穿琥宁肠溶胶囊的研制及临床前实验研究
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摘要
穿琥宁是由中药穿心莲叶中提取的有效成分穿心莲内酯为中间体，在吡啶催化下，与琥珀酸酐反应所得的穿心莲内酯琥珀酸半酯单钾盐。穿琥宁具有抗菌、抗病毒、解热，抗炎等多种功效，在临床上被广泛应用。现市场上只有静脉和肌注两种剂型，使用不方便，而且有大量文献报道穿琥宁注射液有多种配伍禁忌和不良反应。在研究中我们发现穿琥宁在胃中的破坏，是影响穿琥宁口服吸收的主要因素，通过将穿琥宁制备成肠溶胶囊可避免药物在胃中的破坏，有效的提高动物血中的药物浓度。为此我们研制了穿琥宁肠溶胶囊，通过对不同处方制备的穿琥宁肠溶胶囊体外溶出度的测定选择最佳制备条件；采用高效液相色谱法测定穿琥宁肠溶胶囊主药的含量；最优处方制备的穿琥宁肠溶胶囊在人工肠液45min时的体外溶出度为98.36%；同时我们草拟了穿琥宁肠溶胶囊的质量标准草案，使所研制的穿琥宁肠溶胶囊的质量有了初步的保证。为考察穿琥宁口服给药是否对实验动物的神经精神系统、心血管系统和呼吸系统产生明显影响，我们按临床给药途径，进行了穿琥宁肠溶胶囊口服给药的一般药理学研究。为考察穿琥宁经肠给药的绝对生物利用度，我们将小鼠采取麻醉后，直接在
肠部灌注穿琥宁CMC-Na混悬液；犬直接灌服穿琥宁肠溶胶囊；用 HPLC法测定给药后的血浆药物浓度，经3p97药动学程序处理，考察穿琥宁经肠给药囊的小鼠和犬的药代动力学和绝对生物利用度。其主要结果和结论如下：
穿琥宁灌服给药对小鼠神经精神系统无明显的抑制作用，对麻醉大鼠血压、心电图和呼吸频率、幅度均无明显影响。
穿琥宁经肠给药，小鼠和犬的绝对生物利用度分别为15.87%、29.92%。
穿琥宁肠溶胶囊为一可行的口服剂型。
Kalil dehydrographolidi succinatis is produced by the reaction between the effective ingredients extracted from the leaves of andrographis paniculata nees and succinic anhydride under the catalysis of pyridine. It has been widely used in clinic as antipyretic for it is effective in anti-germ,anti-virus and anti-inflammation. But it is not convenient to use for there are only two kinds of preparations(intravenous and intramuscular) available in the market. In this study, we found the main reason that affects the oral absorption of kalil dehydrographolidi succinatis is that it can be destroyed in the stomach. So we design a new preparation--enteric capsulesthe of kalil dehydrographolidi succinatis which may avoid the destruction in the stomach and the blood concentration in animals is
improved in our study.
We made the kalil dehydrographolidi succinatis enteric capsules, and determinded the dissolution in vitro to optimize the conditions for preparation . HPLC was selected to determine the concentration of kalil dehydrographolidi succinatis. The dissolution of kalil dehydrographolidi succinatis enteric capsules prepared in optimum condition was 98.36% in 45 mins . The standard draft was also made to guarantee the quality of kalil dehydrographolidi succinatis enteric capsules. The general pharmacology study was also made to test whether or not it affects neurosystem , blood pressure , cardiograph, respiration on animals by given kalil dehydroandrograpolidi succinas from intestines. In order to detect the bioavailability a single dose of kalil dehydroandrograpolidi succinas was given to mices by intestines, whereas it was given to dogs by oral under the anaesthesia. HPLC was used to measure the concentration of kalil dehydroandrograpolidi succinas in serum . The pharmacokinetic parameters and bioavailability of kalil dehydroandrograpolidi succinas enteric capsules was calculated and analysed by 3p97 program. The result is as follows:
Kalii dehydrographolidi succinatis given from intestines will lead to nonmarked inhibition to neurosystem of mices ,but has no effect on blood pressure , cardiograph, frequency and scope of
breath.
Bioavailability of kalil dehydroandrograpolidi succinatis of mice and dog are 15.87% and 29.92% when kalil dehydroandrograpolidi succinas is given from intestines .
Kalii dehydrographolidi succinatis enteric capsules is a feasible oral dosage form.
肠部灌注穿琥宁CMC-Na混悬液；犬直接灌服穿琥宁肠溶胶囊；用 HPLC法测定给药后的血浆药物浓度，经3p97药动学程序处理，考察穿琥宁经肠给药囊的小鼠和犬的药代动力学和绝对生物利用度。其主要结果和结论如下：
穿琥宁灌服给药对小鼠神经精神系统无明显的抑制作用，对麻醉大鼠血压、心电图和呼吸频率、幅度均无明显影响。
穿琥宁经肠给药，小鼠和犬的绝对生物利用度分别为15.87%、29.92%。
穿琥宁肠溶胶囊为一可行的口服剂型。
Kalil dehydrographolidi succinatis is produced by the reaction between the effective ingredients extracted from the leaves of andrographis paniculata nees and succinic anhydride under the catalysis of pyridine. It has been widely used in clinic as antipyretic for it is effective in anti-germ,anti-virus and anti-inflammation. But it is not convenient to use for there are only two kinds of preparations(intravenous and intramuscular) available in the market. In this study, we found the main reason that affects the oral absorption of kalil dehydrographolidi succinatis is that it can be destroyed in the stomach. So we design a new preparation--enteric capsulesthe of kalil dehydrographolidi succinatis which may avoid the destruction in the stomach and the blood concentration in animals is
improved in our study.
We made the kalil dehydrographolidi succinatis enteric capsules, and determinded the dissolution in vitro to optimize the conditions for preparation . HPLC was selected to determine the concentration of kalil dehydrographolidi succinatis. The dissolution of kalil dehydrographolidi succinatis enteric capsules prepared in optimum condition was 98.36% in 45 mins . The standard draft was also made to guarantee the quality of kalil dehydrographolidi succinatis enteric capsules. The general pharmacology study was also made to test whether or not it affects neurosystem , blood pressure , cardiograph, respiration on animals by given kalil dehydroandrograpolidi succinas from intestines. In order to detect the bioavailability a single dose of kalil dehydroandrograpolidi succinas was given to mices by intestines, whereas it was given to dogs by oral under the anaesthesia. HPLC was used to measure the concentration of kalil dehydroandrograpolidi succinas in serum . The pharmacokinetic parameters and bioavailability of kalil dehydroandrograpolidi succinas enteric capsules was calculated and analysed by 3p97 program. The result is as follows:
Kalii dehydrographolidi succinatis given from intestines will lead to nonmarked inhibition to neurosystem of mices ,but has no effect on blood pressure , cardiograph, frequency and scope of
breath.
Bioavailability of kalil dehydroandrograpolidi succinatis of mice and dog are 15.87% and 29.92% when kalil dehydroandrograpolidi succinas is given from intestines .
Kalii dehydrographolidi succinatis enteric capsules is a feasible oral dosage form.
引文
杨水新，杨月春，张圣民. 高效液相色谱法用于注射用穿琥宁及穿琥宁注射液含量测定的研究[J]. 药物分析杂志，2000，20（6）：381.
殷立新，刘秀菊，胡永福，等．穿琥宁注射液与24种药物配伍的稳定性考察．中国现代应用药学，1999，士6(工)：55—56．
李华娟，郭爱清．穿琥宁与维生素B6注射液存在配伍禁忌．齐鲁护理杂志，2000，6(1)；52．
刘云霞，刘翠香，田霞．静脉滴注穿琥宁引起过敏性休克1例．中国医院药学杂志，2000，20(6)：381．
周圣明．穿琥宁注射液致过敏性休克1例．医药导报，2000．19(3)：309．
郭树范．静脉滴注穿琥宁致过敏性休克1例．小儿急求医学，1999，6(2)：92．
熊丽娟．静滴穿琥宁粉针剂致热原样反应4例．中国中药杂志，2000．25(6)：382—383．
郭春辉，赵安飞，张俊学．穿琥宁注射液致药热反应3例．药物不良反应杂志，1999，(2)：123—124．
肖庆贵．穿琥宁注射液致白细胞锐减3例．药物不良反应杂志，1999，1(2)：122—123．
韦怡，刘昌玉．穿琥宁注射液引起肝功能损害1例．中西医结合肝病杂志，1997，7(2)：95．
张志荣，廖工铁，王炳南等. 脱水穿心莲内酯琥珀酸半酯单钾盐在家兔体内的药代动力学研究[J]. 华西药学杂志，1991，6（3）：129.
郑永，陈峰杰，周远大等.穿琥宁药代动力学及绝对生物利用度的实验研究[J]. 实用医药杂志，2004，21（4）：349－350.
郑永，陈峰杰，周远大等.穿琥宁肠溶胶囊在犬体内的药代动力学及绝对生物利用度[J]. 华西药学杂志，2003，18（2）：101－103.
殷立新，刘秀菊，胡永福，等．穿琥宁注射液与24种药物配伍的稳定性考察．中国现代应用药学，1999，士6(工)：55—56．
李华娟，郭爱清．穿琥宁与维生素B6注射液存在配伍禁忌．齐鲁护理杂志，2000，6(1)；52．
刘云霞，刘翠香，田霞．静脉滴注穿琥宁引起过敏性休克1例．中国医院药学杂志，2000，20(6)：381．
周圣明．穿琥宁注射液致过敏性休克1例．医药导报，2000．19(3)：309．
郭树范．静脉滴注穿琥宁致过敏性休克1例．小儿急求医学，1999，6(2)：92．
熊丽娟．静滴穿琥宁粉针剂致热原样反应4例．中国中药杂志，2000．25(6)：382—383．
郭春辉，赵安飞，张俊学．穿琥宁注射液致药热反应3例．药物不良反应杂志，1999，(2)：123—124．
肖庆贵．穿琥宁注射液致白细胞锐减3例．药物不良反应杂志，1999，1(2)：122—123．
韦怡，刘昌玉．穿琥宁注射液引起肝功能损害1例．中西医结合肝病杂志，1997，7(2)：95．
张志荣，廖工铁，王炳南等. 脱水穿心莲内酯琥珀酸半酯单钾盐在家兔体内的药代动力学研究[J]. 华西药学杂志，1991，6（3）：129.
郑永，陈峰杰，周远大等.穿琥宁药代动力学及绝对生物利用度的实验研究[J]. 实用医药杂志，2004，21（4）：349－350.
郑永，陈峰杰，周远大等.穿琥宁肠溶胶囊在犬体内的药代动力学及绝对生物利用度[J]. 华西药学杂志，2003，18（2）：101－103.