色工艺等进行优化和科学评价,以期为大品种改造提供一种可借鉴的、基于过程深入理解的研究模式。
本文对FKI物质质量传递规律进行了深入研究,在充分理解工艺过程的基础上,以提高药品质量为目标,对生产工艺进行科学评价,寻找关键技术,并开展工艺优化研究。对生产中存在的生产周期长、工艺过程繁杂、炽灼残渣含量超标等问题开展针对性研究。
以总生物碱(苦参碱、氧化苦参碱、槐定碱、氧化槐果碱)和大泽米苷含量为指标,采用正交实验设计对关键工艺(渗漉及活性炭脱色工序)进行优化,最终确定渗漉工艺为：0.8%醋酸,4倍量浸泡,2倍量渗漉,流速为5 mL.min-1·kg-1；浸泡时间时间为9 h。脱色工艺为6‰(W/V)活性炭,于60℃加热20 min。采用单因素法对影响醇沉的参数进行优化、细化研究,调整后的醇沉工艺为：经2次醇沉,醇沉浓度依次为60%,(80%→90%)。对稀配环节进行了工艺简化并探讨了其科学内涵,在保留有效成分的同时大大降低了无机盐的引入,使生产工艺更为合理、科学、经济。同时对醇沉过程中颗粒的沉降规律进行探讨,为醇沉工艺设计及工业化生产提供指导。
通过吐温-80在FKI中的临界胶束浓度(CMC)的确定,结合安全性方面的考量,确定了其最低用量。鉴于不同厂家生产的吐温-80存在的可能的质量差异,为保证产品质量和安全性,对不同厂家生产的吐温-80进行了增溶效果对比研究。
针对FKI质量标准低,专属性差等问题,开展了FKI质量标准的提升工作,并建立了FKI中间体质量标准。改进了生物碱含量测定方法,采用HPLC法对成品及其中间体中苦参碱、槐定碱、氧化苦参碱、氧化槐果碱的含量进行测定,以4种生物碱的总和作为总生物碱含量。同时对来源于白土苓的指标成分大泽米苷含量进行控制,并开展了注射液中总皂苷、葡萄糖以及吐温-80含量测定方法研究,同时结合指纹图谱的研究,全面提高了FKI的质量标准。此外,为了保障临床用药安全,针对其安全性指标方面研究薄弱的现状,还开展了其过敏性实验及降压物质研究,提高了上市产品的安全性,全面提高了产品质量,并纳入标准。
针对FKI灭菌及储存过程中色泽变化的原因进行了初步探讨,证实了5-羟甲基糠醛(5-HMF)与注射液灭菌过程色泽加深没有直接关系。结合FKI生产实际和产品自身特点,建立了成品5-HMF限量标准,并建立了更为科学、客观的色泽检查标准。
对渗漉工艺过程进行了初步的过程控制研究,建立了渗漉液酸度和生物碱含量间的相关关系,为实现在线和过程质量控制提供了科学依据。
研究2：利用脂质体技术降低长春瑞滨毒性的探索研究
重酒石酸长春瑞滨(NVB)为长春碱类抗肿瘤一线药物,具有广谱抗肿瘤效果,临床上主要用于治疗非小细胞肺癌(NSCLC)等,疗效卓越,但是它有一个致命的缺陷--发疱性,致使临床上频发输注性静脉炎,给患者带来严重的副作用和心身痛苦。本文拟采用脂质体技术,采用股动脉血管插管模型及家兔耳缘静脉病理模型,探索和评价其减轻或消除NVB刺激性的可行性。
以大豆卵磷脂和胆固醇为成膜材料,采用薄膜分散-pH梯度法制备NVB脂质体。以包封率为考核指标,采用单因素结合正交设计优化处方,并采用混料均匀设计对脂质体中磷脂、胆固醇、NVB三者之间的配比进行了优化探索,确定了脂质体的处方及工艺。
建立了NVB脂质体包封率测定方法,以高速冷冻离心法分离载药脂质体与游离药物,HPLC法测得所制备的脂质体包封率为85.8%。色谱条件为：Ultimate XB C18柱(4.6mm×250mm,5μm)；流动相：0.05mol·L-1 KH2PO4-乙腈(60:40)；检测波长：269nm,流速1 mL-min-1,柱温30℃。
考察了NVB脂质体的理化性质,光学显微镜下为类圆形,电镜下为单室脂质体。粒径为270nm。经初步稳定性实验证实,NVB具有光不稳定性,应避光保存。4℃时避光放置1个月药物包封率无变化。
采用透析法分别测定了NVB生理盐水溶液剂及其脂质体在pH 6.8磷酸盐缓冲溶液、pH7.4磷酸盐缓冲溶液及人血清中的释药行为,结果表明脂质体可以加快NVB的体外释放,且相比上述两种缓冲介质,NVB在血清中释放更快、更完全。
比较了NVB溶液剂及脂质体在家兔体内的释放行为,结果表明脂质体具有一定的缓释作用,可以维持较高的血药浓度。药物动力学实验表明,两种制剂均符合双室模型,消除半衰期分别为28.152min和11643.144min, AUC分别为126.847μg·mL-1·min和24401.459μg·mL-1·min
考察了脂质体给药系统在降低输注性静脉炎方面的效果,在体股动脉血管插管法及耳缘静脉病理评分法均证实脂质体给药系统可以降低输注性静脉炎的发生率,减轻输注性静脉炎的等级。
TOPIC 1:STUDIES ON THE PROCESS ANALYTICAL TECHNOLOGY AND STANDARD OF FUFANG KUSHEN INJECTION
Fufang Kushen injection (FKI) is a preparation of sophora flavescens radix and heterosmilacis rhizoma, with the function of relieve fever and dampness, cooling blood, detoxification and relieving the pain. It's an effective medicine used in the treatment of tumor clinics for many years, mainly as an anodyne having anti-tumor, elevating immune system activities. As its certain curative effect, the annual sales volume has exceeded over five hundred million yuan in 2010, and showed a trend of rapid growth. To upgrade the technology of FKI, the key processes, such as percolation process, alcohol-purification and discoloration process of activated carbon, were optimized and evaluated as a demonstration research based on Process Analytical Technology or PAT for herbal medicine.
To well understand the processes of FKI, the quality transfer mechanism of multi-ingredients were investigated from crude drug material to finished products. The key processes as focus, such as long production cycle, fussy techniques and high level of ignition residues, were studied.
Total alkaloids (calculated by matrine, oxymatrine, sophoridine and oxysophoridine) and macrozamin were selected as quality evaluation markers. The key processes of percolation with acetic acid and discoloration with activated carbon were optimized by orthogonal experiment method. The optimal condition of percolation process was:soaked for 9h with 4 folds 0.8% acetic acid, then adding 2 folds of 0.8% acetic acid at speed of 5 mL-(min·kg)-1. 6%o(W/V) Activated carbon was added and heated at 60℃for 20 minutes. Process of purification with alcohol was investigated by singal factor method. Purification process:the concentrated solution was suffered by 60%,80% and 90% alcohol (V/V) in turn. The diluted preparation process was simplified and its scientific evidence were explored also. The new diluted process remains the active components with the greatest extent and largely degrades the content of mineral salts. Particle sedimentation mechanism in alcohol-purification process was preliminarily revealed and benificial to technology design and industrial manufacture. The critical micell concentration (CMC) was determined and the dosage of Tween-80 was determined also. We also evaluated the solubilization effect of different manufacturers, the results showed that their effect is differentiated.
By determination of the critical micell concentration (CMC) of Tween-80 in FKI and safety consideration, the minimal dosage of Tween-80 was recommended. Considaration the possible quality differences among the manufactory companies of Tween-80, solubilizing ability of FKI by Tween-80 producted from different companies were compared also.
Due to non-specificity and uncontrollability, the quality standards of FKI and its intermediates were emended. The quantitative assay of FKI and its intermediates were revised as HPLC method by determination of total alkaloids calcaulated by matrine, oxymatrine, sophoridine and oxysophoridine from sophora flavescens radix, and macrozamin from heterosmilacis rhizoma. Determiniation methods of total saponins by UV, glucose by GC and Tween-80 by HPLC, together with the HPLC fingerprint standard of finished product and intermediates were established also. To guarantee the safety of injection, allergy and hypotensive substance were investigated and emended as part of standard.
To understand the mechanism of darkening during the sterilization and storage of FKI, 5-hydroxymethyl furaldehyde (5-HMF) as a marker was observed in the process. Although the result was revealed that 5-HMF has no direct relationship with the darkening in sterilization, the limitation of 5-HMF of finished product was still established to guarantee the quality.
To well understand the percolation process, the relationships between pH and alkaloids' contents in percolation solution were explored for the quality control on-line.
TOPIC 2:TO DEPRESS SUFFERING OF INFUSION PHLEBITIS OF NVB BY LIPOSOME TECHNOLOGY
Vinorelbine (NVB) is efficacy antitumor medicine derived from vinblastine for treatment of non-small cell lung cancer (NSCLC), berast cancer, refractoriness lymphoma and ovarian cancer in clinic. Due to the vesicanting and irritative, NVB was injected to cause venous discoloration and chemical phlebitis proximal to the site of injection, as well as localized rashes and urticaria, blistering, and skin sloughing. Liposome as a delivery was selected to alleviate the side-effects of NVB. The arteriae femoralis intubation model and histopathological examination of rabbit ear vein were introduced and modified to evaluate the alleviating grade of infusion phlebitis.
NVB liposomes were prepared by thin film-pH gradient method with the soybean lecithin (Phosphatidyl cholines, PC) and cholesterol (CH) as film-former. Evaluated by the entrapping efficiency (EE), the formulation was optimiazed by singal factor method and orthogonal experiment method. The mixture uniform design was adopted to optimize the matching of PC, CH and NVB. And then the prescription and preparation process parameters were determined.
Liposomes were separated from free NVB by high speed freezing centrifugation. The EE was determined by HPLC as 85.8%. The chromatographic conditions is Ultimate XB-C18 column (4.6mm×250mm,5μm) at 30℃,0.05 mol-L-1 KH2PO4-acetonitrile(60:40) as mobile phase with flow rate at 1 mL-min-1 and detected at 269nm.
The physical and chemical properties of NVB liposomes were studied. The morphological characteristic of most liposomes was spherical in optical microscope and single compartment structures in electron microscope. The average particle size of NVB liposomes was determined as 270nm. The NVB liposomes were unstable for light revealed by preliminary stability test.
The release behaviors in vitro of NVB and its liposomes in pH 6.8 phosphate buffer solution, pH 7.4 phosphate buffer solution and human serum were determined by the dialysis method respectively. The release of NVB can be accelerated in the form of liposomes, and is faster and more completely in serum compared with phosphate buffers.
Compared the release behavior in vivo of NVB and its liposomes in rabbits, liposomes play some role of sustained-release and can maintain the NVB concentration with a high level in plasma for a long time. After injected NVB solution and NVB liposomes to rabbit, the drug concentrations in blood were monitored by HPLC. The pharmacokinetic processes of the above two preparations were both accorded with two compartmental models. The eliminative half-life and AUC of NVB solution and NVB liposomes were 28.152 min and 11643.144 min, and 126.847μg·mL-1 min and 24401.459μg·mL-1·min, respectively. Effects of liposome delivery system in preventing from infusion phlebitis were studied. Both the arteriae femoralis intubation model and histopathological examination of rabbit ear vein showed that liposome delivery system can reduce the incidence and severity of infusion phlebitis.
复方苦参注射液(FKI)由苦参、白土苓两味中药经提取、精制而成,具有清热利湿、凉血解毒、散结止痛之功效,临床主要用于抗癌,缓解癌痛及出血,提高人体免疫功能等,因其疗效确切,本产品2010年的年销售额突破五亿元,并呈快速增长的趋势。为了深入开展中药大品种的技术升级和产品改造,本文以FKI为研究对象,对其关键生产工艺,如渗漉工艺、醇沉工艺及活性炭脱色工艺等进行优化和科学评价,以期为大品种改造提供一种可借鉴的、基于过程深入理解的研究模式。
本文对FKI物质质量传递规律进行了深入研究,在充分理解工艺过程的基础上,以提高药品质量为目标,对生产工艺进行科学评价,寻找关键技术,并开展工艺优化研究。对生产中存在的生产周期长、工艺过程繁杂、炽灼残渣含量超标等问题开展针对性研究。
以总生物碱(苦参碱、氧化苦参碱、槐定碱、氧化槐果碱)和大泽米苷含量为指标,采用正交实验设计对关键工艺(渗漉及活性炭脱色工序)进行优化,最终确定渗漉工艺为：0.8%醋酸,4倍量浸泡,2倍量渗漉,流速为5 mL.min-1·kg-1；浸泡时间时间为9 h。脱色工艺为6‰(W/V)活性炭,于60℃加热20 min。采用单因素法对影响醇沉的参数进行优化、细化研究,调整后的醇沉工艺为：经2次醇沉,醇沉浓度依次为60%,(80%→90%)。对稀配环节进行了工艺简化并探讨了其科学内涵,在保留有效成分的同时大大降低了无机盐的引入,使生产工艺更为合理、科学、经济。同时对醇沉过程中颗粒的沉降规律进行探讨,为醇沉工艺设计及工业化生产提供指导。
通过吐温-80在FKI中的临界胶束浓度(CMC)的确定,结合安全性方面的考量,确定了其最低用量。鉴于不同厂家生产的吐温-80存在的可能的质量差异,为保证产品质量和安全性,对不同厂家生产的吐温-80进行了增溶效果对比研究。
针对FKI质量标准低,专属性差等问题,开展了FKI质量标准的提升工作,并建立了FKI中间体质量标准。改进了生物碱含量测定方法,采用HPLC法对成品及其中间体中苦参碱、槐定碱、氧化苦参碱、氧化槐果碱的含量进行测定,以4种生物碱的总和作为总生物碱含量。同时对来源于白土苓的指标成分大泽米苷含量进行控制,并开展了注射液中总皂苷、葡萄糖以及吐温-80含量测定方法研究,同时结合指纹图谱的研究,全面提高了FKI的质量标准。此外,为了保障临床用药安全,针对其安全性指标方面研究薄弱的现状,还开展了其过敏性实验及降压物质研究,提高了上市产品的安全性,全面提高了产品质量,并纳入标准。
针对FKI灭菌及储存过程中色泽变化的原因进行了初步探讨,证实了5-羟甲基糠醛(5-HMF)与注射液灭菌过程色泽加深没有直接关系。结合FKI生产实际和产品自身特点,建立了成品5-HMF限量标准,并建立了更为科学、客观的色泽检查标准。
对渗漉工艺过程进行了初步的过程控制研究,建立了渗漉液酸度和生物碱含量间的相关关系,为实现在线和过程质量控制提供了科学依据。
研究2：利用脂质体技术降低长春瑞滨毒性的探索研究
重酒石酸长春瑞滨(NVB)为长春碱类抗肿瘤一线药物,具有广谱抗肿瘤效果,临床上主要用于治疗非小细胞肺癌(NSCLC)等,疗效卓越,但是它有一个致命的缺陷--发疱性,致使临床上频发输注性静脉炎,给患者带来严重的副作用和心身痛苦。本文拟采用脂质体技术,采用股动脉血管插管模型及家兔耳缘静脉病理模型,探索和评价其减轻或消除NVB刺激性的可行性。
以大豆卵磷脂和胆固醇为成膜材料,采用薄膜分散-pH梯度法制备NVB脂质体。以包封率为考核指标,采用单因素结合正交设计优化处方,并采用混料均匀设计对脂质体中磷脂、胆固醇、NVB三者之间的配比进行了优化探索,确定了脂质体的处方及工艺。
建立了NVB脂质体包封率测定方法,以高速冷冻离心法分离载药脂质体与游离药物,HPLC法测得所制备的脂质体包封率为85.8%。色谱条件为：Ultimate XB C18柱(4.6mm×250mm,5μm)；流动相：0.05mol·L-1 KH2PO4-乙腈(60:40)；检测波长：269nm,流速1 mL-min-1,柱温30℃。
考察了NVB脂质体的理化性质,光学显微镜下为类圆形,电镜下为单室脂质体。粒径为270nm。经初步稳定性实验证实,NVB具有光不稳定性,应避光保存。4℃时避光放置1个月药物包封率无变化。
采用透析法分别测定了NVB生理盐水溶液剂及其脂质体在pH 6.8磷酸盐缓冲溶液、pH7.4磷酸盐缓冲溶液及人血清中的释药行为,结果表明脂质体可以加快NVB的体外释放,且相比上述两种缓冲介质,NVB在血清中释放更快、更完全。
比较了NVB溶液剂及脂质体在家兔体内的释放行为,结果表明脂质体具有一定的缓释作用,可以维持较高的血药浓度。药物动力学实验表明,两种制剂均符合双室模型,消除半衰期分别为28.152min和11643.144min, AUC分别为126.847μg·mL-1·min和24401.459μg·mL-1·min
考察了脂质体给药系统在降低输注性静脉炎方面的效果,在体股动脉血管插管法及耳缘静脉病理评分法均证实脂质体给药系统可以降低输注性静脉炎的发生率,减轻输注性静脉炎的等级。
TOPIC 1:STUDIES ON THE PROCESS ANALYTICAL TECHNOLOGY AND STANDARD OF FUFANG KUSHEN INJECTION
Fufang Kushen injection (FKI) is a preparation of sophora flavescens radix and heterosmilacis rhizoma, with the function of relieve fever and dampness, cooling blood, detoxification and relieving the pain. It's an effective medicine used in the treatment of tumor clinics for many years, mainly as an anodyne having anti-tumor, elevating immune system activities. As its certain curative effect, the annual sales volume has exceeded over five hundred million yuan in 2010, and showed a trend of rapid growth. To upgrade the technology of FKI, the key processes, such as percolation process, alcohol-purification and discoloration process of activated carbon, were optimized and evaluated as a demonstration research based on Process Analytical Technology or PAT for herbal medicine.
To well understand the processes of FKI, the quality transfer mechanism of multi-ingredients were investigated from crude drug material to finished products. The key processes as focus, such as long production cycle, fussy techniques and high level of ignition residues, were studied.
Total alkaloids (calculated by matrine, oxymatrine, sophoridine and oxysophoridine) and macrozamin were selected as quality evaluation markers. The key processes of percolation with acetic acid and discoloration with activated carbon were optimized by orthogonal experiment method. The optimal condition of percolation process was:soaked for 9h with 4 folds 0.8% acetic acid, then adding 2 folds of 0.8% acetic acid at speed of 5 mL-(min·kg)-1. 6%o(W/V) Activated carbon was added and heated at 60℃for 20 minutes. Process of purification with alcohol was investigated by singal factor method. Purification process:the concentrated solution was suffered by 60%,80% and 90% alcohol (V/V) in turn. The diluted preparation process was simplified and its scientific evidence were explored also. The new diluted process remains the active components with the greatest extent and largely degrades the content of mineral salts. Particle sedimentation mechanism in alcohol-purification process was preliminarily revealed and benificial to technology design and industrial manufacture. The critical micell concentration (CMC) was determined and the dosage of Tween-80 was determined also. We also evaluated the solubilization effect of different manufacturers, the results showed that their effect is differentiated.
By determination of the critical micell concentration (CMC) of Tween-80 in FKI and safety consideration, the minimal dosage of Tween-80 was recommended. Considaration the possible quality differences among the manufactory companies of Tween-80, solubilizing ability of FKI by Tween-80 producted from different companies were compared also.
Due to non-specificity and uncontrollability, the quality standards of FKI and its intermediates were emended. The quantitative assay of FKI and its intermediates were revised as HPLC method by determination of total alkaloids calcaulated by matrine, oxymatrine, sophoridine and oxysophoridine from sophora flavescens radix, and macrozamin from heterosmilacis rhizoma. Determiniation methods of total saponins by UV, glucose by GC and Tween-80 by HPLC, together with the HPLC fingerprint standard of finished product and intermediates were established also. To guarantee the safety of injection, allergy and hypotensive substance were investigated and emended as part of standard.
To understand the mechanism of darkening during the sterilization and storage of FKI, 5-hydroxymethyl furaldehyde (5-HMF) as a marker was observed in the process. Although the result was revealed that 5-HMF has no direct relationship with the darkening in sterilization, the limitation of 5-HMF of finished product was still established to guarantee the quality.
To well understand the percolation process, the relationships between pH and alkaloids' contents in percolation solution were explored for the quality control on-line.
TOPIC 2:TO DEPRESS SUFFERING OF INFUSION PHLEBITIS OF NVB BY LIPOSOME TECHNOLOGY
Vinorelbine (NVB) is efficacy antitumor medicine derived from vinblastine for treatment of non-small cell lung cancer (NSCLC), berast cancer, refractoriness lymphoma and ovarian cancer in clinic. Due to the vesicanting and irritative, NVB was injected to cause venous discoloration and chemical phlebitis proximal to the site of injection, as well as localized rashes and urticaria, blistering, and skin sloughing. Liposome as a delivery was selected to alleviate the side-effects of NVB. The arteriae femoralis intubation model and histopathological examination of rabbit ear vein were introduced and modified to evaluate the alleviating grade of infusion phlebitis.
NVB liposomes were prepared by thin film-pH gradient method with the soybean lecithin (Phosphatidyl cholines, PC) and cholesterol (CH) as film-former. Evaluated by the entrapping efficiency (EE), the formulation was optimiazed by singal factor method and orthogonal experiment method. The mixture uniform design was adopted to optimize the matching of PC, CH and NVB. And then the prescription and preparation process parameters were determined.
Liposomes were separated from free NVB by high speed freezing centrifugation. The EE was determined by HPLC as 85.8%. The chromatographic conditions is Ultimate XB-C18 column (4.6mm×250mm,5μm) at 30℃,0.05 mol-L-1 KH2PO4-acetonitrile(60:40) as mobile phase with flow rate at 1 mL-min-1 and detected at 269nm.
The physical and chemical properties of NVB liposomes were studied. The morphological characteristic of most liposomes was spherical in optical microscope and single compartment structures in electron microscope. The average particle size of NVB liposomes was determined as 270nm. The NVB liposomes were unstable for light revealed by preliminary stability test.
The release behaviors in vitro of NVB and its liposomes in pH 6.8 phosphate buffer solution, pH 7.4 phosphate buffer solution and human serum were determined by the dialysis method respectively. The release of NVB can be accelerated in the form of liposomes, and is faster and more completely in serum compared with phosphate buffers.
Compared the release behavior in vivo of NVB and its liposomes in rabbits, liposomes play some role of sustained-release and can maintain the NVB concentration with a high level in plasma for a long time. After injected NVB solution and NVB liposomes to rabbit, the drug concentrations in blood were monitored by HPLC. The pharmacokinetic processes of the above two preparations were both accorded with two compartmental models. The eliminative half-life and AUC of NVB solution and NVB liposomes were 28.152 min and 11643.144 min, and 126.847μg·mL-1 min and 24401.459μg·mL-1·min, respectively. Effects of liposome delivery system in preventing from infusion phlebitis were studied. Both the arteriae femoralis intubation model and histopathological examination of rabbit ear vein showed that liposome delivery system can reduce the incidence and severity of infusion phlebitis.
引文
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