氟苯尼考琥珀酸钠的合成及其在家兔体内药动学研究
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摘要
氟苯尼考(florfenicol)属于氯霉素类抗生素,氟苯尼考在结构上以F原子取代了氯霉素的-OH和以甲砜基(CH3SO2-)基团取代了氯霉素的硝基(-N02)基团。相对于氯霉素,其在达到比氯霉素更好的抗菌效果的同时不会引起再生性障碍贫血。然而,氟苯尼考水溶性极低,影响了其生物利用度。目前大多用有机溶剂、包合、固体分散体等方法来增加其溶解性,但有机溶剂刺激性和毒性较大,其它方法增溶效果差,都不能达到理想效果。因此,利用化学方法将氟苯尼考制成水溶性前药,具有良好的应用前景。
氟苯尼考分子中具有一个仲羟基,在碱性催化剂存在下,可以与羧基酸或酸酐发生酯化反应而得到氟苯尼考的前体药物。本研究利用氟苯尼考和琥珀酸酐反应合成得到氟苯尼考琥珀酸酯(Fl-S)及其钠盐,并利用单因素和正交试验筛选了最佳的Fl-S合成工艺流程,结果表明：以4-二甲氨基吡啶(DMAP)为催化剂,丙酮为溶剂,氟苯尼考：琥珀酸酐DMAP=1:1.2:1.2(摩尔比),温度为60℃,反应时间为8h的条件可以使Fl-S收率最高。利用碳酸氢钠溶液和盐酸可以达到纯化和结晶Fl-S的效果,利用冷冻干燥法可以制备出性状优良的Fl-S的钠盐Fl-SNa。
本研究合成的Fl-S,通过熔点仪及高效液相色谱仪(HPLC)分析,该化合物熔点为128.9-129.4℃,化合物纯度较高,氟苯尼考、Fl-S保留时间分别为7.850min和12.175min。紫外吸收光谱测定表明修饰物可能有苯环、-OH.-X及C=O存在；红外吸收光谱测定表明修饰物结构与氟苯尼考相似,但增加了羧酸羰基和酯羰基；通过强碱性条件的水解实验,Fl-S可以水解成氟苯尼考,综上确证了Fl-S合成的成功。
对氟苯尼考和Fl-SNa在25℃纯水的溶解度和脂水分配系数的测定结果表明：氟苯尼考溶解度为0.135±0.002g100mL,Fl-SNa为54.524±0.12g/100mL,Fl-SNa水溶性明显增大。氟苯尼考脂水分配系数为2.38,Fl-SNa为0.16。Fl-SNa溶血实验表明,当其浓度达到100mg/mL都没有发生溶血现象,证明其具有做成水溶性注射液或粉针制剂的潜力；通过对Fl-SNa粉末的高温(60℃)、高湿(90%±5%,75±5%)和强光(4500lx±500 lx)的影响因素实验,表明Fl-SNa受高温和强光影响较小,受高湿的影响极大,在75%的条件下5d就增重25.6%。
将Fl-SNa做成水溶液和常规氟苯尼考注射剂对健康家兔进行肌肉注射,以氟苯尼考为参照对象,进行药动学的比较。采用HPLC测定血浆药物浓度,血浆浓度最低检测限为0.1ug/mL,并以DAS2.0药动学程序分析药动学参数,用SPSS (17.0)分析所得数据。结果表明A、B组药时数据均符合一级吸收二室模型(权重=1/CC),主要药动学参数如下：A组：Ka为(1.483±0.031)1/h,T1／2α为(0.576±044)h,T1／2β为(2.501±0.203)h,AUC(0-∞)为(28.851±0.494)mg/L*h, Cmax为(8.863±0.254)mg/L,Tmax为(1±0.000h,其拟合方程为：C=73.69e-1.208t +5.592e-0.278t -79.282e-1.483t。B组：Ka为(0.703±0.084)1/h,T1/2α为(1.324±0.295)h,T1/2β为(1.475±0.168)h,AUC(0-·∞)为(39.187±0.413)mg/L*h, Cmax为(7.363±0.085)mg/L, Tmax为(2±0.000)h,拟合方程为：C=126.57e-0.539t +12.417e-0.474t -138.987e-0.703t。
本课题根据前药原理,将琥珀酸酐与氟苯尼考的羟基形成酯键,成功合成其前药氟苯尼考琥珀酸单酯(Fl-S),然后将Fl-S与碱性盐反应成水溶性极好的氟苯尼考琥珀酸钠(Fl-SNa)。初步研究了Fl-SNa的表征及Fl-SNa在家兔体内的药动学。本方法操作简单,产物收率较高,反应要求较低,适合工业化生产。
Florfenicol is an antibiotic of chloramphenicol, it has F and CH3SO2- to substitute with-OH and -NO2 of chloramphenicol. Therefore, Florfenicol shows better antibacterial effect than chloramphenicol and doesn't cause anaemia of regeneration barriers. However, the water solublility of florfenicol is very low and this has an impact on its bioavailability. There are currently organic solvent, inclusion, solid dispersion and other methods to increase its solubility, but can not achieve the desired effect. Therefore, to make water-soluble florfenicol prodrug by chemical methods shows a good prospect and will be the trend of such studies.
Florfenicol molecule has a p-hydroxyl group, in the presence of alkaline catalyst, could be esterified with carboxylic acid or anhydride. The best synthesis process of Fl-S was chosed by single factor and orthogonal test.The results showed that:4 dimethylaminopyridine (DMAP) as catalyst and acetone as the solvent, florfenicol: Succinic Anhydride:DMAP=1:1.2:1.2 (molar ratio), temperature:60℃, reaction time:8h conditions can make the highest synthesis rate of Fl-S. Use of bicarbonate sodium solution and hydrochloric acid can achieve the effect of purification and crystallizeation of Fl-S. Fl-SNa obtaining excellent characteristics can be prepared by freeze-drying.
In this study, the high purity of Fl-S was determined by the melting point apparatus and high performance liquid chromatography (HPLC) analysis. Retention time of florfenicol and Fl-S was 7.850min and 12.175min, respectively. UV absorption spectra showd that the modification of florfenicol may be phenyl, hydroxyl, chlorine group atom andcarbonyl; infrared absorption spectra showed that florfenicol and its modification had a similar structure, but the modification possessed carboxylic acid carbonyl and ester carbonyl; Fl-S can be hydrolyzed to florfenicol by strong alkaline hydrolysis. In summary, the successful synthesis of Fl-S could be confirmed.
Results of water solubility and partition coefficient florfelicol and Fl-SNa at 25℃: solubility of florfelicol was 0.135±0.002g/100mL, Fl-S-Na was 54.524±0.12g/100mL, solubility of Fl-SNa was greatly increased. Lipid-water partition coefficient of florfenicol was 2.38, Fl-S-Na was 0.16. Hemolysis experiments of Fl-SNa showed that there was no hemolysis when the concentration of Fl-SNa was achieved 10mg/mL. It was proved that their potential application in water-soluble injection or injection powder preparation for intramuscular or intravenous injection in animals. Factor experiments of high temperature (60℃), high humidity (90%±5%,75±5%) and strong light (4500lx±500lx) of Fl-SNa powder showed that Fl-SNa was greatly influenced by humidity, its weight was improved 25.6% after 5d under the conditions of 75% humidity.
The Fl-SNa solution and conventional florfenicol injection were administrated on health rabbits by intramuscular injection. Using florfenicol as a reference, their pharmaco-kinetic differences were compared. Plasma drug concentration was determined by HPLC, limit of detection of plasma concentrationwas O.lug/mL. Pharmacokinetic parameters were analyzed by DAS2.0 pharmacokinetic program. The data was analyzed by SPSS (17.0). The results showed that data of A, B group was in line with a two-compartment model (weight=1/CC), The main pharmacokinetic parameters and the fitting equation as follows: A group:Ka was (1.483±0.031) 1/h, T1/2αwas (0.576±0.044) h, T1/2βwas (2.501±0.203) h, AUC (0-∞) was (28.851±0.494) mg/L* h, Cmax was (8.863±0.254) mg/L, Tmax was (1±0.000) h, the fitting equation:C=73.69e-1.208t+5.592e-0.278t-79.282e-1.483t. B Group:Ka was (0.703±0.084) 1/h, T1/2αwas (1.324±0.295) h, T1/2βwas (1.475±0.168) h, AUC (0-∞) was (39.187±0.413) mg/L* h, Cmax was (7.363±0.085) mg/L, Tmax was (2±0.000) h, the fitting equation:C=126.57e-0.539t+12.417e-0.474t-138.987e-0.703t。
In summary, According to the principle of prodrug, this issue made succinic anhydride and hydroxyl of florfenicol to form ester, to synthesize its prodrug of florfenicol Succinate (Fl-S), Fl-S then reacted with alkaline salts to form the water-soluble florfenicol succinate sodium (Fl-SNa). Preliminary studies of characterization and pharmacokinetics in rabbits of Florfenicol and Fl-SNa were carried out. The method is simple, the yield is high, the reaction required less, and it is suitable for industrial production.
氟苯尼考分子中具有一个仲羟基,在碱性催化剂存在下,可以与羧基酸或酸酐发生酯化反应而得到氟苯尼考的前体药物。本研究利用氟苯尼考和琥珀酸酐反应合成得到氟苯尼考琥珀酸酯(Fl-S)及其钠盐,并利用单因素和正交试验筛选了最佳的Fl-S合成工艺流程,结果表明：以4-二甲氨基吡啶(DMAP)为催化剂,丙酮为溶剂,氟苯尼考：琥珀酸酐DMAP=1:1.2:1.2(摩尔比),温度为60℃,反应时间为8h的条件可以使Fl-S收率最高。利用碳酸氢钠溶液和盐酸可以达到纯化和结晶Fl-S的效果,利用冷冻干燥法可以制备出性状优良的Fl-S的钠盐Fl-SNa。
本研究合成的Fl-S,通过熔点仪及高效液相色谱仪(HPLC)分析,该化合物熔点为128.9-129.4℃,化合物纯度较高,氟苯尼考、Fl-S保留时间分别为7.850min和12.175min。紫外吸收光谱测定表明修饰物可能有苯环、-OH.-X及C=O存在；红外吸收光谱测定表明修饰物结构与氟苯尼考相似,但增加了羧酸羰基和酯羰基；通过强碱性条件的水解实验,Fl-S可以水解成氟苯尼考,综上确证了Fl-S合成的成功。
对氟苯尼考和Fl-SNa在25℃纯水的溶解度和脂水分配系数的测定结果表明：氟苯尼考溶解度为0.135±0.002g100mL,Fl-SNa为54.524±0.12g/100mL,Fl-SNa水溶性明显增大。氟苯尼考脂水分配系数为2.38,Fl-SNa为0.16。Fl-SNa溶血实验表明,当其浓度达到100mg/mL都没有发生溶血现象,证明其具有做成水溶性注射液或粉针制剂的潜力；通过对Fl-SNa粉末的高温(60℃)、高湿(90%±5%,75±5%)和强光(4500lx±500 lx)的影响因素实验,表明Fl-SNa受高温和强光影响较小,受高湿的影响极大,在75%的条件下5d就增重25.6%。
将Fl-SNa做成水溶液和常规氟苯尼考注射剂对健康家兔进行肌肉注射,以氟苯尼考为参照对象,进行药动学的比较。采用HPLC测定血浆药物浓度,血浆浓度最低检测限为0.1ug/mL,并以DAS2.0药动学程序分析药动学参数,用SPSS (17.0)分析所得数据。结果表明A、B组药时数据均符合一级吸收二室模型(权重=1/CC),主要药动学参数如下：A组：Ka为(1.483±0.031)1/h,T1／2α为(0.576±044)h,T1／2β为(2.501±0.203)h,AUC(0-∞)为(28.851±0.494)mg/L*h, Cmax为(8.863±0.254)mg/L,Tmax为(1±0.000h,其拟合方程为：C=73.69e-1.208t +5.592e-0.278t -79.282e-1.483t。B组：Ka为(0.703±0.084)1/h,T1/2α为(1.324±0.295)h,T1/2β为(1.475±0.168)h,AUC(0-·∞)为(39.187±0.413)mg/L*h, Cmax为(7.363±0.085)mg/L, Tmax为(2±0.000)h,拟合方程为：C=126.57e-0.539t +12.417e-0.474t -138.987e-0.703t。
本课题根据前药原理,将琥珀酸酐与氟苯尼考的羟基形成酯键,成功合成其前药氟苯尼考琥珀酸单酯(Fl-S),然后将Fl-S与碱性盐反应成水溶性极好的氟苯尼考琥珀酸钠(Fl-SNa)。初步研究了Fl-SNa的表征及Fl-SNa在家兔体内的药动学。本方法操作简单,产物收率较高,反应要求较低,适合工业化生产。
Florfenicol is an antibiotic of chloramphenicol, it has F and CH3SO2- to substitute with-OH and -NO2 of chloramphenicol. Therefore, Florfenicol shows better antibacterial effect than chloramphenicol and doesn't cause anaemia of regeneration barriers. However, the water solublility of florfenicol is very low and this has an impact on its bioavailability. There are currently organic solvent, inclusion, solid dispersion and other methods to increase its solubility, but can not achieve the desired effect. Therefore, to make water-soluble florfenicol prodrug by chemical methods shows a good prospect and will be the trend of such studies.
Florfenicol molecule has a p-hydroxyl group, in the presence of alkaline catalyst, could be esterified with carboxylic acid or anhydride. The best synthesis process of Fl-S was chosed by single factor and orthogonal test.The results showed that:4 dimethylaminopyridine (DMAP) as catalyst and acetone as the solvent, florfenicol: Succinic Anhydride:DMAP=1:1.2:1.2 (molar ratio), temperature:60℃, reaction time:8h conditions can make the highest synthesis rate of Fl-S. Use of bicarbonate sodium solution and hydrochloric acid can achieve the effect of purification and crystallizeation of Fl-S. Fl-SNa obtaining excellent characteristics can be prepared by freeze-drying.
In this study, the high purity of Fl-S was determined by the melting point apparatus and high performance liquid chromatography (HPLC) analysis. Retention time of florfenicol and Fl-S was 7.850min and 12.175min, respectively. UV absorption spectra showd that the modification of florfenicol may be phenyl, hydroxyl, chlorine group atom andcarbonyl; infrared absorption spectra showed that florfenicol and its modification had a similar structure, but the modification possessed carboxylic acid carbonyl and ester carbonyl; Fl-S can be hydrolyzed to florfenicol by strong alkaline hydrolysis. In summary, the successful synthesis of Fl-S could be confirmed.
Results of water solubility and partition coefficient florfelicol and Fl-SNa at 25℃: solubility of florfelicol was 0.135±0.002g/100mL, Fl-S-Na was 54.524±0.12g/100mL, solubility of Fl-SNa was greatly increased. Lipid-water partition coefficient of florfenicol was 2.38, Fl-S-Na was 0.16. Hemolysis experiments of Fl-SNa showed that there was no hemolysis when the concentration of Fl-SNa was achieved 10mg/mL. It was proved that their potential application in water-soluble injection or injection powder preparation for intramuscular or intravenous injection in animals. Factor experiments of high temperature (60℃), high humidity (90%±5%,75±5%) and strong light (4500lx±500lx) of Fl-SNa powder showed that Fl-SNa was greatly influenced by humidity, its weight was improved 25.6% after 5d under the conditions of 75% humidity.
The Fl-SNa solution and conventional florfenicol injection were administrated on health rabbits by intramuscular injection. Using florfenicol as a reference, their pharmaco-kinetic differences were compared. Plasma drug concentration was determined by HPLC, limit of detection of plasma concentrationwas O.lug/mL. Pharmacokinetic parameters were analyzed by DAS2.0 pharmacokinetic program. The data was analyzed by SPSS (17.0). The results showed that data of A, B group was in line with a two-compartment model (weight=1/CC), The main pharmacokinetic parameters and the fitting equation as follows: A group:Ka was (1.483±0.031) 1/h, T1/2αwas (0.576±0.044) h, T1/2βwas (2.501±0.203) h, AUC (0-∞) was (28.851±0.494) mg/L* h, Cmax was (8.863±0.254) mg/L, Tmax was (1±0.000) h, the fitting equation:C=73.69e-1.208t+5.592e-0.278t-79.282e-1.483t. B Group:Ka was (0.703±0.084) 1/h, T1/2αwas (1.324±0.295) h, T1/2βwas (1.475±0.168) h, AUC (0-∞) was (39.187±0.413) mg/L* h, Cmax was (7.363±0.085) mg/L, Tmax was (2±0.000) h, the fitting equation:C=126.57e-0.539t+12.417e-0.474t-138.987e-0.703t。
In summary, According to the principle of prodrug, this issue made succinic anhydride and hydroxyl of florfenicol to form ester, to synthesize its prodrug of florfenicol Succinate (Fl-S), Fl-S then reacted with alkaline salts to form the water-soluble florfenicol succinate sodium (Fl-SNa). Preliminary studies of characterization and pharmacokinetics in rabbits of Florfenicol and Fl-SNa were carried out. The method is simple, the yield is high, the reaction required less, and it is suitable for industrial production.
引文
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