盐酸川芎嗪微乳抗腹腔粘连的实验研究
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摘要
腹部手术中，术后腹腔粘连的发生率较高。国外资料报导，术后腹腔粘连发生率高达90％。因此，如何预防腹部术后出现的腹腔粘连是个紧迫的问题。
腹腔粘连是术后腹膜进行修复的必然过程。没有粘连就没有修复，但当其修复无序或纤维降解不全以致成为点状、成角、索带样粘连时就是机械性肠梗阻的发病学基础了。外科手术虽然是人类意志和智慧的体现，但它依然遵循着创伤修复的基本规律，外科临床工作的指导思想应该是引导、支持手术后脏器顺应创伤修复的客观规律进行重建而不是将其视为个别脏器的孤立行为。目前防治腹腔粘连主要从腹腔灌注、改进术式、术后外治和理疗等方面着手，但存在技巧的不确定性、药效短、疗效不稳定等问题，而中医药和高分子聚合物隔离防治腹腔粘连则是前沿的研究热点。
现有研究证实：活血化瘀类中药川芎能有效增加微血管的开放数目，加快微循环的血流速度、抗血小板凝集、抑制平滑肌收缩及抗炎等作用，并具有抗腹腔粘连的作用，但单纯给药吸收快、疗效短。微乳具延缓药物的释放，提高脂溶性药物的吸收、降低毒性、提高药物生物利用度等功能。其中，w／o型微乳能形成膜样物理屏障，在生物医学工程以及其它生物技术领域具有广泛的应用前景。川芎嗪是从中药川芎中提取出来的一TKH分子化合物，其水溶性良好，具有抗腹腔粘连功效。因此我们在以往研究的基础上，拟就这方面进行探索，将中医传统外治法引入腹腔内，制备成w／o型微乳，采用腹腔给药，通过遴选有效的微乳处方，利用w／o微乳缓释技术和成膜特性，研制出稳定性好、可降解、生物相容性好及无毒副作用的中药微乳制剂，采用大鼠术中腹腔内给药途径，拟最大限度减轻术后可能存在的点状、成角、索带样病理性粘连，为杜绝粘连性肠梗阻提供应用基础研究。
本论文对术后腹腔粘连的中西医防治进展、药物微乳技术进行了系统的文献检索，回顾了腹腔粘连形成的病因病理及目前防治从中西药腹腔灌注、中医辨证治疗、改进术式、术后外治和理疗等方面着手。本研究拟将传统中医外治法引入腹腔内，通过中药结合现代微乳技术，研制具有缓释作用和能成膜的中药微乳进行腹腔灌注，实现机械屏障的浆膜面隔离和药物屏障川芎嗪微乳缓释以预防术后腹腔粘连的发生，为此进行了药物遴选研究、W／O微乳处方设计、盐酸川芎嗪微乳的制备、盐酸川芎嗪微乳的质量评价及盐酸川芎嗪微乳有效性验证等部分应用基础的研究。
药物遴选研究昆明小鼠造模后随机分成生理盐水、丹参酮ⅡA、盐酸川芎嗪、尿激酶及阿司匹林五组，术后给药，于术后第15d处死小鼠，进行腹膜粘连评分及病理HE染色、Masson染色及免疫组化SABC法观察、分析。结果提示：盐酸川芎嗪与尿激酶防治小鼠腹腔粘连效果最佳。
W／O微乳处方设计在具备优良的生物相容性的基础上，以HLB值为参考指标选择表面活性剂，以Span-80，OP乳化剂，Span-80和Tween-80复配为表面活性剂筛选对象；以丙三醇，1，2-丙二醇为助表面活性剂筛选对象；以IPM，油酸乙酯为油相筛选对象。从而得出能够形成较稳定空白微乳的处方为：Km=1∶1，OP／丙三醇／油酸乙酯／水组；Km=2∶1，OP／丙三醇／IPM／水组；Km=2∶1，OP／丙三醇／油酸乙酯／水组。绘制伪三元相图，比较成乳区面积，其中Km=1∶1，OP／丙三醇／油酸乙酯／水组含有较大载水量，形成稳定微乳。
川芎嗪微乳制备在空白微乳制备的基础上，以一定浓度盐酸川芎嗪水溶液代替水进行滴定，筛选处方。以能够形成稳定含药微乳处方：OP／丙三醇／油酸乙酯／含药水组为基础，考察盐酸川芎嗪浓度对制剂稳定性的影响，以含药量最高的稳定微乳处方为最佳。从不同药物浓度含药微乳伪三元相图结合稳定性考察得出：盐酸川芎嗪水溶液的药液浓度为50mg／mL时微乳最佳。
川芎嗪微乳的质量评价微乳离心10min(1500rad·min~(-1))试验，体系保持澄清透明。电导率测定在1～10μs／cm数量级，可以判断为w／o型微乳液。测定含药微乳平均粒径：79.5nm，小于58.2nm的粒子占54％，小于89.0nm的粒子占89.5％，粒径分布范围窄，粒径比较均匀。微乳含量测定平均载药量8.0417mg／mL。体外释放度考察盐酸川芎嗪微乳在前4个小时内稳定释放，几乎成一条直线(r=0.9957)，符合Higuichi方程。
川芎嗪微乳药效学基础研究将48只SD大鼠造模后随机分成生理盐水、盐酸川芎嗪、空白微乳和盐酸川芎嗪微乳高剂量、中剂量、低剂量组。采取术中腹腔给药，于术后第22d处死大鼠，进行腹腔粘连根据Nair五分级标准评分、常规病理根据HE染色纤维结缔组织增生及胶原化的程度进行半定量观察、免疫组化根据Collagen I增生情况进行半定量观察及据Masson染色以肠壁粘连时总胶原的增生情况进行半定量观察等统计分析。结果提示：盐酸川芎嗪微乳对防治腹腔粘连有一定的疗效，其中低剂量组效果最佳。
结论：优选盐酸川芎嗪微乳处方为：OP为表面活性剂，丙三醇为助表面活性剂，油酸乙酯为油相，盐酸川芎嗪水溶液浓度为50mg／mL。四者比例为4∶4∶2∶0.95(25℃)时制剂稳定。平均载药量为8.0417mg／mL。该方法配制简单，重现性好，制剂稳定。动物实验说明盐酸川芎嗪微乳在适宜的剂量下能发挥最佳药效。结果提示盐酸川芎嗪微乳低剂量组效果最佳，并初步证实盐酸川芎嗪微乳抗大鼠术后腹腔粘连的有效性。
In the ventral operation, celiac adherence occurred frequently. So, how to prevent it is a urgent question. Celiac adherence is an inevitable course to restore the peritoneum after the operation. No adherence, no restoring. When it has a disorder or the fibre decompound incompletion, adherence will be the foundation of the mechanical enteric block. The surgery follows this law all along, and we should focus on guiding to obey this rule. At present, the treatment consists celiac douche therapy, improving on surgical ways, exterior and physical treatment. But there are some shortcomings more or less. Now, treatment with traditional Chinese medicine and macromolecule polymer is the hotspot of the research foreland. A study validated that chuanxiong, a herbal medicine classified with promoting blood circulation, can increase the amount of opened tiny blood vessel, speed up the blood circulation, resist blood platelet congregation, restrain the smooth muscle constriction and anti-inflammatory. And it also can resist the celiac adherence. Microemulsion prolong the releasing time, facilitate the absorbtion of sebaceous soluble medicine, debase the toxicity and enhance the biology using degree. Meanwhile, the W/O microemulsion form a physical barrier and it has a wide foreground in the biological technology area. Based on the previous investigation, insuffiation with the W/O microemulsion preparation of traditional Chinese medicine will introduce the traditional therapy into the abdomen. We will focus on mitigating the pathological adherence and supplying basement research to prevent the mechanical enteric block.
Large numbers of literatures have retrieved on the prevention development of postoperative abdominal adhesion with Chinese and western integrative medicine and drug microemulsion technique. The genesis and preventive methods of the abdominal adhesion was reviewed in this paper. At present, the prevention and treatment of the abdominal adhesion was concentrated on the intraperitoneal perfusion of drugs, the treatment with chinese traditional medicine, the improvement of operative technique, physical treatment and so on. Nowadays more attention has been focused on the dialectically application of Chinese traditional medicine and macromolecular isolation. In the present study, we combined the Chinese traditional medicine with modern microemulsion technique to prepare a kind of microemulsion with chinese medicine which has sustained release and membrane formation characteristics and examined if intraperitoneal perfusion of this microemulaion has the preventive effect on the postoperative abdominal adhesion.. There are some parts in our study: the W/O microemulsion preformulation, Ligustrazine microemulsion preparation, the biodegradation and compatibility of microemulsion and microemulsion efficacy validation.
Drug screen PA model rats were randomly divide into 5 different groups treated with normal saline,TanshinoneⅡA,ligustrazine hydrochloride,urine kinase and aspirin respectively for 15 days,PA grade was assessed by pathology HE dye, Masson dye and immunohistochemical(SABC) observation and analysis, conclusion: ligustrazine hydrochloride and urine kinase prevent and cure PA better.
W/O microemulsion preformulation: HLB value was used as index for selecting emulsifier. Emulsifier was selected from Span-80, OP and Span-80 combining with Tween-80. Coemulsifier was selected from glycerol and 1,2-glycol. Oil phase was selected from IPM and ethyl oleate. The prescription which could form stable blank microemulsion was: Km=1:1, OP/glycerol/ethyl oleate/water; Km=2:1, OP/glycerol/IPM/water; Km=2:1, OP/glycerol/ethyl oleate/water. Temary phase diagrams were drawed, and microemulsion area was used as index: the prescription of Km=1:1, OP/glycerol/ethyl oleate/water could form stable microemulsion, and also carry the most water.
Preparation of Ligustrazine Hydrochloride microemulsion: Based on the blank microemulsion preparation, we used Ligustrazine Hydrochloride solutions of different concentration instead of water to select the prescription. Based on the drug-carried microemulsion prescription OP/glycerol/ethyl oleate/water, we investigated the effect of Ligustrazine Hydrochloride concentration on the stability of the emulsion. The best prescription has the highest drug content. From the temary phase diagram and the stability investigation, we knew that the most proper concentration was 50mg/mL.
Quality evaluation of Ligustrazine Hydrochloride microemulsion: We centrifuged the microemulsion for 10 min (1500rad·min~(-1)), the system was clear and transparence. When the conductivity was 1～10μs/cm, we consider it as W/O microemulsion. The average diameter of the drug-carried microemulsion was 79.5nm, 54% of which＜58.2nm and 89.5% of which＜89.0nm. The particle distribution is narrow and the particle size is homogeneous. The average drug content was 8.0417mg/mL. Drug release investigation in vitro showed that Ligustrazine Hydrochloride microemulsion released stably within the first 4 hours with good linear relationship(r=0.9975), which was consistent with Higuichi equation.
Study on the pharmacodynamics of Ligustrazine Hydrochloride microemulsion: 48 SD model rats were randomly divided into four groups: Sodium Chloride group, Ligustrazine Hydrochloride group, blank microemulsion group and Ligustrazine Hydrochloride microemulsion groups (high dosage, moderate dosage and low dosage). The drug was administrated intraperitoneally during operation. The rats were put to death on the 22th day after operation. Abdominal adhesion was evaluated according to the Nair five-class standard. HE stain, Masson stain and immunohistochemistry methods was used to semiquantitatively evaluated the grade of the abdominal adhesion. The results showed Ligustrazine Hydrochloride microemulsion with low dosage was the best one.
Conclusions: The best Ligustrazine Hydrochloride microemulsion is prepared using OP as emulsifier, glycerol as coemulsifier, ethyl oleate as oil phase and 50mg/mL Ligustrazine Hydrochloride solusion, which is the most stablethe with the proportion 4:4:2:0.95. The average drug content is 8.0417mg/ml. The animal experiments show Ligustrazine Hydrochloride microemulsion of the optimal dosage has the best efficacy and the supplementary component play a part in the prevention of the abdominal adhesion. The results suggest the low dosage is better than the high and moderate dosage. It proved the efficacy of Ligustrazine Hydrochloride microemulsion in the prevention and treatment of abdominal adhesion.
腹腔粘连是术后腹膜进行修复的必然过程。没有粘连就没有修复，但当其修复无序或纤维降解不全以致成为点状、成角、索带样粘连时就是机械性肠梗阻的发病学基础了。外科手术虽然是人类意志和智慧的体现，但它依然遵循着创伤修复的基本规律，外科临床工作的指导思想应该是引导、支持手术后脏器顺应创伤修复的客观规律进行重建而不是将其视为个别脏器的孤立行为。目前防治腹腔粘连主要从腹腔灌注、改进术式、术后外治和理疗等方面着手，但存在技巧的不确定性、药效短、疗效不稳定等问题，而中医药和高分子聚合物隔离防治腹腔粘连则是前沿的研究热点。
现有研究证实：活血化瘀类中药川芎能有效增加微血管的开放数目，加快微循环的血流速度、抗血小板凝集、抑制平滑肌收缩及抗炎等作用，并具有抗腹腔粘连的作用，但单纯给药吸收快、疗效短。微乳具延缓药物的释放，提高脂溶性药物的吸收、降低毒性、提高药物生物利用度等功能。其中，w／o型微乳能形成膜样物理屏障，在生物医学工程以及其它生物技术领域具有广泛的应用前景。川芎嗪是从中药川芎中提取出来的一TKH分子化合物，其水溶性良好，具有抗腹腔粘连功效。因此我们在以往研究的基础上，拟就这方面进行探索，将中医传统外治法引入腹腔内，制备成w／o型微乳，采用腹腔给药，通过遴选有效的微乳处方，利用w／o微乳缓释技术和成膜特性，研制出稳定性好、可降解、生物相容性好及无毒副作用的中药微乳制剂，采用大鼠术中腹腔内给药途径，拟最大限度减轻术后可能存在的点状、成角、索带样病理性粘连，为杜绝粘连性肠梗阻提供应用基础研究。
本论文对术后腹腔粘连的中西医防治进展、药物微乳技术进行了系统的文献检索，回顾了腹腔粘连形成的病因病理及目前防治从中西药腹腔灌注、中医辨证治疗、改进术式、术后外治和理疗等方面着手。本研究拟将传统中医外治法引入腹腔内，通过中药结合现代微乳技术，研制具有缓释作用和能成膜的中药微乳进行腹腔灌注，实现机械屏障的浆膜面隔离和药物屏障川芎嗪微乳缓释以预防术后腹腔粘连的发生，为此进行了药物遴选研究、W／O微乳处方设计、盐酸川芎嗪微乳的制备、盐酸川芎嗪微乳的质量评价及盐酸川芎嗪微乳有效性验证等部分应用基础的研究。
药物遴选研究昆明小鼠造模后随机分成生理盐水、丹参酮ⅡA、盐酸川芎嗪、尿激酶及阿司匹林五组，术后给药，于术后第15d处死小鼠，进行腹膜粘连评分及病理HE染色、Masson染色及免疫组化SABC法观察、分析。结果提示：盐酸川芎嗪与尿激酶防治小鼠腹腔粘连效果最佳。
W／O微乳处方设计在具备优良的生物相容性的基础上，以HLB值为参考指标选择表面活性剂，以Span-80，OP乳化剂，Span-80和Tween-80复配为表面活性剂筛选对象；以丙三醇，1，2-丙二醇为助表面活性剂筛选对象；以IPM，油酸乙酯为油相筛选对象。从而得出能够形成较稳定空白微乳的处方为：Km=1∶1，OP／丙三醇／油酸乙酯／水组；Km=2∶1，OP／丙三醇／IPM／水组；Km=2∶1，OP／丙三醇／油酸乙酯／水组。绘制伪三元相图，比较成乳区面积，其中Km=1∶1，OP／丙三醇／油酸乙酯／水组含有较大载水量，形成稳定微乳。
川芎嗪微乳制备在空白微乳制备的基础上，以一定浓度盐酸川芎嗪水溶液代替水进行滴定，筛选处方。以能够形成稳定含药微乳处方：OP／丙三醇／油酸乙酯／含药水组为基础，考察盐酸川芎嗪浓度对制剂稳定性的影响，以含药量最高的稳定微乳处方为最佳。从不同药物浓度含药微乳伪三元相图结合稳定性考察得出：盐酸川芎嗪水溶液的药液浓度为50mg／mL时微乳最佳。
川芎嗪微乳的质量评价微乳离心10min(1500rad·min~(-1))试验，体系保持澄清透明。电导率测定在1～10μs／cm数量级，可以判断为w／o型微乳液。测定含药微乳平均粒径：79.5nm，小于58.2nm的粒子占54％，小于89.0nm的粒子占89.5％，粒径分布范围窄，粒径比较均匀。微乳含量测定平均载药量8.0417mg／mL。体外释放度考察盐酸川芎嗪微乳在前4个小时内稳定释放，几乎成一条直线(r=0.9957)，符合Higuichi方程。
川芎嗪微乳药效学基础研究将48只SD大鼠造模后随机分成生理盐水、盐酸川芎嗪、空白微乳和盐酸川芎嗪微乳高剂量、中剂量、低剂量组。采取术中腹腔给药，于术后第22d处死大鼠，进行腹腔粘连根据Nair五分级标准评分、常规病理根据HE染色纤维结缔组织增生及胶原化的程度进行半定量观察、免疫组化根据Collagen I增生情况进行半定量观察及据Masson染色以肠壁粘连时总胶原的增生情况进行半定量观察等统计分析。结果提示：盐酸川芎嗪微乳对防治腹腔粘连有一定的疗效，其中低剂量组效果最佳。
结论：优选盐酸川芎嗪微乳处方为：OP为表面活性剂，丙三醇为助表面活性剂，油酸乙酯为油相，盐酸川芎嗪水溶液浓度为50mg／mL。四者比例为4∶4∶2∶0.95(25℃)时制剂稳定。平均载药量为8.0417mg／mL。该方法配制简单，重现性好，制剂稳定。动物实验说明盐酸川芎嗪微乳在适宜的剂量下能发挥最佳药效。结果提示盐酸川芎嗪微乳低剂量组效果最佳，并初步证实盐酸川芎嗪微乳抗大鼠术后腹腔粘连的有效性。
In the ventral operation, celiac adherence occurred frequently. So, how to prevent it is a urgent question. Celiac adherence is an inevitable course to restore the peritoneum after the operation. No adherence, no restoring. When it has a disorder or the fibre decompound incompletion, adherence will be the foundation of the mechanical enteric block. The surgery follows this law all along, and we should focus on guiding to obey this rule. At present, the treatment consists celiac douche therapy, improving on surgical ways, exterior and physical treatment. But there are some shortcomings more or less. Now, treatment with traditional Chinese medicine and macromolecule polymer is the hotspot of the research foreland. A study validated that chuanxiong, a herbal medicine classified with promoting blood circulation, can increase the amount of opened tiny blood vessel, speed up the blood circulation, resist blood platelet congregation, restrain the smooth muscle constriction and anti-inflammatory. And it also can resist the celiac adherence. Microemulsion prolong the releasing time, facilitate the absorbtion of sebaceous soluble medicine, debase the toxicity and enhance the biology using degree. Meanwhile, the W/O microemulsion form a physical barrier and it has a wide foreground in the biological technology area. Based on the previous investigation, insuffiation with the W/O microemulsion preparation of traditional Chinese medicine will introduce the traditional therapy into the abdomen. We will focus on mitigating the pathological adherence and supplying basement research to prevent the mechanical enteric block.
Large numbers of literatures have retrieved on the prevention development of postoperative abdominal adhesion with Chinese and western integrative medicine and drug microemulsion technique. The genesis and preventive methods of the abdominal adhesion was reviewed in this paper. At present, the prevention and treatment of the abdominal adhesion was concentrated on the intraperitoneal perfusion of drugs, the treatment with chinese traditional medicine, the improvement of operative technique, physical treatment and so on. Nowadays more attention has been focused on the dialectically application of Chinese traditional medicine and macromolecular isolation. In the present study, we combined the Chinese traditional medicine with modern microemulsion technique to prepare a kind of microemulsion with chinese medicine which has sustained release and membrane formation characteristics and examined if intraperitoneal perfusion of this microemulaion has the preventive effect on the postoperative abdominal adhesion.. There are some parts in our study: the W/O microemulsion preformulation, Ligustrazine microemulsion preparation, the biodegradation and compatibility of microemulsion and microemulsion efficacy validation.
Drug screen PA model rats were randomly divide into 5 different groups treated with normal saline,TanshinoneⅡA,ligustrazine hydrochloride,urine kinase and aspirin respectively for 15 days,PA grade was assessed by pathology HE dye, Masson dye and immunohistochemical(SABC) observation and analysis, conclusion: ligustrazine hydrochloride and urine kinase prevent and cure PA better.
W/O microemulsion preformulation: HLB value was used as index for selecting emulsifier. Emulsifier was selected from Span-80, OP and Span-80 combining with Tween-80. Coemulsifier was selected from glycerol and 1,2-glycol. Oil phase was selected from IPM and ethyl oleate. The prescription which could form stable blank microemulsion was: Km=1:1, OP/glycerol/ethyl oleate/water; Km=2:1, OP/glycerol/IPM/water; Km=2:1, OP/glycerol/ethyl oleate/water. Temary phase diagrams were drawed, and microemulsion area was used as index: the prescription of Km=1:1, OP/glycerol/ethyl oleate/water could form stable microemulsion, and also carry the most water.
Preparation of Ligustrazine Hydrochloride microemulsion: Based on the blank microemulsion preparation, we used Ligustrazine Hydrochloride solutions of different concentration instead of water to select the prescription. Based on the drug-carried microemulsion prescription OP/glycerol/ethyl oleate/water, we investigated the effect of Ligustrazine Hydrochloride concentration on the stability of the emulsion. The best prescription has the highest drug content. From the temary phase diagram and the stability investigation, we knew that the most proper concentration was 50mg/mL.
Quality evaluation of Ligustrazine Hydrochloride microemulsion: We centrifuged the microemulsion for 10 min (1500rad·min~(-1)), the system was clear and transparence. When the conductivity was 1～10μs/cm, we consider it as W/O microemulsion. The average diameter of the drug-carried microemulsion was 79.5nm, 54% of which＜58.2nm and 89.5% of which＜89.0nm. The particle distribution is narrow and the particle size is homogeneous. The average drug content was 8.0417mg/mL. Drug release investigation in vitro showed that Ligustrazine Hydrochloride microemulsion released stably within the first 4 hours with good linear relationship(r=0.9975), which was consistent with Higuichi equation.
Study on the pharmacodynamics of Ligustrazine Hydrochloride microemulsion: 48 SD model rats were randomly divided into four groups: Sodium Chloride group, Ligustrazine Hydrochloride group, blank microemulsion group and Ligustrazine Hydrochloride microemulsion groups (high dosage, moderate dosage and low dosage). The drug was administrated intraperitoneally during operation. The rats were put to death on the 22th day after operation. Abdominal adhesion was evaluated according to the Nair five-class standard. HE stain, Masson stain and immunohistochemistry methods was used to semiquantitatively evaluated the grade of the abdominal adhesion. The results showed Ligustrazine Hydrochloride microemulsion with low dosage was the best one.
Conclusions: The best Ligustrazine Hydrochloride microemulsion is prepared using OP as emulsifier, glycerol as coemulsifier, ethyl oleate as oil phase and 50mg/mL Ligustrazine Hydrochloride solusion, which is the most stablethe with the proportion 4:4:2:0.95. The average drug content is 8.0417mg/ml. The animal experiments show Ligustrazine Hydrochloride microemulsion of the optimal dosage has the best efficacy and the supplementary component play a part in the prevention of the abdominal adhesion. The results suggest the low dosage is better than the high and moderate dosage. It proved the efficacy of Ligustrazine Hydrochloride microemulsion in the prevention and treatment of abdominal adhesion.
引文
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