芳基丙酸类非甾体抗炎药前体药物的合成及其微乳、亚微乳剂的研究
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摘要
萘普生、氟比洛芬为芳基丙酸类非甾体抗炎药的代表性药物，具有抗炎、止痛等功效。研究表明长期口服此类药物易引起胃肠道不良反应，主要表现为胃肠道溃疡及由此引起的消化道出血、穿孔等。利用非甾体抗炎药中的羧酸基团将其制备为前药可有效降低其胃肠道的毒副作用是目前可行的方法之一。
丁香酚为植物丁香挥发油的主要成分，近年来研究表明具有抑菌、镇痛、麻醉等活性，临床主要用于牙科龋齿、牙髓止痛。但由于其结构中含有酚羟基，久置空气中易被氧化变质，且有特殊气味，不易长期保存及制剂。本文利用前药原理将具有相近药理活性的萘普生、氟比洛芬与丁香酚拼合成前体药物，期望寻找到即可以降低非甾体类抗炎药的引起的胃肠道副作用，同时又能够增强丁香酚的稳定性的前体药物。
本文首先合成了两个前体药物，系统研究了前体药物的理化性质和稳定性。在此基础上设计并制备了可供口服的微乳和可供静脉注射的亚微乳，并对此两种制剂进行了体内的药动学、组织分布和药效学研究，旨在通过研究为该类药物的结构改造和制剂探索方向。
以萘普生（或氟比洛芬）和丁香酚为原料药，以草酰氯（或二氯亚砜）为酰化剂，通过酰化反应合成了前体药物萘普生丁香酚酯（NEE）和氟比洛芬丁香酚酯（FEE）；所得化合物结构均经过IR、MS和1H-NMR确认了结构。建立了NEE、FEE体外分析方法，对NEE和FEE的初步稳定性及理化性质进行了研究。稳定性研究表明NEE和FEE在光照、高温、高湿条件下均很稳定。溶解性实验表明NEE和FEE皆为水难溶性药物，而FEE在短链醇及油中的溶解性较NEE好，考虑到以乳剂为载体的药物要在油相中具有一定溶解性才能满足载药量的前提，本文选用FEE为模拟药物进行制剂及药动学方面的研究。在不同pH缓冲液的稳定性研究表明，FEE在中性和偏酸性条件下较为稳定，碱性条件下极不稳定。
为了改善药物的溶解性、提高生物利用度，在理化性质研究基础上，选用微乳为药物载体，制备了可供口服的微乳剂。以滴定法绘制伪三元相图，以三元相图中的O/W微乳区的面积大小为评价指标，考察了不同的油相、不同的表面活性剂和助表面活性剂组成变化对微乳形成的影响，最终确定了以油酸乙酯（EO）为油相、聚氧乙烯蓖麻油（Cremophor EL)为表面活性剂、聚乙二醇400(PEG-400)为助表面活性剂制备了微乳制剂，确定了微乳的最佳处方组成（EO:Cremophor EL:PEG-400:Water=5:20:10:65）。考察了微乳的理化性质，微乳透射电镜下呈圆球状，平均粒径为26.74±5.52nm，Zeta电位为-7.88±2.88mV，电导率为48.8μs/cm，粘度为59.7mPa s，相变温度为72℃。对微乳的稳定性进行了初步考察，实验表明在高温条件下该体系不稳定。
为了扩展不同的给药途径，满足不同患者的给药需求，本文还采用两步均质法制备了FEE可供静脉注射用的亚微乳制剂。以粒径、电位及稳定系数Ke为评价指标，采用单因素和正交实验考察了亚微乳制剂的处方组成及工艺条件。最终确定了以20%的注射用大豆油为油相，乳化剂总量为1.5%（大豆磷脂:F68=3:1），油酸用量为0.1%，以高速剪切分散机8000rpm/min在60℃条件下剪切分散8min制备初乳，将初乳移至高压均质机中以12000psi压力均质12次，充氮气灌封，121℃灭菌15min。理化性质研究表明以此法制得的三批亚微乳平均粒径为220nm左右，zeta电位为-40mV左右。稳定性试验表明：本品经生理盐水或葡萄糖稀释后，其粒径、电位无明显变化；高温、光照、低温实验表明该制剂应尽量避光保存。
建立了血浆及组织匀浆中氟比洛芬测定的HPLC法，体外血浆及肝匀浆的降解动力学实验表明，FEE可迅速转化为氟比洛芬，具备成为前药的条件。以大鼠为试验对象，对FEE口服微乳和静脉注射用亚微乳进行体内药动学研究，并以自制的氟比洛芬混悬剂和注射剂为参比制剂进行比较，以药动学软件BAPP2.0计算了药动学参数。结果表明（1）灌胃氟比洛芬混悬剂药动学过程符合一室开放模型，FEE微乳符合二室开放模型；FEE微乳与氟比洛芬混悬剂药动学参数相比，Tmax有所延长，AUC有显著性增加。（2）FEE亚微乳和氟比洛芬溶液组的药动学过程符合二室模型，药时曲线和药动学参数无明显差异。组织分布研究表明，FEE亚微乳大鼠尾静脉注射后，其在肝、肺分布较多，在脑中含量最低。
急性毒性试验表明，口服微乳的LD50为514.4mg/kg，静脉注射亚微乳的LD50279.7mg/kg；安全性试验表明FEE亚微乳制剂体外不引起溶血，对家兔的耳缘静脉注射无刺激性。药效学实验结果表明：口服微乳或静脉注射亚微乳，对醋酸扭体和热板法所致小鼠疼痛的镇痛效果与参比制剂相当，对二甲苯所致的小鼠耳肿胀也有较好的抑制效果。
Naproxen and Flurbiprofen are typical drugs of aryl propionic acid non-steroidalanti-inflammatory drugs (NSAIDs), with anti-inflammatory, anagesic properties.However, some research have indicate that long-term oral administration ofNSAIDs may cause gastrointestinal adverse reactions, mainly gastrointestinal ulcersand arising therefrom gastrointestinal bleeding and gastric perforation.The use ofcarboxyl group structure in NSAIDs synthesizing prodrug is one of effective ways toreduce gastrointestinal toxic and side effects.
Eugenol is the main component of the clove volatile oil. In recent years, studiesshowed that eugenol have effects of antibiotic, analgesic and anesthetic, mainly usedfor dental caries, dental pulp analgesic clinically. Due to phenolic hydroxyl group inthe structure, it is easy oxidation metamorphism when contacting air for a long time.It is not esay to preserve and preparate drugs with the special smell. This article usednaproxen and flurbiprofen which have similar pharmacological activity and eugenolas the raw materials, and made them into prodrug with combination principle. Weexpect to find new prodrug through structure reform which can reduce NSAIDsgastrointestinal adverse reactions and improve the stability of eugenol.
This article synthesized two prodrugs firstly, and studied the physical andchemical properties and stability. On this basis we designed and prepared emulsion fororal administration and submicroemulsion for intravenous injection. Based on thevivo pharmacokinetics, tissue distribution and pharmacodynamic studies of thesedrugs, the purpose of the research is exploring new direction of structuremodification and preparations.
Using naproxen(or flurbiprofen)and eugenol as the raw materials, with oxalyl chloride(or thionyl chloride) as acylating agent, synthesized the prodrug of naproxeneugenol ester(NEE) and flurbiprofen eugenol ester(FEE) via acylation. The structureof NEE and FEE were confirmed by IR、MS and1H-NMR spectrum. HPLC methodwas established for assay of FEE and NEE. Preliminary stability and physical andchemical properties of the NEE and FEE were studied. The stability test showed thatNEE and FEE are relatively stable in the high temperature, high humidity andlight conditions. Solubility experiments demonstrate that NEE and FEE areundissolved in water. However, the solubility of FEE in short chain alcohol and oilphrase is better than the one of NEE. Using emulsion as the carrier, the drug hasto own certain solubility in the oil phase. Considering this problem, this articleselects FEE as imitate drug for preparation and pharmacokinetic studies. Stabilitystudy in different pH buffer indicated that FEE relatively stable in neutral andacidic conditions, but accelerated the hydrolysis rate in alkaline condition.
In order to improve the absorption of the drug and enhance thebioavailability, according to physical and chemical properties study, we selectedmicroemulsion as a drug carrier and prepared for oral administration. Referencetitration drawing pseudo-ternary phase diagrams, using the size of the O/Wmicroemulsion region as the main evaluation index, we investigated the effect ofdifferent factors such as oil phase, surfactants and co-surfactants. For themicroemulsions, Ethyl Oleate (EO) is chosen as oil phase, Cremophor EL asSurfactant, PEG-400as co-surfactant. The consist of optimize formulation wasEO：Cremophor EL：PEG-400：Water=5：20：10：65. We studied the physical andchemical properties of the emulsion: It is globular under TEM; The averageparticle size and distribution is26.74±5.52nm; Potential is-7.88±2.88mV;Conductivity is48.8μs/cm; Viscosity is59.7mPa s; Phase-transition temperature is72℃. The emulsion is unstable under the condition of high temperature.
At the same time, in order to expand different administration routes, to meetdifferent needs of patient to medicine, the FEE submicroemulsion which wasused by intravenous injection was obtained by passing the two-step homogenization method. Applying particle size, Zeta and stability coefficient Keas evaluation index, we studied the prescription and process optimization byorthogonal experiment design and signal factor studies. The best formulation was:the oil phase was20%soybean oil, the total amount of emulsifier was1.5%(soyabean lecithin:F68=3:1), the oleic acid was0.1%. we got the emulsionunder the condition8000rpm/min by high-speed shearing dispersion machine,8minutes. In high pressure homogenizer, the condition was12000psi,12times,sealed with nitrogen and sterilized. The particle size is220nm, potential is about-40mV. Stability tests showed that there was no signigicant changes of thepartical size and potential when the emulsion was diluted by saline or glucose.High temperature, illumination and low temperature stability experiment showedthe peparation should be stored away from light.
A HPLC method was established to determine flurbiprofen in plasma andtissue homogenate. Plasma and liver homogenate in vitro degradation kineticsexperiments show that, FEE have the condition to become a prodrug because itcan quickly convert to flurbiprofen. Take rats as test object, we studied thepharmacokinetic of FEE microemulsion for oral and FEE submicroemulsion forintravenous. We calculated pharmacokinetic parameters with pharmacokineticsoftware BAPP2.0, and compared with flurbiprofen suspension and injectionhomemade. The result show that:1The pharmacokinetic process of flurbiprofensuspension lavage conform to open one compartment model, and FEEmicroemulsion conform to open two compartment model; Using flurbiprofensuspension as the reference preparation, the studies showed that the Tmaxof FEEemulsion is later than flurbiprofen. AUC has distinguished difference.2FEEsubmicroemulsion and flurbiprofen solution conform to open two compartmentmodel, there is no significant difference of the curve and pharmacokineticparameters. The distribution study after intravenous administration indicated thatthis drug concentration in liver and lung, minimum in brain.
Acute toxicity results suggested that the LD50of FEE emulsion for oral is 514.4mg/kg, the LD50of FEE submicroemulsion for intravenous injection is279.7mg/kg. The pharmaceutical safety test results indicated that none of thenegative effects of FEE submicroemulsion preparation in vitro. There isnonirritant for rabbit intravenous injection. Pharmacodynamics experiments showthat the analgesic activity of this drug was the same as the contrast drug in miceutilizing hot plate method and acetic acid writhing analgesic method. In addition,it has good inhibitory effect for mice ear swelling caused by dimethylbenzene.
丁香酚为植物丁香挥发油的主要成分，近年来研究表明具有抑菌、镇痛、麻醉等活性，临床主要用于牙科龋齿、牙髓止痛。但由于其结构中含有酚羟基，久置空气中易被氧化变质，且有特殊气味，不易长期保存及制剂。本文利用前药原理将具有相近药理活性的萘普生、氟比洛芬与丁香酚拼合成前体药物，期望寻找到即可以降低非甾体类抗炎药的引起的胃肠道副作用，同时又能够增强丁香酚的稳定性的前体药物。
本文首先合成了两个前体药物，系统研究了前体药物的理化性质和稳定性。在此基础上设计并制备了可供口服的微乳和可供静脉注射的亚微乳，并对此两种制剂进行了体内的药动学、组织分布和药效学研究，旨在通过研究为该类药物的结构改造和制剂探索方向。
以萘普生（或氟比洛芬）和丁香酚为原料药，以草酰氯（或二氯亚砜）为酰化剂，通过酰化反应合成了前体药物萘普生丁香酚酯（NEE）和氟比洛芬丁香酚酯（FEE）；所得化合物结构均经过IR、MS和1H-NMR确认了结构。建立了NEE、FEE体外分析方法，对NEE和FEE的初步稳定性及理化性质进行了研究。稳定性研究表明NEE和FEE在光照、高温、高湿条件下均很稳定。溶解性实验表明NEE和FEE皆为水难溶性药物，而FEE在短链醇及油中的溶解性较NEE好，考虑到以乳剂为载体的药物要在油相中具有一定溶解性才能满足载药量的前提，本文选用FEE为模拟药物进行制剂及药动学方面的研究。在不同pH缓冲液的稳定性研究表明，FEE在中性和偏酸性条件下较为稳定，碱性条件下极不稳定。
为了改善药物的溶解性、提高生物利用度，在理化性质研究基础上，选用微乳为药物载体，制备了可供口服的微乳剂。以滴定法绘制伪三元相图，以三元相图中的O/W微乳区的面积大小为评价指标，考察了不同的油相、不同的表面活性剂和助表面活性剂组成变化对微乳形成的影响，最终确定了以油酸乙酯（EO）为油相、聚氧乙烯蓖麻油（Cremophor EL)为表面活性剂、聚乙二醇400(PEG-400)为助表面活性剂制备了微乳制剂，确定了微乳的最佳处方组成（EO:Cremophor EL:PEG-400:Water=5:20:10:65）。考察了微乳的理化性质，微乳透射电镜下呈圆球状，平均粒径为26.74±5.52nm，Zeta电位为-7.88±2.88mV，电导率为48.8μs/cm，粘度为59.7mPa s，相变温度为72℃。对微乳的稳定性进行了初步考察，实验表明在高温条件下该体系不稳定。
为了扩展不同的给药途径，满足不同患者的给药需求，本文还采用两步均质法制备了FEE可供静脉注射用的亚微乳制剂。以粒径、电位及稳定系数Ke为评价指标，采用单因素和正交实验考察了亚微乳制剂的处方组成及工艺条件。最终确定了以20%的注射用大豆油为油相，乳化剂总量为1.5%（大豆磷脂:F68=3:1），油酸用量为0.1%，以高速剪切分散机8000rpm/min在60℃条件下剪切分散8min制备初乳，将初乳移至高压均质机中以12000psi压力均质12次，充氮气灌封，121℃灭菌15min。理化性质研究表明以此法制得的三批亚微乳平均粒径为220nm左右，zeta电位为-40mV左右。稳定性试验表明：本品经生理盐水或葡萄糖稀释后，其粒径、电位无明显变化；高温、光照、低温实验表明该制剂应尽量避光保存。
建立了血浆及组织匀浆中氟比洛芬测定的HPLC法，体外血浆及肝匀浆的降解动力学实验表明，FEE可迅速转化为氟比洛芬，具备成为前药的条件。以大鼠为试验对象，对FEE口服微乳和静脉注射用亚微乳进行体内药动学研究，并以自制的氟比洛芬混悬剂和注射剂为参比制剂进行比较，以药动学软件BAPP2.0计算了药动学参数。结果表明（1）灌胃氟比洛芬混悬剂药动学过程符合一室开放模型，FEE微乳符合二室开放模型；FEE微乳与氟比洛芬混悬剂药动学参数相比，Tmax有所延长，AUC有显著性增加。（2）FEE亚微乳和氟比洛芬溶液组的药动学过程符合二室模型，药时曲线和药动学参数无明显差异。组织分布研究表明，FEE亚微乳大鼠尾静脉注射后，其在肝、肺分布较多，在脑中含量最低。
急性毒性试验表明，口服微乳的LD50为514.4mg/kg，静脉注射亚微乳的LD50279.7mg/kg；安全性试验表明FEE亚微乳制剂体外不引起溶血，对家兔的耳缘静脉注射无刺激性。药效学实验结果表明：口服微乳或静脉注射亚微乳，对醋酸扭体和热板法所致小鼠疼痛的镇痛效果与参比制剂相当，对二甲苯所致的小鼠耳肿胀也有较好的抑制效果。
Naproxen and Flurbiprofen are typical drugs of aryl propionic acid non-steroidalanti-inflammatory drugs (NSAIDs), with anti-inflammatory, anagesic properties.However, some research have indicate that long-term oral administration ofNSAIDs may cause gastrointestinal adverse reactions, mainly gastrointestinal ulcersand arising therefrom gastrointestinal bleeding and gastric perforation.The use ofcarboxyl group structure in NSAIDs synthesizing prodrug is one of effective ways toreduce gastrointestinal toxic and side effects.
Eugenol is the main component of the clove volatile oil. In recent years, studiesshowed that eugenol have effects of antibiotic, analgesic and anesthetic, mainly usedfor dental caries, dental pulp analgesic clinically. Due to phenolic hydroxyl group inthe structure, it is easy oxidation metamorphism when contacting air for a long time.It is not esay to preserve and preparate drugs with the special smell. This article usednaproxen and flurbiprofen which have similar pharmacological activity and eugenolas the raw materials, and made them into prodrug with combination principle. Weexpect to find new prodrug through structure reform which can reduce NSAIDsgastrointestinal adverse reactions and improve the stability of eugenol.
This article synthesized two prodrugs firstly, and studied the physical andchemical properties and stability. On this basis we designed and prepared emulsion fororal administration and submicroemulsion for intravenous injection. Based on thevivo pharmacokinetics, tissue distribution and pharmacodynamic studies of thesedrugs, the purpose of the research is exploring new direction of structuremodification and preparations.
Using naproxen(or flurbiprofen)and eugenol as the raw materials, with oxalyl chloride(or thionyl chloride) as acylating agent, synthesized the prodrug of naproxeneugenol ester(NEE) and flurbiprofen eugenol ester(FEE) via acylation. The structureof NEE and FEE were confirmed by IR、MS and1H-NMR spectrum. HPLC methodwas established for assay of FEE and NEE. Preliminary stability and physical andchemical properties of the NEE and FEE were studied. The stability test showed thatNEE and FEE are relatively stable in the high temperature, high humidity andlight conditions. Solubility experiments demonstrate that NEE and FEE areundissolved in water. However, the solubility of FEE in short chain alcohol and oilphrase is better than the one of NEE. Using emulsion as the carrier, the drug hasto own certain solubility in the oil phase. Considering this problem, this articleselects FEE as imitate drug for preparation and pharmacokinetic studies. Stabilitystudy in different pH buffer indicated that FEE relatively stable in neutral andacidic conditions, but accelerated the hydrolysis rate in alkaline condition.
In order to improve the absorption of the drug and enhance thebioavailability, according to physical and chemical properties study, we selectedmicroemulsion as a drug carrier and prepared for oral administration. Referencetitration drawing pseudo-ternary phase diagrams, using the size of the O/Wmicroemulsion region as the main evaluation index, we investigated the effect ofdifferent factors such as oil phase, surfactants and co-surfactants. For themicroemulsions, Ethyl Oleate (EO) is chosen as oil phase, Cremophor EL asSurfactant, PEG-400as co-surfactant. The consist of optimize formulation wasEO：Cremophor EL：PEG-400：Water=5：20：10：65. We studied the physical andchemical properties of the emulsion: It is globular under TEM; The averageparticle size and distribution is26.74±5.52nm; Potential is-7.88±2.88mV;Conductivity is48.8μs/cm; Viscosity is59.7mPa s; Phase-transition temperature is72℃. The emulsion is unstable under the condition of high temperature.
At the same time, in order to expand different administration routes, to meetdifferent needs of patient to medicine, the FEE submicroemulsion which wasused by intravenous injection was obtained by passing the two-step homogenization method. Applying particle size, Zeta and stability coefficient Keas evaluation index, we studied the prescription and process optimization byorthogonal experiment design and signal factor studies. The best formulation was:the oil phase was20%soybean oil, the total amount of emulsifier was1.5%(soyabean lecithin:F68=3:1), the oleic acid was0.1%. we got the emulsionunder the condition8000rpm/min by high-speed shearing dispersion machine,8minutes. In high pressure homogenizer, the condition was12000psi,12times,sealed with nitrogen and sterilized. The particle size is220nm, potential is about-40mV. Stability tests showed that there was no signigicant changes of thepartical size and potential when the emulsion was diluted by saline or glucose.High temperature, illumination and low temperature stability experiment showedthe peparation should be stored away from light.
A HPLC method was established to determine flurbiprofen in plasma andtissue homogenate. Plasma and liver homogenate in vitro degradation kineticsexperiments show that, FEE have the condition to become a prodrug because itcan quickly convert to flurbiprofen. Take rats as test object, we studied thepharmacokinetic of FEE microemulsion for oral and FEE submicroemulsion forintravenous. We calculated pharmacokinetic parameters with pharmacokineticsoftware BAPP2.0, and compared with flurbiprofen suspension and injectionhomemade. The result show that:1The pharmacokinetic process of flurbiprofensuspension lavage conform to open one compartment model, and FEEmicroemulsion conform to open two compartment model; Using flurbiprofensuspension as the reference preparation, the studies showed that the Tmaxof FEEemulsion is later than flurbiprofen. AUC has distinguished difference.2FEEsubmicroemulsion and flurbiprofen solution conform to open two compartmentmodel, there is no significant difference of the curve and pharmacokineticparameters. The distribution study after intravenous administration indicated thatthis drug concentration in liver and lung, minimum in brain.
Acute toxicity results suggested that the LD50of FEE emulsion for oral is 514.4mg/kg, the LD50of FEE submicroemulsion for intravenous injection is279.7mg/kg. The pharmaceutical safety test results indicated that none of thenegative effects of FEE submicroemulsion preparation in vitro. There isnonirritant for rabbit intravenous injection. Pharmacodynamics experiments showthat the analgesic activity of this drug was the same as the contrast drug in miceutilizing hot plate method and acetic acid writhing analgesic method. In addition,it has good inhibitory effect for mice ear swelling caused by dimethylbenzene.
引文
[1] Singh G, Rosen RD. NSAID induced gastrointestinal complications: the ARAMISperspective-1997. Arthritis, Rheumatism, and Aging Medical InformationSystem[J]. J Rheumatol Suppl,1998,51:8-16.
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