酮洛芬酯类前体药物亚微乳剂的研究
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摘要
酮洛芬(Ketoprofen)是一种苯丙酸类非甾体抗炎药衍生物，具有解热、抗炎、镇痛作用。与其它非甾体抗炎药一样，口服酮洛芬易引起胃肠道不良反应。本研究合成了两种酮洛芬酯类前体药物，通过体外水解动力学考察，筛选出适合于制备亚微乳剂的前体药物。系统的研究该前体药物的理化性质、稳定性，在此基础上成功的制备可供静脉注射的亚微乳剂，对该制剂的体内药动学行为、体内分布及药效学进行了研究，旨在探讨通过结构改造和剂型设计来提高药物疗效，降低毒副作用，拓宽药物的临床使用范围。
以酮洛芬为原料，通过有机酸酯化反应合成了酮洛芬乙酸乙烯酯(KPA)和酮洛芬异丙酯(KPI)。该合成方法简单，目标化合物收率高，适合大批量生产。通过UV、IR、~1H-NMR、~(13)C-NMR及MS鉴定，确证了所合成的化合物的结构。
建立了KPA和KPI体外高效液相色谱分析方法。对KPA和KPI的体外水解动力学进行了考察，结果显示，KPA表现出对体系的pH值及温度均较为敏感，在剂型制备过程中易于被催化水解。因此选择KPI进行进一步研究。
KPI在不同pH条件下的溶解度及表观油水分配系数的测定结果表明，KPI在水中难溶，且受pH影响较小；LogP为4.26，具有较强的亲脂性；高温、高湿、光照实验结果表明，KPI稳定性良好；KPI在大鼠血浆及肝匀浆中的降解属酶促反应，均可迅速水解为原型药物酮洛芬，具备用作前体药物的条件。
在处方前研究的基础上，采用高压均质法制备了KPI静脉注射亚微乳剂。考察了高压均质温度、压力及次数，卵磷脂的不同加入方法、载药量对亚微乳剂粒径及稳定性的影响，优化了乳化剂中卵磷脂与F68的比例和用量、油酸钠的用量，并考察了pH对亚微乳剂的影响。结果表明，乳化剂用量及卵磷脂与F68的比例等是影响亚微乳剂稳定性的主要因素。以卵磷脂—F68(2∶1)作为乳化剂，总量为1.2％时亚微乳剂稳定性较好且粒度分布均匀。确定了KPI亚微乳剂的最终处方及制备工艺为：以10％注射用大豆油为油相，乳化剂总量为1.2％(卵磷脂：F68=2：1)，油酸钠0.1％，均质前调节pH至8.0，高压均质温度为40～50℃下，以800bar压力均质6～10次，充氮灌封，灭菌。以上方法制得的三批亚微乳剂的平均粒径为186.2nm，ζ电位为—30.34mv，含量为100.9％，包封率为98.8％。
与稀释剂混合后考察亚微乳剂稳定性的结果显示，本品以生理盐水稀释后，ζ电位经时变化较大，提示制剂可能不稳定；以葡萄糖稀释后8h，粒径、ζ电位、包封率无显著变化。影响因素实验及长期稳定性结果显示在高温光照条件下放置10天以及在25±2℃及6±2℃条件下放置6个月本品的外观、pH、药物含量以及平均粒径、药物包封率等都没有显著变化。
建立了大鼠血浆及组织匀浆中酮洛芬分析的高效液相色谱法。以自制酮洛芬溶液剂为参比制剂，考察了大鼠静脉注射KPI亚微乳剂的药动学过程，测定不同时间的血药浓度，以统计矩法计算体内药动学参数。结果表明，KPI亚微乳剂的药时曲线下面积为(903.28±240.66)μg·h／ml，为参比制剂的100.3％。两制剂的药时曲线相似，各药动学参数无显著性差异。KPI亚微乳剂静脉注射后，在大鼠肝、脾、脑中分布略高，与静脉注射酮洛芬溶液剂相比，酮洛芬在各主要组织中的分布无显著性差异。
采用微渗析技术测定了大鼠静脉注射KPI亚微乳剂及酮洛芬注射液后血液及脑脊液中游离酮洛芬的浓度，以统计矩法计算游离酮洛芬的体内药动学参数。结果表明，两制剂静脉给药后，血液中游离酮洛芬的Ke分别为(0.0042±0.0004)和(0.0039±0.0003)min~(-1)，t_(1／2)分别为(166.36±15.72)和(180.83±16.26)min，两制剂间无显著性差异。表明前体药物在血浆中短时间内水解为原型药物。酮洛芬溶液剂静脉注射后脑脊液中酮洛芬的AUC约为KPI亚微乳剂静脉注射后2.19倍，推测可能是由于剂型原因导致这种现象的出现。
急性毒性实验结果显示，小鼠静脉注射KPI亚微乳剂的LD_(50)值为207.2mg／kg。安全性实验结果表明，KPI亚微乳剂体外不引起溶血，对家兔耳缘静脉无血管刺激性，豚鼠无过敏性；药效学实验结果表明，小鼠静脉注射给药时，KPI亚微乳剂对小鼠热板及热水致痛的镇痛效果好于或与酮洛芬相当，对由二甲苯引起的小鼠耳肿胀具有非常显著的抑制作用，效果好于等剂量阳性对照药物氢化可的松及酮洛芬。
Ketoprofen, a potent non-steroidal anti-inflammatory drug (NSAIDs), is a racemic proprionic acid derivative with well-recognized analgesic, anti-inflammatory and antipyretic properties. However, it is known that oral ketoprofen, like other NSAIDs, may cause gastrointestinal disturbances at a high incidence. In this study, two ester prodrugs of ketoprofen were synthesized. In vitro hydrolysis kinetics was investigated and the prodrug, which was suited to prepare the SE, was selected. Meanwhile the physical-chemical properties and stability were also investigated. KPI can be applied to the SE for intravenous administration. The pharmacokinetics, distribution and pharmacodynamics of the formulation were examined in order to explore the possibility of increasing the curative effect, decreasing the side effect and enlarging the clinical serviceable range by structure transform and formulation design.Ketoprofen vinyl acetate (KPA) and ketoprofen isopropyl ester (KPI) were synthesized by organic acid esterification method using ketoprofen as raw materials. The method was simple and reproducible. It can be applied to mass production. The structures of KPA and KPI were confirmed by UV、IR、~1H-NMR、~(13)C-NMR and MS, respectively.HPLC method was developed for the assay of KPA and KPI. The in vitro hydrolysis kinectics of KPA and KPI were studied. KPA was sensitive to pH and temperature of the system and was easily hydrolyzed. So, KPI was selected to further investigation.The solubility and oil/water partition coefficient of KPI in different pH was determined. The solubility of KPI in water was very low, and was not affected by pH. The LogP was 4.26, showed that it was highly lipophilic. KPI shows its well stability by the results of the experiments in high temperature, humidity and light studies. The degradation of KPI in rat plasma and liver homogenate was belonged to enzymatic reaction, and KPI can be degraded to ketoprofen fastly.According to the results of pre-formulation study, high-pressure homogenization method was developed to prepared KPI intravenous SE. The homogenization temperature, pressure, times and the way of addition of lecithin was studied. The ratio of the emulsifiers and the dosage of sodium oleate were optimized, and the effect of pH was also detected. The result showed that the amount and composition hold the most distinct influence on the stability of KPI SE. The formula showed satisfactory stability character when the total amount of emulsifier was 1.2％with the lecithin-F68 (2:1). The formulation and preparation technology of emulsifier was: the oil phase was 10％soybean oil, the total amount of emulsifier was 1.2％with the lecithin-F68 (2:1), and the sodium oleate was 0.1％. pH was adjusted to 8.0 before homogenization, and the condition was 800bar, 6～10 times, sealed with nitrogen and sterilized. The mean particle size was 186.2nm,ζpotential was-30.34mv, drug content was 100.9％and the encapsulation efficiency was 98.8％.
Dilution test revealed that the sodium chloride injection (0.9％) diluted samples turned to unstable withζpotential changing markedly. The samples diluted with glucose injection (5.4％) showed good stability within 8 h. The influencing factor test showed that KPI SE has no significant change in 10 days under high temperature and illumination, and long-term stability study showed that KPI SE was stable after 6 months under 25±2℃and 6±2℃.
The in vivo pharmacokinetic behavior of KPI SE was studied utilizing HPLC method. The pharmacokinetic study of KPI SE after intravenous administration in rats was performed. The pharmacokinetic parameters were studied according to non- compartment model. The result showed that the AUC value of KPI SE was (903.28+240.66)/μg·h/ml and 100.3％compared to ketoprofen solution. The concentration-time curves were alike and pharmacokinetic parameters showed no distinct difference. The distribution study after intravenous administration in rats of KPI SE indicated that no significant different of ketoprofen concentration in main tissues of rat compared to ketoprofen solution.
Microdialysis technique was used to determine the concentration of free ketoprofen in rat plasma and CSF after intravenous administration of KPI SE and ketoprofen solution. The results showed that Ke and t_(1/2) of free ketoprofen in rat plasma of KPI SE were (0.0042±0.0004) min~(-1) and (166.36±15.72) min. Those of ketoprofen solution were (0.0039±0.0003)min~(-1) and (180.83±16.26)min. The AUC value of free ketoprofen in CSF of solution was 2.19 times larger than that of KPI SE.
Acute toxicity result suggested that the LD_(50) of KPI SE for intravenous formulation were 201.2 mg/kg. The pharmaceutical safety test results indicated that haemolysis, stimulation and hypersensitiveness, none of these negative effects was found. The analgesic activity of KPI SE was better or the same as the ketoprofen in mice utilizing hot plate method and hot water method after intravenous administration in pharmacodynamics test. Inhibitory effect of KPI SE highly significant by using dimethylbenzene induced ear swelling in mice. And the effect was better than the same dosage of hydrocortisone and ketoprofen.
以酮洛芬为原料，通过有机酸酯化反应合成了酮洛芬乙酸乙烯酯(KPA)和酮洛芬异丙酯(KPI)。该合成方法简单，目标化合物收率高，适合大批量生产。通过UV、IR、~1H-NMR、~(13)C-NMR及MS鉴定，确证了所合成的化合物的结构。
建立了KPA和KPI体外高效液相色谱分析方法。对KPA和KPI的体外水解动力学进行了考察，结果显示，KPA表现出对体系的pH值及温度均较为敏感，在剂型制备过程中易于被催化水解。因此选择KPI进行进一步研究。
KPI在不同pH条件下的溶解度及表观油水分配系数的测定结果表明，KPI在水中难溶，且受pH影响较小；LogP为4.26，具有较强的亲脂性；高温、高湿、光照实验结果表明，KPI稳定性良好；KPI在大鼠血浆及肝匀浆中的降解属酶促反应，均可迅速水解为原型药物酮洛芬，具备用作前体药物的条件。
在处方前研究的基础上，采用高压均质法制备了KPI静脉注射亚微乳剂。考察了高压均质温度、压力及次数，卵磷脂的不同加入方法、载药量对亚微乳剂粒径及稳定性的影响，优化了乳化剂中卵磷脂与F68的比例和用量、油酸钠的用量，并考察了pH对亚微乳剂的影响。结果表明，乳化剂用量及卵磷脂与F68的比例等是影响亚微乳剂稳定性的主要因素。以卵磷脂—F68(2∶1)作为乳化剂，总量为1.2％时亚微乳剂稳定性较好且粒度分布均匀。确定了KPI亚微乳剂的最终处方及制备工艺为：以10％注射用大豆油为油相，乳化剂总量为1.2％(卵磷脂：F68=2：1)，油酸钠0.1％，均质前调节pH至8.0，高压均质温度为40～50℃下，以800bar压力均质6～10次，充氮灌封，灭菌。以上方法制得的三批亚微乳剂的平均粒径为186.2nm，ζ电位为—30.34mv，含量为100.9％，包封率为98.8％。
与稀释剂混合后考察亚微乳剂稳定性的结果显示，本品以生理盐水稀释后，ζ电位经时变化较大，提示制剂可能不稳定；以葡萄糖稀释后8h，粒径、ζ电位、包封率无显著变化。影响因素实验及长期稳定性结果显示在高温光照条件下放置10天以及在25±2℃及6±2℃条件下放置6个月本品的外观、pH、药物含量以及平均粒径、药物包封率等都没有显著变化。
建立了大鼠血浆及组织匀浆中酮洛芬分析的高效液相色谱法。以自制酮洛芬溶液剂为参比制剂，考察了大鼠静脉注射KPI亚微乳剂的药动学过程，测定不同时间的血药浓度，以统计矩法计算体内药动学参数。结果表明，KPI亚微乳剂的药时曲线下面积为(903.28±240.66)μg·h／ml，为参比制剂的100.3％。两制剂的药时曲线相似，各药动学参数无显著性差异。KPI亚微乳剂静脉注射后，在大鼠肝、脾、脑中分布略高，与静脉注射酮洛芬溶液剂相比，酮洛芬在各主要组织中的分布无显著性差异。
采用微渗析技术测定了大鼠静脉注射KPI亚微乳剂及酮洛芬注射液后血液及脑脊液中游离酮洛芬的浓度，以统计矩法计算游离酮洛芬的体内药动学参数。结果表明，两制剂静脉给药后，血液中游离酮洛芬的Ke分别为(0.0042±0.0004)和(0.0039±0.0003)min~(-1)，t_(1／2)分别为(166.36±15.72)和(180.83±16.26)min，两制剂间无显著性差异。表明前体药物在血浆中短时间内水解为原型药物。酮洛芬溶液剂静脉注射后脑脊液中酮洛芬的AUC约为KPI亚微乳剂静脉注射后2.19倍，推测可能是由于剂型原因导致这种现象的出现。
急性毒性实验结果显示，小鼠静脉注射KPI亚微乳剂的LD_(50)值为207.2mg／kg。安全性实验结果表明，KPI亚微乳剂体外不引起溶血，对家兔耳缘静脉无血管刺激性，豚鼠无过敏性；药效学实验结果表明，小鼠静脉注射给药时，KPI亚微乳剂对小鼠热板及热水致痛的镇痛效果好于或与酮洛芬相当，对由二甲苯引起的小鼠耳肿胀具有非常显著的抑制作用，效果好于等剂量阳性对照药物氢化可的松及酮洛芬。
Ketoprofen, a potent non-steroidal anti-inflammatory drug (NSAIDs), is a racemic proprionic acid derivative with well-recognized analgesic, anti-inflammatory and antipyretic properties. However, it is known that oral ketoprofen, like other NSAIDs, may cause gastrointestinal disturbances at a high incidence. In this study, two ester prodrugs of ketoprofen were synthesized. In vitro hydrolysis kinetics was investigated and the prodrug, which was suited to prepare the SE, was selected. Meanwhile the physical-chemical properties and stability were also investigated. KPI can be applied to the SE for intravenous administration. The pharmacokinetics, distribution and pharmacodynamics of the formulation were examined in order to explore the possibility of increasing the curative effect, decreasing the side effect and enlarging the clinical serviceable range by structure transform and formulation design.Ketoprofen vinyl acetate (KPA) and ketoprofen isopropyl ester (KPI) were synthesized by organic acid esterification method using ketoprofen as raw materials. The method was simple and reproducible. It can be applied to mass production. The structures of KPA and KPI were confirmed by UV、IR、~1H-NMR、~(13)C-NMR and MS, respectively.HPLC method was developed for the assay of KPA and KPI. The in vitro hydrolysis kinectics of KPA and KPI were studied. KPA was sensitive to pH and temperature of the system and was easily hydrolyzed. So, KPI was selected to further investigation.The solubility and oil/water partition coefficient of KPI in different pH was determined. The solubility of KPI in water was very low, and was not affected by pH. The LogP was 4.26, showed that it was highly lipophilic. KPI shows its well stability by the results of the experiments in high temperature, humidity and light studies. The degradation of KPI in rat plasma and liver homogenate was belonged to enzymatic reaction, and KPI can be degraded to ketoprofen fastly.According to the results of pre-formulation study, high-pressure homogenization method was developed to prepared KPI intravenous SE. The homogenization temperature, pressure, times and the way of addition of lecithin was studied. The ratio of the emulsifiers and the dosage of sodium oleate were optimized, and the effect of pH was also detected. The result showed that the amount and composition hold the most distinct influence on the stability of KPI SE. The formula showed satisfactory stability character when the total amount of emulsifier was 1.2％with the lecithin-F68 (2:1). The formulation and preparation technology of emulsifier was: the oil phase was 10％soybean oil, the total amount of emulsifier was 1.2％with the lecithin-F68 (2:1), and the sodium oleate was 0.1％. pH was adjusted to 8.0 before homogenization, and the condition was 800bar, 6～10 times, sealed with nitrogen and sterilized. The mean particle size was 186.2nm,ζpotential was-30.34mv, drug content was 100.9％and the encapsulation efficiency was 98.8％.
Dilution test revealed that the sodium chloride injection (0.9％) diluted samples turned to unstable withζpotential changing markedly. The samples diluted with glucose injection (5.4％) showed good stability within 8 h. The influencing factor test showed that KPI SE has no significant change in 10 days under high temperature and illumination, and long-term stability study showed that KPI SE was stable after 6 months under 25±2℃and 6±2℃.
The in vivo pharmacokinetic behavior of KPI SE was studied utilizing HPLC method. The pharmacokinetic study of KPI SE after intravenous administration in rats was performed. The pharmacokinetic parameters were studied according to non- compartment model. The result showed that the AUC value of KPI SE was (903.28+240.66)/μg·h/ml and 100.3％compared to ketoprofen solution. The concentration-time curves were alike and pharmacokinetic parameters showed no distinct difference. The distribution study after intravenous administration in rats of KPI SE indicated that no significant different of ketoprofen concentration in main tissues of rat compared to ketoprofen solution.
Microdialysis technique was used to determine the concentration of free ketoprofen in rat plasma and CSF after intravenous administration of KPI SE and ketoprofen solution. The results showed that Ke and t_(1/2) of free ketoprofen in rat plasma of KPI SE were (0.0042±0.0004) min~(-1) and (166.36±15.72) min. Those of ketoprofen solution were (0.0039±0.0003)min~(-1) and (180.83±16.26)min. The AUC value of free ketoprofen in CSF of solution was 2.19 times larger than that of KPI SE.
Acute toxicity result suggested that the LD_(50) of KPI SE for intravenous formulation were 201.2 mg/kg. The pharmaceutical safety test results indicated that haemolysis, stimulation and hypersensitiveness, none of these negative effects was found. The analgesic activity of KPI SE was better or the same as the ketoprofen in mice utilizing hot plate method and hot water method after intravenous administration in pharmacodynamics test. Inhibitory effect of KPI SE highly significant by using dimethylbenzene induced ear swelling in mice. And the effect was better than the same dosage of hydrocortisone and ketoprofen.
引文
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