安宫牛黄鼻用脑靶向制剂的研究
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摘要
安宫牛黄丸是传统中药中的经典急救方,临床上用来治疗高热、昏迷、中风等中枢性急重症,目前常用剂型有丸剂、散剂和简化方的注射剂等,但这几种给药方式都具有一定的局限性。鼻腔给药途径是近年来研究较多的给药系统之一,其吸收迅速、给药方便,此外还可用作脑内靶向的递药手段。为了改善患者的顺应性,充分发挥急救方的疗效,探索安宫牛黄丸经鼻脑靶向给药系统的可行性,本研究在对9味原药材不同前处理的基础上,确定了安宫牛黄鼻用制剂的处方,重点对安宫牛黄丸中起中枢解热的重要物质基础——黄芩苷的经鼻给药后,鼻.脑通路的存在与否、处方因素、剂型因素以及其吸收机制做了详细探索,在制备出黄芩苷载药脂质微球的基础上,制备一种载有多种成分的安宫牛黄鼻用脑靶向双相载药脂质微球。
本文首先建立了黄芩苷、栀子苷、姜黄素、盐酸小檗碱、胆酸、冰片、胆红素的体外分析方法,分别对栀子原药材进行了提取,测定了提取物中栀子苷的含量;对人工牛黄进行乙醇提取,测定了醇提物中胆酸的含量,计算了提取物的收率;测定了黄芩苷在水中的溶解度;制备了姜黄素包合物并以DSC法进行验证,测定了包合物的溶解度和姜黄素在包合物中的含量;测定了冰片的含量并制备了麝香酮和冰片混合物的随机甲基化-β-环糊精包合物水溶液;对水牛角和珍珠粉进行了水解,计算了收率。最后根据各种提取物或中间产物中各指标性成分的含量确定了安宫牛黄鼻用制剂的处方。
采用大鼠在体鼻腔灌流模型(in situ rat nasal perfusion method)初步考察了栀子苷、盐酸小檗碱、姜黄素和黄芩苷的鼻腔吸收情况。除栀子苷外,黄芩苷、姜黄素和盐酸小檗碱吸收均比较明显,此后重点研究了黄芩苷的鼻腔吸收规律和吸收促进剂对其鼻腔吸收的促进作用,结果表明,黄芩苷鼻腔吸收符合一级吸收动力学,不同添加剂对其吸收的促进作用存在以下关系:1%去氧胆酸钠>>0.5%壳聚糖≈0.5%冰片≈5%甲基化-β-环糊精>5%HP-β-CD>5%β-CD>1%Tween 80≈0.1%EDTA-Na_2≈I%磷脂,其中加入最后三者的促吸收效果与不加吸收促进剂时无显著性差异。
建立了大鼠给药后脑渗析和血液渗析同时采集脑脊液样品和血浆样品的方法,分别以零净流量法和反向渗析法测定了两部位渗析的体内和体外回收率,其中脑部和血浆中探针的体内回收率分别为17.52%和15.O%。此外,建立了UPLC-MS/MS法测定大鼠渗析液中黄芩苷的分析方法。随后对四种黄芩苷鼻用溶液剂,即pH5.4组(INl)、pH4.9组(IN2)、5%随机甲基化-β-环糊精组(IN3)以及1%冰片组(IN4),及一静脉注射给药组(IVl)分别进行了大鼠血浆中和脑脊液中的药物动力学研究,剂量均为12mg·kg~(-1),DAS 2.0药代动力学软件非隔室模型处理体内数据。结果表明,黄芩苷静脉注射后具有微弱的血脑屏障透过能力,经鼻给药后,黄芩苷血浆中游离药物浓度远低于静注后的血药浓度,且达峰时间有明显的滞后,CSF中的浓度水平与静注后相当,提示黄芩苷的实际鼻腔吸收效果并不理想。IN1、IN2、IN3和IN4四种鼻用溶液剂血浆中的生物利用度分别为11.7%、12.5%、21.O%和11.0%,高低顺序依次为IN3>IN2>IN1>IN4,其中由于环糊精的促吸收作用,IN3的生物利用度最高,与其他三者问存在显著性差异;脑内生物利用度分别为69.3%、58.2%、89.0%和72.5%,高低顺序依次为IN3>IN4>IN1>IN2,加入环糊精的制剂虽然在脑脊液中的达峰时间延迟,但入脑量最高,脑靶向性指数(DTI)和脑部药物直接转运百分比(DTP)计算结果表明黄芩苷可经嗅觉通路入脑,存在鼻-脑通路。
以反应溶剂、药脂比例为考察项,确定黄芩苷磷脂复合物的制备工艺为:黄芩苷:磷脂1:5(w/w),室温下四氢呋喃中反应3小时,蒸发除去溶剂即得。利用DSC和X-射线衍射技术确证分析了黄芩苷磷脂复合物的形成以及药物和磷脂两者间可能存在的相互作用。采用高压均质法制备了黄芩苷脂质微球,以复合物在油中溶解状态、稳定性常数Ke、粒度分布、(?)-电位和包封率确定了黄芩苷脂质微球的最终处方和工艺为:按质量百分比,油相组成为:磷脂复合物以黄芩苷计为1%、中链油(MCT)为20%、外加豆磷脂1%、油酸0.06%,水相组成为:甘油2.5%、F-68 1%、EDTA 0.006%,制备初乳后,高压均质参数为700bar压力下循环7次,均质前调节pH值至5.0。大鼠体内药动学研究表明,黄芩苷鼻用脂质微球(2.4mg·kg~(-1))经鼻吸收后其血浆中生物利用度为55.2%,脑脊液中为227%,分别为溶液剂组(IN1,pH5.4)的5倍和3倍。由AUC_csF/AUCplasma计算结果可知,相比于溶液剂,脂质微球组的脑靶向指数有所降低。
根据黄芩苷鼻用脂质微球的处方工艺以及安宫牛黄鼻用制剂的处方,制备安宫牛黄鼻用脑靶向脂质微球,测定了其粒度分布和稳定性常数Ke,并以黄芩苷计对包封率和载药量进行了测定。以在体蟾蜍上颚粘膜法评价了安宫牛黄鼻用溶液剂和安宫牛黄鼻用脂质微球的蟾蜍上颚纤毛毒性,与阴性对照相比,两制剂组均有比较明显的纤毛毒性。以生化指标法评价了处方中使用较多的吸收促进剂兼增溶剂——随机甲基化-β-环糊精的鼻粘膜毒性,结果显示,5%的RAMEB无明显黏膜毒性,10%和20%的黏膜毒性较大。
The prescription of Angong Niuhuang(AN) was a classic formulation in Traditional Chinese Medicine(TCM) for emergency medical treatment,such as high fever,coma,stroke, etc.The common used dosage forms are pills and powder of AN for oral administration,and its simplified prescription of Qingkailing for intravenous(i.v.) administration.However,all these preparations have some limitations in clinical use.Intranasal(i.n.) administration is one of the drug delivery system being given more research in recent years.It has the advantage of rapid absorption,administration convenience,and circumvention of blood brain barrier(BBB) for brain-targeting.In order to fully exert the therapeutic effects of AN for the treatment of central nervous system(CNS) disease,and improve the compliance of the patients,a new nasal formulation of AN was established,on the basis of pre-process of every raw material in the traditional AN prescription.Then,the exist of nose-brain route,formulation factors and dosage form factors affecting nasal absorprion,and the absorption mechanism was studied detailedly after i.n.administration of baicalin,which was the most important ingredient in AN on relieving high fever with definite antipyretic mechanism in CNS.And finally,based on the preparation of baicalin lipid microspheres(BLM),a kind of brain-targeted two-phase drug loading lipid microsphere of AN for nasal use was prepared.
At first,eight analytical method for the quality control of baicalin,jasminoidin, curcumine,berberine,cholalic acid,bilirubin and borneol was established.Then,different kinds of pre-process methods were performed with every raw material:jasminoidin and cholalic acid were extracted from gardenia and artificial calculus bovis,respectively;borneol and muscone was solubilized by randomly methylated -/?-cyclodextrin(RAMEB);the inclusion complex of curcumine with RAMEB was prepared and verified by DSC;powder of pearl and buffalo horn was hydrolyzed together;and the solubility of baicalin and berberine in aqueous solution was determinied.According to the content of index ingrediant in pre-processed product and CHP 2005,the formulation and preparation of nasal AN solution (AN-S) were established. The in situ rat nasal perfusion technique was used in the investigation of nasal absorption of index ingredients in the AN formution.The respective absorption study of the index ingredients showed that baiclain,berberine and curcumine had obvious absorption from the nose of rats,except for jasminoidin.The detailed absorption study of baicalin indicated that the absorption of baicalin followed first-order absorption kinetics,and the order of increasing absorption of baicalin caused by the enhancers was 1%sodium deoxycholate ? 0.5% chitosan≈5%borneol≈5%RAMEB >5%HP-β-CD > 5%β-CD>l%Tw-een-80≈0.1% EDTA-Na2≈1%lecithin.
A simultaneous blood and brain microdialysis coupled with UPLC-MS/MS method was established for in vivo analysis of baicalin.In vitro recoveries of the probes determined by no net flux method were 19.26%and 18.38%,while in vivo recoveries of the probes determined by retrodialysis were 15.0%and 17.5%for blood and brain,respectively.The pharmacokinetics and brain-targeting study were investigated after i.n.administration (12mg.kg~-1) baicalin solution(BS) of pH5.4(INI),BS of pH 4.8(IN2),BS with 5%RAMEB added(IN3) and BS with 1%borneol added(IN4),and i.v.administration(12mg.kg-~1) of BS (IV1),respectively.Pharmacokinetic calculations were performed on each individual set of animal data using the pharmacokinetic calculation software DAS(drug and statistics) version 2.0 by the statistical moment method.The result showed that baicalin has a slight BBB permeability after i.v administration.The much lower concentration level of baicalin in plasma and delayed Tmax after i.n.administration mean a poor absorption from nasal cavity. The bioavailability of baicalin was 11.7%,12.5%,21.0%and 11.0%in plasma,69.3%,58.2%, 89.0%and 72.5%in CSF,for INI,IN2,IN3 and IN4,repectively.Probably due to the absorption enhancing effect of RAMEB,both bioavailability of IN3 in plasma and CSF were significantly higher than the other three i.n.formulations.Although borneol also has enhancing effect in CSF transport,the effect was not significant.In addition,Drug targeting index(DTI) was 5.86,4.64,4.23,6.55,and direct transport percentage(DTP) to brain was 83.0%,78.6%,76.5%,84.8%,for the four formulations,respectively.And this result supported strongly that there was direct access from nose to brain for baicalin getting into brain through olfactory pathway.
The reaction solvents,the ratios of phospholipids were investigated,and the baicalin-phospholipid complex(BPC) was finally prepared with baicalin and soybean lecithin at a ratio of 1:5 in tetrahydrofuran at room for 3h,and then the reaction solvent was evaporated to obtain dry residue.DSC and and X-ray diffraction were also employed to identify the formation of the complex and analyze the possible interaction between clarithormyin and phospholipids.
High pressure homogenization was used to prepare baicalin lipid microspheres(BLM). HPLC,dynamic light scattering,electrophoretic light scattering technology,and ultrafiltration were also employed.Taking physical appearance,pH,particle size distribution(PSD), ^-potential,content,entrapment efficiency as index,the final formulation and preparation process for BLM were as follows:as quality percentage,oil phase was composed of 1% baicalin in the form of the complex,20%MCT,1%soybean lecithin;the water phase was composed of 2.5%glycerol,1%F-68,0.06%oleic acid and 0.006%EDTA-Na2;and the oil phase and water phase were both heated to 70°C;the homogenization pressure and cycles were 700bar and 7 times;the pH was adjusted to 5.0 before homogenization.The pharmacokinetic study of BLM(2.4mg.kg(~-1)) after i.n.administration(BLM-IN) to rats showed that the absolute bioavailabilities in plasma and CSF were 55.2 and 227%,which were 5 and 3 times of INI,respectively.By comparing the ratio of AUCcsf/ AUCpiasma between BLM-IN and INI(0.302 vs 0.434),it can be seen that although the absorption of baicalin was greatly improved after i.n.administration of BLM,its brain targeting efficiency became lower.
According to the formulation and preparation of BLM,and the AN formulation eatablished in Chapter 1,a kind of AN lipid microsphere(AN-LM) was prepared.The drug loading and entrapment efficiency(EE) were determined based on the content of baicalin.To assess the ciliary toxicity of nasal preparations of AN-S and AN-LM,the hoptoad in situ maxilla mucosa method was used by determining the ciliary movement time.In addition,the method of biochemical index was emploied to evaluate the nasal mucosa toxicity of RAMEB. The result showed that the two dosage forms of AN has obvious ciliary toxicity,and 10%and 20%(w/v) RAMEB has some impact on the physiological change of nasal mucosa of rats.
本文首先建立了黄芩苷、栀子苷、姜黄素、盐酸小檗碱、胆酸、冰片、胆红素的体外分析方法,分别对栀子原药材进行了提取,测定了提取物中栀子苷的含量;对人工牛黄进行乙醇提取,测定了醇提物中胆酸的含量,计算了提取物的收率;测定了黄芩苷在水中的溶解度;制备了姜黄素包合物并以DSC法进行验证,测定了包合物的溶解度和姜黄素在包合物中的含量;测定了冰片的含量并制备了麝香酮和冰片混合物的随机甲基化-β-环糊精包合物水溶液;对水牛角和珍珠粉进行了水解,计算了收率。最后根据各种提取物或中间产物中各指标性成分的含量确定了安宫牛黄鼻用制剂的处方。
采用大鼠在体鼻腔灌流模型(in situ rat nasal perfusion method)初步考察了栀子苷、盐酸小檗碱、姜黄素和黄芩苷的鼻腔吸收情况。除栀子苷外,黄芩苷、姜黄素和盐酸小檗碱吸收均比较明显,此后重点研究了黄芩苷的鼻腔吸收规律和吸收促进剂对其鼻腔吸收的促进作用,结果表明,黄芩苷鼻腔吸收符合一级吸收动力学,不同添加剂对其吸收的促进作用存在以下关系:1%去氧胆酸钠>>0.5%壳聚糖≈0.5%冰片≈5%甲基化-β-环糊精>5%HP-β-CD>5%β-CD>1%Tween 80≈0.1%EDTA-Na_2≈I%磷脂,其中加入最后三者的促吸收效果与不加吸收促进剂时无显著性差异。
建立了大鼠给药后脑渗析和血液渗析同时采集脑脊液样品和血浆样品的方法,分别以零净流量法和反向渗析法测定了两部位渗析的体内和体外回收率,其中脑部和血浆中探针的体内回收率分别为17.52%和15.O%。此外,建立了UPLC-MS/MS法测定大鼠渗析液中黄芩苷的分析方法。随后对四种黄芩苷鼻用溶液剂,即pH5.4组(INl)、pH4.9组(IN2)、5%随机甲基化-β-环糊精组(IN3)以及1%冰片组(IN4),及一静脉注射给药组(IVl)分别进行了大鼠血浆中和脑脊液中的药物动力学研究,剂量均为12mg·kg~(-1),DAS 2.0药代动力学软件非隔室模型处理体内数据。结果表明,黄芩苷静脉注射后具有微弱的血脑屏障透过能力,经鼻给药后,黄芩苷血浆中游离药物浓度远低于静注后的血药浓度,且达峰时间有明显的滞后,CSF中的浓度水平与静注后相当,提示黄芩苷的实际鼻腔吸收效果并不理想。IN1、IN2、IN3和IN4四种鼻用溶液剂血浆中的生物利用度分别为11.7%、12.5%、21.O%和11.0%,高低顺序依次为IN3>IN2>IN1>IN4,其中由于环糊精的促吸收作用,IN3的生物利用度最高,与其他三者问存在显著性差异;脑内生物利用度分别为69.3%、58.2%、89.0%和72.5%,高低顺序依次为IN3>IN4>IN1>IN2,加入环糊精的制剂虽然在脑脊液中的达峰时间延迟,但入脑量最高,脑靶向性指数(DTI)和脑部药物直接转运百分比(DTP)计算结果表明黄芩苷可经嗅觉通路入脑,存在鼻-脑通路。
以反应溶剂、药脂比例为考察项,确定黄芩苷磷脂复合物的制备工艺为:黄芩苷:磷脂1:5(w/w),室温下四氢呋喃中反应3小时,蒸发除去溶剂即得。利用DSC和X-射线衍射技术确证分析了黄芩苷磷脂复合物的形成以及药物和磷脂两者间可能存在的相互作用。采用高压均质法制备了黄芩苷脂质微球,以复合物在油中溶解状态、稳定性常数Ke、粒度分布、(?)-电位和包封率确定了黄芩苷脂质微球的最终处方和工艺为:按质量百分比,油相组成为:磷脂复合物以黄芩苷计为1%、中链油(MCT)为20%、外加豆磷脂1%、油酸0.06%,水相组成为:甘油2.5%、F-68 1%、EDTA 0.006%,制备初乳后,高压均质参数为700bar压力下循环7次,均质前调节pH值至5.0。大鼠体内药动学研究表明,黄芩苷鼻用脂质微球(2.4mg·kg~(-1))经鼻吸收后其血浆中生物利用度为55.2%,脑脊液中为227%,分别为溶液剂组(IN1,pH5.4)的5倍和3倍。由AUC_csF/AUCplasma计算结果可知,相比于溶液剂,脂质微球组的脑靶向指数有所降低。
根据黄芩苷鼻用脂质微球的处方工艺以及安宫牛黄鼻用制剂的处方,制备安宫牛黄鼻用脑靶向脂质微球,测定了其粒度分布和稳定性常数Ke,并以黄芩苷计对包封率和载药量进行了测定。以在体蟾蜍上颚粘膜法评价了安宫牛黄鼻用溶液剂和安宫牛黄鼻用脂质微球的蟾蜍上颚纤毛毒性,与阴性对照相比,两制剂组均有比较明显的纤毛毒性。以生化指标法评价了处方中使用较多的吸收促进剂兼增溶剂——随机甲基化-β-环糊精的鼻粘膜毒性,结果显示,5%的RAMEB无明显黏膜毒性,10%和20%的黏膜毒性较大。
The prescription of Angong Niuhuang(AN) was a classic formulation in Traditional Chinese Medicine(TCM) for emergency medical treatment,such as high fever,coma,stroke, etc.The common used dosage forms are pills and powder of AN for oral administration,and its simplified prescription of Qingkailing for intravenous(i.v.) administration.However,all these preparations have some limitations in clinical use.Intranasal(i.n.) administration is one of the drug delivery system being given more research in recent years.It has the advantage of rapid absorption,administration convenience,and circumvention of blood brain barrier(BBB) for brain-targeting.In order to fully exert the therapeutic effects of AN for the treatment of central nervous system(CNS) disease,and improve the compliance of the patients,a new nasal formulation of AN was established,on the basis of pre-process of every raw material in the traditional AN prescription.Then,the exist of nose-brain route,formulation factors and dosage form factors affecting nasal absorprion,and the absorption mechanism was studied detailedly after i.n.administration of baicalin,which was the most important ingredient in AN on relieving high fever with definite antipyretic mechanism in CNS.And finally,based on the preparation of baicalin lipid microspheres(BLM),a kind of brain-targeted two-phase drug loading lipid microsphere of AN for nasal use was prepared.
At first,eight analytical method for the quality control of baicalin,jasminoidin, curcumine,berberine,cholalic acid,bilirubin and borneol was established.Then,different kinds of pre-process methods were performed with every raw material:jasminoidin and cholalic acid were extracted from gardenia and artificial calculus bovis,respectively;borneol and muscone was solubilized by randomly methylated -/?-cyclodextrin(RAMEB);the inclusion complex of curcumine with RAMEB was prepared and verified by DSC;powder of pearl and buffalo horn was hydrolyzed together;and the solubility of baicalin and berberine in aqueous solution was determinied.According to the content of index ingrediant in pre-processed product and CHP 2005,the formulation and preparation of nasal AN solution (AN-S) were established. The in situ rat nasal perfusion technique was used in the investigation of nasal absorption of index ingredients in the AN formution.The respective absorption study of the index ingredients showed that baiclain,berberine and curcumine had obvious absorption from the nose of rats,except for jasminoidin.The detailed absorption study of baicalin indicated that the absorption of baicalin followed first-order absorption kinetics,and the order of increasing absorption of baicalin caused by the enhancers was 1%sodium deoxycholate ? 0.5% chitosan≈5%borneol≈5%RAMEB >5%HP-β-CD > 5%β-CD>l%Tw-een-80≈0.1% EDTA-Na2≈1%lecithin.
A simultaneous blood and brain microdialysis coupled with UPLC-MS/MS method was established for in vivo analysis of baicalin.In vitro recoveries of the probes determined by no net flux method were 19.26%and 18.38%,while in vivo recoveries of the probes determined by retrodialysis were 15.0%and 17.5%for blood and brain,respectively.The pharmacokinetics and brain-targeting study were investigated after i.n.administration (12mg.kg~-1) baicalin solution(BS) of pH5.4(INI),BS of pH 4.8(IN2),BS with 5%RAMEB added(IN3) and BS with 1%borneol added(IN4),and i.v.administration(12mg.kg-~1) of BS (IV1),respectively.Pharmacokinetic calculations were performed on each individual set of animal data using the pharmacokinetic calculation software DAS(drug and statistics) version 2.0 by the statistical moment method.The result showed that baicalin has a slight BBB permeability after i.v administration.The much lower concentration level of baicalin in plasma and delayed Tmax after i.n.administration mean a poor absorption from nasal cavity. The bioavailability of baicalin was 11.7%,12.5%,21.0%and 11.0%in plasma,69.3%,58.2%, 89.0%and 72.5%in CSF,for INI,IN2,IN3 and IN4,repectively.Probably due to the absorption enhancing effect of RAMEB,both bioavailability of IN3 in plasma and CSF were significantly higher than the other three i.n.formulations.Although borneol also has enhancing effect in CSF transport,the effect was not significant.In addition,Drug targeting index(DTI) was 5.86,4.64,4.23,6.55,and direct transport percentage(DTP) to brain was 83.0%,78.6%,76.5%,84.8%,for the four formulations,respectively.And this result supported strongly that there was direct access from nose to brain for baicalin getting into brain through olfactory pathway.
The reaction solvents,the ratios of phospholipids were investigated,and the baicalin-phospholipid complex(BPC) was finally prepared with baicalin and soybean lecithin at a ratio of 1:5 in tetrahydrofuran at room for 3h,and then the reaction solvent was evaporated to obtain dry residue.DSC and and X-ray diffraction were also employed to identify the formation of the complex and analyze the possible interaction between clarithormyin and phospholipids.
High pressure homogenization was used to prepare baicalin lipid microspheres(BLM). HPLC,dynamic light scattering,electrophoretic light scattering technology,and ultrafiltration were also employed.Taking physical appearance,pH,particle size distribution(PSD), ^-potential,content,entrapment efficiency as index,the final formulation and preparation process for BLM were as follows:as quality percentage,oil phase was composed of 1% baicalin in the form of the complex,20%MCT,1%soybean lecithin;the water phase was composed of 2.5%glycerol,1%F-68,0.06%oleic acid and 0.006%EDTA-Na2;and the oil phase and water phase were both heated to 70°C;the homogenization pressure and cycles were 700bar and 7 times;the pH was adjusted to 5.0 before homogenization.The pharmacokinetic study of BLM(2.4mg.kg(~-1)) after i.n.administration(BLM-IN) to rats showed that the absolute bioavailabilities in plasma and CSF were 55.2 and 227%,which were 5 and 3 times of INI,respectively.By comparing the ratio of AUCcsf/ AUCpiasma between BLM-IN and INI(0.302 vs 0.434),it can be seen that although the absorption of baicalin was greatly improved after i.n.administration of BLM,its brain targeting efficiency became lower.
According to the formulation and preparation of BLM,and the AN formulation eatablished in Chapter 1,a kind of AN lipid microsphere(AN-LM) was prepared.The drug loading and entrapment efficiency(EE) were determined based on the content of baicalin.To assess the ciliary toxicity of nasal preparations of AN-S and AN-LM,the hoptoad in situ maxilla mucosa method was used by determining the ciliary movement time.In addition,the method of biochemical index was emploied to evaluate the nasal mucosa toxicity of RAMEB. The result showed that the two dosage forms of AN has obvious ciliary toxicity,and 10%and 20%(w/v) RAMEB has some impact on the physiological change of nasal mucosa of rats.
引文
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