愈肠宁复方释药制剂的研究
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摘要
基于复方药效组分的多样性、疾病病理病机的复杂性,本论文提出了现代中药复方释药系统的研究思路,并以愈肠宁为模型药物,对其制剂设计、制备、评价进行系统研究,得到具有胃、结肠二元释药特征的愈肠宁复方释药制剂,探讨了复方释药系统的设计思路、制备方法、评价技术等共性问题,为该研究提供了示范。
以“方-证-剂”对应思想和现代制剂理论为指导,通过对中医“方-证-剂”对应信息,溃疡性结肠炎及愈肠宁方中有效组分的现代医药学信息的系统研究和分析,结合药效对比实验,拟定了将愈肠宁方中黄芪多糖、皂苷制备成胃部释药单元,苦参碱、氧化苦参碱制备成结肠定位释药单元,两单元组合成二元释药的复方释药系统。
对黄芪微丸、苦参微丸的制备方法、制剂处方、包衣处方及包衣工艺进行了系统筛选,制备得到在人工胃液20min中累积释放度分别为94.7%、96.3%的黄芪微丸、苦参微丸。针对结肠定位释药单元,分别以Eudragit S100、Eudragit E100、Eudragit L100、壳聚糖为包衣材料,设计制备得到了pH敏感单层型、pH敏感双层型、pH敏感-酶触发双控型三种包衣微丸。同时,研究明确了壳聚糖用于结肠定位给药包衣的相关性质。对两释药单元的混合填装工艺进行了研究,结果表明能实现混合均匀并填装胶囊。
体内外释放度研究结果表明,胃部释药单元在胃液中30分钟内基本释药完全,三种结肠定位包衣微丸在体内外均具有结肠定位释药特征,并明确了各包衣微丸在不同条件下的释药性能,探讨了其释药特征。药代动力学研究结果表明,与普通溶液口服相比,结肠定位包衣微丸中大部分药物未被肠道吸收进入体循环,而高浓度分布于结肠内容物和结肠粘膜组织,愈肠宁分释胶囊达到了胃、结肠二步释药的制剂设计目标。药效评价结果表明,愈肠宁胃—结肠分释胶囊能显著对抗三硝基苯磺酸导致的大鼠结肠组织病理损伤,通过抑制促炎因子分泌、炎性细胞浸润,调节自由基系统、免疫反应等途径发挥作用,与同剂量的愈肠宁混合溶液相比,具有明显的疗效优势。
In this paper,the research thinking of TCM drug delivery system was proposed,according to the diversity of effective composition of compound TCM and complexity of pathology and pathogenesis.Through investigating design,preparation and evaluation of YuChang ning,which is the model drug,we not only obtained the capsule releasing in the stomach-colon respectively but also studyed the key problems such as the design thinking, preparing method, evalution technique and so on.In a word,this study made a good example for the research of TCM drug delivery system.
With the guidance of corresponding thinking of "prescription-pattern-agent" and theory of modern pharmaceutics, we did systematic research and analysis of modern medical information,which include ulcerative colitis,astragalan,saponin, matrine, as well as oxymatrine.Combining these with pharmacodynamic experiments,we studied out TCM drug delivery system.This system consists of stomach-specific-released unit which was prepared by astragalan and saponin and colon-specific-released unit,which was prepared by matrine and oxymatrine.
Screening for preparation method, preparation prescription, coating prescription and coating process, we got the astragalus-micropill and sophora-micropill whose accumulated release rate is 94.7%、96.3% separately in the artificial gastric juice in 20 min.Regarding to colon-specific-released unit, we designed three types of coating-pill that is pH-sensitive monolayer, pH-sensitive double-layer as well as pH-sensitive and enzyme-promoting double controlling type with Eudragit S100、Eudragit E100、Eudragit L100 and chitosan as coating materials.Meanwhile, the relative properties of chitosan applied to administration for the colon-specific was reserached. We also investigated the mixing process of the two units,and the result showed that they could be well-mixed and loaded successfully for once.
As can be seen from results of release rate in vitro and in vivo,stomach specific released unit released completely within 30 minutes in gastric juice.It was also indicated that three coating-pills of colon-site-specific posses colon-specific-drug-released characteristics in vitro and in vivo.Beside this,we identified release-mechanism and stability of kinds of coated pellets.Pharmacokinetics results manifested that most drugs in the colon-coated pellets was not absorbed in gastrointestinal tract,but distributed in the colon contents and colon tissue with high-concentration compared with the general solution of oral.Therefore, we reached design objective that the capsule of YuChang delivered to the stomach and colon with two steps.Pharmacodynamic evaluation results showed that the capsule of YuChang ning-delivered-respectively has significant antagonism to the pathological injury of colon tissue induced by trinitrobenzenesulfonic acid in rats.Compared with the same dose of the mixed solution of YuChang ning, the capsule of YuChang ning-delivered-respectively has obvious advantages by inhibiting pro-inflammatory cytokine secretion and inflammatory cell infiltration,as well as regulating free radical systems and immune response.
以“方-证-剂”对应思想和现代制剂理论为指导,通过对中医“方-证-剂”对应信息,溃疡性结肠炎及愈肠宁方中有效组分的现代医药学信息的系统研究和分析,结合药效对比实验,拟定了将愈肠宁方中黄芪多糖、皂苷制备成胃部释药单元,苦参碱、氧化苦参碱制备成结肠定位释药单元,两单元组合成二元释药的复方释药系统。
对黄芪微丸、苦参微丸的制备方法、制剂处方、包衣处方及包衣工艺进行了系统筛选,制备得到在人工胃液20min中累积释放度分别为94.7%、96.3%的黄芪微丸、苦参微丸。针对结肠定位释药单元,分别以Eudragit S100、Eudragit E100、Eudragit L100、壳聚糖为包衣材料,设计制备得到了pH敏感单层型、pH敏感双层型、pH敏感-酶触发双控型三种包衣微丸。同时,研究明确了壳聚糖用于结肠定位给药包衣的相关性质。对两释药单元的混合填装工艺进行了研究,结果表明能实现混合均匀并填装胶囊。
体内外释放度研究结果表明,胃部释药单元在胃液中30分钟内基本释药完全,三种结肠定位包衣微丸在体内外均具有结肠定位释药特征,并明确了各包衣微丸在不同条件下的释药性能,探讨了其释药特征。药代动力学研究结果表明,与普通溶液口服相比,结肠定位包衣微丸中大部分药物未被肠道吸收进入体循环,而高浓度分布于结肠内容物和结肠粘膜组织,愈肠宁分释胶囊达到了胃、结肠二步释药的制剂设计目标。药效评价结果表明,愈肠宁胃—结肠分释胶囊能显著对抗三硝基苯磺酸导致的大鼠结肠组织病理损伤,通过抑制促炎因子分泌、炎性细胞浸润,调节自由基系统、免疫反应等途径发挥作用,与同剂量的愈肠宁混合溶液相比,具有明显的疗效优势。
In this paper,the research thinking of TCM drug delivery system was proposed,according to the diversity of effective composition of compound TCM and complexity of pathology and pathogenesis.Through investigating design,preparation and evaluation of YuChang ning,which is the model drug,we not only obtained the capsule releasing in the stomach-colon respectively but also studyed the key problems such as the design thinking, preparing method, evalution technique and so on.In a word,this study made a good example for the research of TCM drug delivery system.
With the guidance of corresponding thinking of "prescription-pattern-agent" and theory of modern pharmaceutics, we did systematic research and analysis of modern medical information,which include ulcerative colitis,astragalan,saponin, matrine, as well as oxymatrine.Combining these with pharmacodynamic experiments,we studied out TCM drug delivery system.This system consists of stomach-specific-released unit which was prepared by astragalan and saponin and colon-specific-released unit,which was prepared by matrine and oxymatrine.
Screening for preparation method, preparation prescription, coating prescription and coating process, we got the astragalus-micropill and sophora-micropill whose accumulated release rate is 94.7%、96.3% separately in the artificial gastric juice in 20 min.Regarding to colon-specific-released unit, we designed three types of coating-pill that is pH-sensitive monolayer, pH-sensitive double-layer as well as pH-sensitive and enzyme-promoting double controlling type with Eudragit S100、Eudragit E100、Eudragit L100 and chitosan as coating materials.Meanwhile, the relative properties of chitosan applied to administration for the colon-specific was reserached. We also investigated the mixing process of the two units,and the result showed that they could be well-mixed and loaded successfully for once.
As can be seen from results of release rate in vitro and in vivo,stomach specific released unit released completely within 30 minutes in gastric juice.It was also indicated that three coating-pills of colon-site-specific posses colon-specific-drug-released characteristics in vitro and in vivo.Beside this,we identified release-mechanism and stability of kinds of coated pellets.Pharmacokinetics results manifested that most drugs in the colon-coated pellets was not absorbed in gastrointestinal tract,but distributed in the colon contents and colon tissue with high-concentration compared with the general solution of oral.Therefore, we reached design objective that the capsule of YuChang delivered to the stomach and colon with two steps.Pharmacodynamic evaluation results showed that the capsule of YuChang ning-delivered-respectively has significant antagonism to the pathological injury of colon tissue induced by trinitrobenzenesulfonic acid in rats.Compared with the same dose of the mixed solution of YuChang ning, the capsule of YuChang ning-delivered-respectively has obvious advantages by inhibiting pro-inflammatory cytokine secretion and inflammatory cell infiltration,as well as regulating free radical systems and immune response.
引文
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