两性霉素B微乳的制备工艺及体外经皮渗透研究
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摘要
目的为避免两性霉素B(AmB)溶解度差的缺点,减小注射给药引起的全身毒性,本文用十四酸异丙酯(IPM)、吐温80、异丙醇和蒸馏水制备了两性霉素B微乳经皮给药制剂。筛选出对两性霉素B具有较大增溶作用的微乳的制备方法,考查了pH值对微乳载药量、药物在微乳中分布和微乳透皮吸收效果的影响,确定了具有最大透皮速率的微乳处方。方法通过处方前研究,建立了两性霉素B的高效液相色谱分析方法,进行了两性霉素B原料药影响因素实验,测定了两性霉素B在水及系列磷酸盐缓冲液中的溶解度,测定了两性霉素B在正辛醇/水体系中的油水分配系数,筛选了两性霉素B透皮吸收的接受液。通过制备工艺研究,筛选了表面活性剂、油相和助表面活性剂的种类及比例。通过电导率、黏度测定确定了微乳的微观结构。筛选了对两性霉素B具有最大增溶量的载药方法,考查了空白微乳结构、pH值对微乳载药量的影响。通过电子透射电镜观察和药物含量测定推断了微乳对于两性霉素B的增溶部位及PIT(相转变温度)法的增溶机理。通过粒径及粒度分布和黏度测定对优化微乳进行了表征。通过离心实验、高温实验和加速实验对空白微乳和载药微乳的稳定性进行了考查。在体外经皮渗透实验中,研究了pH值、渗透促进剂对两性霉素B微乳透皮吸收效果的影响。最后,进行了制剂的皮肤刺激性实验。
结果建立的高效液相色谱分析方法符合分析学要求。两性霉素B原料药易受光照影响。两性霉素B在水中的溶解度为31.97μg/ml,为水难溶性药物,在缓冲液溶液中的溶解度具有pH依赖性。在正辛醇/水体系中表观油水分配系数为56.95,可推断两性霉素B是较理想的透皮给药模型药物。20 %乙醇-pH7.4的磷酸盐缓冲液被选作两性霉素B的透皮渗透接受液。以吐温80为表面活性剂、IPM为油相、异丙醇为助表面活性剂,当Km为1:1时,形成的微乳区域最大。电导测定结果表明当O/SC<2:8时,水的质量分数为55 %~70 %范围内形成的微乳为O/W型微乳。用PIT法将药物载入O/W型空白微乳中时,两性霉素B的增溶量最大,药物含量可达29.6 mg/10 ml。当pH值小于5.2或大于8.5时,微乳的载药量不会发生明显降低。PIT法通过提高药物的亲水性来提高微乳对两性霉素B的载药量,微乳对两性霉素B的增溶部位是在亲水液滴的表面。所测试的空白微乳和载药微乳均符合微乳的特性,在实验条件下均稳定。在两性霉素B微乳体外经皮渗透实验中,微乳A在pH5.14时透皮速率最快,被先为优化处方。氮酮是两性霉素B的优良渗透促进剂,增渗比可达5倍以上,优化处方中加入1%的氮酮,效果最好,渗透速率可提高1.4倍。两性霉素B微乳最优处方在家兔正常皮肤上无明显可见的刺激。
结论两性霉素B是较理想的透皮给药模型药物。使用PIT法,当空白微乳属于O/W型时,可获得最大的药物增溶量。调节pH值有助于药物由水相向微乳界面转移,当pH值为5.14时载药微乳稳定,且具有最大透皮速率。两性霉素B微乳经皮给药制剂的最优处方为Km=1:1、O/SC=1:9、水含量为64 %、氮酮1 %、载药量为2.96 mg/ml。
Objective In order to solve the drawback of poor solubility and infusion-related side effect for Amphotericin B (AmB), a microemulsion vehicle composed of isopropyl myristate (IPM), Tween80, isopropyl alcohol and distilled water for transdermal delivery was designed in this study. The purpose of this study was to explore a drug-loaded method with a powerful solubilization for AmB, and to find out the formula of microemulsion with the optimum skin permeability for AmB. The influence of pH value on content of drug-loaded, distribution of AmB in microemulsion and permeability of AmB microemulsion was investigated.
Method During the preformulation study, the analytical method of high performance liquid chromatogram (HPLC) for AmB was established. The influential factor experiment of crude drug of AmB was carried out. The solubilities of AmB in distilled water and a series of phosphate buffers and the oil/water partition coefficients in n-octyl alcohol/water were determined, and the receptor mediums of percutaneous experiment for AmB were screened. During the preparation technology study, the types and proportions of surfactant, oil phase and cosurfactant were screened. The microstructure of microemulsions was identified by determining the conductivity and viscosity. Three different kind methods were tested to incorporate AmB into the microemulsion. The effects of structure of blank microemulsion and pH value on the drug quantity loaded in microemulsion were investigated. The solubilizing position of AmB in microemulsion and solubilizing mechanism of PIT (Phase Inversion Temperature) method were determined. The optimized formulation was characterized in terms of pH, viscosity, droplets dimensional distribution and mean droplet size. The stability of blank and drug loaded microemulsions was investigated by the centrifugalization test, high temperature test and accelerated test. During the vitro percutaneous permeation test, the effects of pH values and permeation enhancers on permeation rate were studied. Finally, the skin irritation test was carried out.
Results The established HPLC method for AmB corresponded with the standards of analytics. The crude drug of AmB was easily influenced by the illumination. The solubility of AmB in water was 31.97μg/ml, which is a poor water soluble drug. The solubilities of AmB in buffer solutions depended on pH values. The oil/water partition coefficient in n-octyl alcohol/water was 56.95, which demonstrated that AmB possibly is an ideal model drug of cutaneous penetration. The receptor medium for AmB was selected as 20 % ethanol-pH7.4 buffer phosphate. Tween80, IPM and isopropyl alcohol were selected as surfactant, oil phase and cosurfactant respectively. At Km=1:1, O/SC<2:8 andФw with in the range of 55%~70%, the type of microemulsion determined by conductivity was O/W. The incorporation of AmB to the O/W microemulsion following the PIT method resulted in the maximum solubilization for AmB, and the content of AmB can attain 29.6 mg/10 ml. When the pH value was less than 5.2 or larger than 8.5, the drug quantity loaded in microemulsion had no obvious decrease. The strong solubilization for AmB based on PIT method can result in the increasing of hydrophilicity of AmB. The solubilized position of microemulsion for AmB was in the hydrophilic shell of the microemulsion droplets. Microemulsion A0 and A corresponded to the characteristics of microemulsion and were stable in the experiment conditions. During the vitro percutaneous permeation test, microemulsion M3 with appropriate pH (5.14) for skin showed the best percutaneous ability and was selected as optimized formula. The water-soluble azone was the good permeation enhancer for AmB and its anatonosis ratio was 5.167. The optimum percent of water-soluble azone in the optimized formula was 1%, which can increase the permeation rate of microemulsion M3 by 1.4 times. The optimal formula had no obvious visible stimulus on the normal skins of rabbits.
Conclusion AmB possibly is an ideal model drug of cutaneous penetration. The incorporation of AmB to the O/W microemulsion following the PIT method resulted in the maximum solubilization for AmB. The adjustment of pH forced AmB converting from aqueous phase to the hydrophilic shell of the microemulsion droplets. At pH 5.14, optimized AmB microemulsion was stable in the condition of experiment, and exhibited the maxium permeation rate. The optimal formula for transdermal drug delivery of Amphotericin B was that Km-1:1, O/SC-1:9, aqueous phase-64%, water-soluble azone-1% and content of AmB-2.96 mg/ml.
结果建立的高效液相色谱分析方法符合分析学要求。两性霉素B原料药易受光照影响。两性霉素B在水中的溶解度为31.97μg/ml,为水难溶性药物,在缓冲液溶液中的溶解度具有pH依赖性。在正辛醇/水体系中表观油水分配系数为56.95,可推断两性霉素B是较理想的透皮给药模型药物。20 %乙醇-pH7.4的磷酸盐缓冲液被选作两性霉素B的透皮渗透接受液。以吐温80为表面活性剂、IPM为油相、异丙醇为助表面活性剂,当Km为1:1时,形成的微乳区域最大。电导测定结果表明当O/SC<2:8时,水的质量分数为55 %~70 %范围内形成的微乳为O/W型微乳。用PIT法将药物载入O/W型空白微乳中时,两性霉素B的增溶量最大,药物含量可达29.6 mg/10 ml。当pH值小于5.2或大于8.5时,微乳的载药量不会发生明显降低。PIT法通过提高药物的亲水性来提高微乳对两性霉素B的载药量,微乳对两性霉素B的增溶部位是在亲水液滴的表面。所测试的空白微乳和载药微乳均符合微乳的特性,在实验条件下均稳定。在两性霉素B微乳体外经皮渗透实验中,微乳A在pH5.14时透皮速率最快,被先为优化处方。氮酮是两性霉素B的优良渗透促进剂,增渗比可达5倍以上,优化处方中加入1%的氮酮,效果最好,渗透速率可提高1.4倍。两性霉素B微乳最优处方在家兔正常皮肤上无明显可见的刺激。
结论两性霉素B是较理想的透皮给药模型药物。使用PIT法,当空白微乳属于O/W型时,可获得最大的药物增溶量。调节pH值有助于药物由水相向微乳界面转移,当pH值为5.14时载药微乳稳定,且具有最大透皮速率。两性霉素B微乳经皮给药制剂的最优处方为Km=1:1、O/SC=1:9、水含量为64 %、氮酮1 %、载药量为2.96 mg/ml。
Objective In order to solve the drawback of poor solubility and infusion-related side effect for Amphotericin B (AmB), a microemulsion vehicle composed of isopropyl myristate (IPM), Tween80, isopropyl alcohol and distilled water for transdermal delivery was designed in this study. The purpose of this study was to explore a drug-loaded method with a powerful solubilization for AmB, and to find out the formula of microemulsion with the optimum skin permeability for AmB. The influence of pH value on content of drug-loaded, distribution of AmB in microemulsion and permeability of AmB microemulsion was investigated.
Method During the preformulation study, the analytical method of high performance liquid chromatogram (HPLC) for AmB was established. The influential factor experiment of crude drug of AmB was carried out. The solubilities of AmB in distilled water and a series of phosphate buffers and the oil/water partition coefficients in n-octyl alcohol/water were determined, and the receptor mediums of percutaneous experiment for AmB were screened. During the preparation technology study, the types and proportions of surfactant, oil phase and cosurfactant were screened. The microstructure of microemulsions was identified by determining the conductivity and viscosity. Three different kind methods were tested to incorporate AmB into the microemulsion. The effects of structure of blank microemulsion and pH value on the drug quantity loaded in microemulsion were investigated. The solubilizing position of AmB in microemulsion and solubilizing mechanism of PIT (Phase Inversion Temperature) method were determined. The optimized formulation was characterized in terms of pH, viscosity, droplets dimensional distribution and mean droplet size. The stability of blank and drug loaded microemulsions was investigated by the centrifugalization test, high temperature test and accelerated test. During the vitro percutaneous permeation test, the effects of pH values and permeation enhancers on permeation rate were studied. Finally, the skin irritation test was carried out.
Results The established HPLC method for AmB corresponded with the standards of analytics. The crude drug of AmB was easily influenced by the illumination. The solubility of AmB in water was 31.97μg/ml, which is a poor water soluble drug. The solubilities of AmB in buffer solutions depended on pH values. The oil/water partition coefficient in n-octyl alcohol/water was 56.95, which demonstrated that AmB possibly is an ideal model drug of cutaneous penetration. The receptor medium for AmB was selected as 20 % ethanol-pH7.4 buffer phosphate. Tween80, IPM and isopropyl alcohol were selected as surfactant, oil phase and cosurfactant respectively. At Km=1:1, O/SC<2:8 andФw with in the range of 55%~70%, the type of microemulsion determined by conductivity was O/W. The incorporation of AmB to the O/W microemulsion following the PIT method resulted in the maximum solubilization for AmB, and the content of AmB can attain 29.6 mg/10 ml. When the pH value was less than 5.2 or larger than 8.5, the drug quantity loaded in microemulsion had no obvious decrease. The strong solubilization for AmB based on PIT method can result in the increasing of hydrophilicity of AmB. The solubilized position of microemulsion for AmB was in the hydrophilic shell of the microemulsion droplets. Microemulsion A0 and A corresponded to the characteristics of microemulsion and were stable in the experiment conditions. During the vitro percutaneous permeation test, microemulsion M3 with appropriate pH (5.14) for skin showed the best percutaneous ability and was selected as optimized formula. The water-soluble azone was the good permeation enhancer for AmB and its anatonosis ratio was 5.167. The optimum percent of water-soluble azone in the optimized formula was 1%, which can increase the permeation rate of microemulsion M3 by 1.4 times. The optimal formula had no obvious visible stimulus on the normal skins of rabbits.
Conclusion AmB possibly is an ideal model drug of cutaneous penetration. The incorporation of AmB to the O/W microemulsion following the PIT method resulted in the maximum solubilization for AmB. The adjustment of pH forced AmB converting from aqueous phase to the hydrophilic shell of the microemulsion droplets. At pH 5.14, optimized AmB microemulsion was stable in the condition of experiment, and exhibited the maxium permeation rate. The optimal formula for transdermal drug delivery of Amphotericin B was that Km-1:1, O/SC-1:9, aqueous phase-64%, water-soluble azone-1% and content of AmB-2.96 mg/ml.
引文
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[1] Marco Antonio Moreno, Paloma Frutos, M Paloma Ballesteros. Lyophilized lecithin based oil-water microemulsions as a new and low toxic delivery system for Amphotericin B[J]. Pharmaceutical Research, 2001,18(3):344~351.
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[1] Marco Antonio Moreno, Paloma Frutos, M Paloma Ballesteros. Lyophilized lecithin based oil-water microemulsions as a new and low toxic delivery system for Amphotericin B[J]. Pharmaceutical Research, 2001,18(3):344~351.
[2]何蕾,王桂玲,张强.紫杉醇纳米乳剂的体内外考察[J].药学学报, 2003, 38(3): 67~70.
[3] Kemben H. Influence of supersaturation on the pharmacodynamic effect of bupranoloe after dermal administration using microemulsion as vehicel. Pharm Res, 1992, 9: 554.
[4] Sintov AC, Shapiro L. New microemulsion vehicel facilitates percutaneous penetration in vitro and cutaneous drug bioavailability in vivo. J Control Release, 2004, 95: 173.
[5] Lee PJ, Langer R, Shastri VP. Novel microemulsion enhancer formulation for simultaneous transdermal delivery of hydrophilic and hydrophobic drugs. Pharm Res, 2003, 20(2): 264~269.
[6] Kriwet K, Mrller-Goymann CC. Diclofenac release from phospholipid drug systems and permeation through excised human stratum corneum. Int J Pharm, 1995, 125: 231.
[7] Kantaria S, Rees GD, Lawrence MJ. Gelatin-stabilised microemulsion-based organogels: rheology and application in iontophoretic transdermal drug delivery. J Control Release, 1999, 60: 355.
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