体温敏感吲达帕胺缓释脂质体凝胶剂的研究
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摘要
吲达帕胺为疗效可靠、副作用小的利尿降压药物，用于治疗轻度或中度的高血压。高血压患者通常需要长期用药，以缓解症状。吲达帕胺主要为口服制剂，为了减少用药次数，提高高血压患者的顺应性。本课题提出将它修饰成它的前体药物月桂酰吲达帕胺后，包封入脂质体中，再制成体温敏感脂质体凝胶剂，肌注以达到在机体内长时间缓慢释放吲达帕胺的目的。根据这一目标，本论文从各个方面进行了实验。
吲达帕胺为一亲脂性较强的难溶于水的药物，却很难包封进脂质体中，在脂质体中包封率极低，为了把它包封进脂质体，本文采取在它的游离的氨基上接上一长的脂肪碳链修饰成月桂酰吲达帕胺。合成的药物经过硅胶柱分离纯化后，用傅立叶红外(FTIR)光谱、核磁共振氢谱(~1H-NMR)及紫外分光光谱(UV)对它的结构进行了确证。
用一定比例的丙酮／水混合溶液为溶剂溶解药物后，测定了不同比例的丙酮／水混合溶液中不同浓度的月桂酰吲达帕胺的电离常数pKa，采取外推法求出了纯水中药物浓度无限稀释时的pKa值即为药物的特征pKa值。并用摇瓶法测定了药物的脂／水(正丁醇／水，25℃)分配系数。结果发现药物的pKa值为3.87，1gP值为2.588，证明药物为一亲脂性的弱酸。采取丙酮／缓冲溶液(9∶1，v／v)做溶剂测定了药物在不同pH值条件下的降解速度常数，结果发现药物月桂酰吲达帕胺在pH6.8时最稳定，混合溶液溶解的游离药物和包进脂质体中的药物在不同pH值条件下的降解速度之间存在良好的线性相关性。
月桂酰吲达帕胺为强亲脂性的药物，用乙醇注入法包封药物时，包封率却极低，但在分散介质中加入少量的二价、三价或更高价的阳离子能让药物在脂质体中包封率达到很高的水平(至90％)。经过~1H-~(15)N异核多重键相关谱(HMBC)和~(15)N-NMR谱及~1H-NMR谱证明，二价的阳离子Ca~(2+)能消除溶剂分子对药物分子的吸附，从而消除药物分子和溶剂分子之间形成的氢键。同时药物分子中月桂酰基连接的N上的氢为钙离子所取代，两者的协同作用促进了药物脂质体的包封。
采取冷法制备了体温敏感凝胶，并分别考察了各个不同因素对凝胶胶凝温度的影响，结果发现体温敏感凝胶中PF127的浓度越高凝胶的胶凝温度越低，其他辅料如PF68和PEG则能提高凝胶的胶凝温度，氯化钠和Tris缓冲盐等则能降低凝胶的胶凝温度。在体温敏感凝胶的基础上制成的月桂酰吲达帕胺脂质体凝胶剂，同样具有反相胶凝的性质。体温敏感脂质体凝胶胶凝时脂质体以包埋的形式存在于凝胶中，胶凝对脂质体粒径仅有轻微的改变，而对药物的包封率基本不影响。
采取无膜释放模型研究了体温敏感脂质体凝胶中药物的释放行为，发现药物是以脂质体的形式从脂质体凝胶中释放出来，并且脂质体粒径及它对药物的包封率中几乎不变，用透射电镜(TEM)能观察到脂质体的完整形态。药物的释放与脂质体凝胶的溶蚀均遵循零级动力学，并且前者受后者的控制，两者之间存在着良好的线性相关性，它们都受到搅拌桨的搅拌速度及距溶出杯底部的高度，释放面积，释放介质的种类，渗透压及脂质体凝胶的处方组成等的影响。脂质体凝胶表面边界层的厚度及脂质体通过边界层的传质系数是决定脂质体凝胶溶蚀和药物释放速度的重要因素。
用自由扩散模型研究了药物月桂酰吲达帕胺在凝胶中的扩散行为。同时监测了各个凝胶片层中药物和磷脂的浓度，发现各凝胶片层中药物和磷脂的摩尔比接近脂质体的药／脂比，推论药物总是以脂质体的形式在凝胶中扩散，且遵循Fick扩散定律，同时发现脂质体膜柔韧性越大扩散越快，粒径越小扩散越快。含药脂质体在凝胶中的扩散速度随着凝胶中水性通道的增加而加快，而随着水性通道的曲折程度和脂质体凝胶粘度的增加而减慢。
将月桂酰吲达帕胺脂质体和大鼠血液在37℃恒温水浴上培养，结果发现月桂酰吲达帕胺几乎能定量降解为其母体药物吲达帕胺，转化率在90％以上，而且月桂酰吲达帕胺降解百分率和吲达帕胺的生成百分率之间存在良好的线性相关性。
大鼠肌肉注射体温敏感月桂酰吲达帕胺脂质体凝胶剂后，在大鼠体内能同时监测到吲达帕胺和月桂酰吲达帕胺，它们的消除半衰期分别为15.298h和21.19h，相对于单纯的月桂酰吲达帕胺脂质体大鼠肌肉注射而言，它们的半衰期分别延长3.37倍和4.48倍，达峰时间分别延长了8.94和7.09倍，AUC也分别增大近7.95倍和6.58倍，并且能持续192h缓慢释放月桂酰吲达帕胺和吲达帕胺。
体温敏感月桂酰吲达帕胺脂质体凝胶剂主要通过脂质体凝胶在肌肉组织体液中缓慢地溶蚀而释放脂质体，释放出来的脂质体进入血液中并迅速破坏，释放包封的药物，药物在血液中断链降解为母体药物吲达帕胺。通过上面的实验，总体看来体温敏感月桂酰吲达帕胺脂质体凝胶剂在机体内能按预期的目标缓慢地释放吲达帕胺，以达到长效利尿降压的目的。
Indapamide is an effective antihypertensive diuretic agent with little side effect, mainly used to treat mild or moderate hypertension. The patient often need long time administration of drug to relieve the symptoms. Currently, Indapamide is only available in its oral dosage form. In order to reduce the frequency of its administration, we brought forward liposomal encapsulation of lauroyl-indapamide, the prodrug of indapamide, which was then incorporated into temperature-sensitive hydrogel to obtain a long-term sustained release of indapamide after its i.m. administration. According to this aim, a series of experiments were conducted.Indapamide is a water-insoluble highly lipophilic drug, which is difficult to be encapsulated into liposomes with its entrapment efficiency much lower. In order to encapsulate it into liposomes, a modified indapamide substituted at the free amino with a long carbonic chain, lauroyl-indapamide, was synthesized, whose structure was confirmed by FTIR, ~1H-NMR and UV after its purification with silica column.The pKa values of lauroyl-indapamide at different concentrations were determined when lauroyl-indapamide were dissolved in a mixed acetone/buffer solutions at different ratios, they were then extrapolated to obtain the characteristic pKa. value of the drug at extremely diluted concentration in purified water. The w/o partition coefficient of lauroyl-indapamide between butyl alcohol and water was determined with bottle shaking method. The results proved that the pKa value is 3.87 and lgP is 2.588 respectively, which demonstrate that the drug is a lipophilic weak acid. The degradation kinetic parameters of drug in mixture of acetone/buffer solution (9:1, v/v) at different pH were determined, and the results proved that lauroyl-indapamide is most stable at pH6.8, and a good correlation of the degradation rates of free drug and that encapsulated in liposomes was showed.Lauroyl-indapamide is a highly lipophilic drug, but showed much lower entrapment efficiency in liposomes when prepared with ethanol injection method, only in the presence of divalent, trivalent or higher valent cations can it be encapsulated in liposomes, and obtained a much higher entrapment efficiency (more than 90%). It was demonstrated by ~(15)N-NMR, ~1H-NMR and ~1H-~(15)N-NMR(HMBC) that Ca~(2+) can eliminate the adsorption of solvent molecule on drug molecule and the hydrogen bond between them. The hydrogen at the N linked with lauroyl group substituted by Ca~(2+) may also favor the liposomal encapsulation of drug lauroyl-indapamide.The temperature-sensitive hydrogel was prepared with cold method, and the factors that may influence the gel temperature have been explored, and proved that gel temperature decreased with the concentration of PF127 increased, and the addition of PF68 and PEG could increase the gel temperature, while the addition of sodium chloride and Tris buffer solution showed an opposite effect. Based on the formulation of temperature-sensitive hydrogel, a liposomal lauroyl-indapamide hydrogel was prepared, which also showed reversible gel properties, and the liposomal lauroyl-indapamide was imbedded in the semisolid gel when its temperature rose, and the gel process has little influence on the liposomes size and entrapment efficiency of drug.The membraneless-dissolution model was used to explore the release behavior of drug in dissolution apparatus, and the results proved that the drug was released in liposome rather than in free form from the liposomal hydrogel with its size and entrapment efficiency of drug changing little, and the morphologies of liposomes have also been observed under Transmission Electronic Micrograph (TEM). Both drug release and liposomal hydrogel dissolution rates were followed zero-order kinetics, the later controlled the former and a good correlation between them was showed. Both drug release and liposomal hydrogel dissolution rate were influenced by such as the stirring speed and the height from the bottom of vessel of the stirring peddles, release area, sort of buffer solution, osmotic pressure and composition of the formulation and so on. The boundary layer thickness and mass transfer coefficient of liposomes across this boundary layer were the determinants that controlled the liposomal hydrogel dissolution and drug release.
The diffusion of drug in the gel was measure by a free-diffusion model, and found that the drug is always diffused, following a Fickian law, in liposome rather than in free form in the hydrogel, which was demonstrated by the near constant molar ratios of drug to lipid in each gel slice. And also found the more flexible the liposomal membrane was, the faster the drug diffused, the smaller the liposome was the fast the drug diffused. The drug diffused fast with water channel increased in the liposomal hydrogel, while the diffusivity decreased when the polymer concentration was increased, due to the distorted aqueous channels and higher microviscosity.
The results of liposomal lauroyl-indapamide incubated with rat blood at 37℃proved that lauroyl-indapamide degraded into indapamide almost quantitatively (more than 90%), and the correlation between the percentage of lauroyl-indapamide degraded and that of indapamide produced showed a good linearity.
The concentrations of lauroyl-indapamide and indapamide afterⅰ.m. administration of the temperature-sensitive liposomal lauroyl-indapamide hydrogel can be followed simultaneous, and found that their half-lives were 15.298h and 21.19h respectively, compared withⅰ.m. administration of liposomal lauroyl-indapamide, their half-lives were extended 3.37 times and 4.49 times, and their peak times were extended 8.94 times and 7.09 times, their AUC(area under the curve) were increased 7.95 times and 6.58 times respectively, and the formulation can sustained-release lauroyl-indapamide and indapamide for 192h.
Temperature-sensitive liposomal lauroyl-indapamide hydrogel can sustained-release liposomes mainly through the slowly dissolution of the liposomal hydrogel by biological fluids in muscle, the released liposomes then quickly enter blood stream where they are not stable and disrupted, and followed by the release of lauroyl-indapamide that they contained, which is then experienced chain broken and degraded into its parent drug indapamide in blood.
The overall result is that the temperature-sensitive liposomal lauroyl-indapamide hydrogel can release indapamide in a sustained manner to exert its long-term antihypertensive diuretic activity.
吲达帕胺为一亲脂性较强的难溶于水的药物，却很难包封进脂质体中，在脂质体中包封率极低，为了把它包封进脂质体，本文采取在它的游离的氨基上接上一长的脂肪碳链修饰成月桂酰吲达帕胺。合成的药物经过硅胶柱分离纯化后，用傅立叶红外(FTIR)光谱、核磁共振氢谱(~1H-NMR)及紫外分光光谱(UV)对它的结构进行了确证。
用一定比例的丙酮／水混合溶液为溶剂溶解药物后，测定了不同比例的丙酮／水混合溶液中不同浓度的月桂酰吲达帕胺的电离常数pKa，采取外推法求出了纯水中药物浓度无限稀释时的pKa值即为药物的特征pKa值。并用摇瓶法测定了药物的脂／水(正丁醇／水，25℃)分配系数。结果发现药物的pKa值为3.87，1gP值为2.588，证明药物为一亲脂性的弱酸。采取丙酮／缓冲溶液(9∶1，v／v)做溶剂测定了药物在不同pH值条件下的降解速度常数，结果发现药物月桂酰吲达帕胺在pH6.8时最稳定，混合溶液溶解的游离药物和包进脂质体中的药物在不同pH值条件下的降解速度之间存在良好的线性相关性。
月桂酰吲达帕胺为强亲脂性的药物，用乙醇注入法包封药物时，包封率却极低，但在分散介质中加入少量的二价、三价或更高价的阳离子能让药物在脂质体中包封率达到很高的水平(至90％)。经过~1H-~(15)N异核多重键相关谱(HMBC)和~(15)N-NMR谱及~1H-NMR谱证明，二价的阳离子Ca~(2+)能消除溶剂分子对药物分子的吸附，从而消除药物分子和溶剂分子之间形成的氢键。同时药物分子中月桂酰基连接的N上的氢为钙离子所取代，两者的协同作用促进了药物脂质体的包封。
采取冷法制备了体温敏感凝胶，并分别考察了各个不同因素对凝胶胶凝温度的影响，结果发现体温敏感凝胶中PF127的浓度越高凝胶的胶凝温度越低，其他辅料如PF68和PEG则能提高凝胶的胶凝温度，氯化钠和Tris缓冲盐等则能降低凝胶的胶凝温度。在体温敏感凝胶的基础上制成的月桂酰吲达帕胺脂质体凝胶剂，同样具有反相胶凝的性质。体温敏感脂质体凝胶胶凝时脂质体以包埋的形式存在于凝胶中，胶凝对脂质体粒径仅有轻微的改变，而对药物的包封率基本不影响。
采取无膜释放模型研究了体温敏感脂质体凝胶中药物的释放行为，发现药物是以脂质体的形式从脂质体凝胶中释放出来，并且脂质体粒径及它对药物的包封率中几乎不变，用透射电镜(TEM)能观察到脂质体的完整形态。药物的释放与脂质体凝胶的溶蚀均遵循零级动力学，并且前者受后者的控制，两者之间存在着良好的线性相关性，它们都受到搅拌桨的搅拌速度及距溶出杯底部的高度，释放面积，释放介质的种类，渗透压及脂质体凝胶的处方组成等的影响。脂质体凝胶表面边界层的厚度及脂质体通过边界层的传质系数是决定脂质体凝胶溶蚀和药物释放速度的重要因素。
用自由扩散模型研究了药物月桂酰吲达帕胺在凝胶中的扩散行为。同时监测了各个凝胶片层中药物和磷脂的浓度，发现各凝胶片层中药物和磷脂的摩尔比接近脂质体的药／脂比，推论药物总是以脂质体的形式在凝胶中扩散，且遵循Fick扩散定律，同时发现脂质体膜柔韧性越大扩散越快，粒径越小扩散越快。含药脂质体在凝胶中的扩散速度随着凝胶中水性通道的增加而加快，而随着水性通道的曲折程度和脂质体凝胶粘度的增加而减慢。
将月桂酰吲达帕胺脂质体和大鼠血液在37℃恒温水浴上培养，结果发现月桂酰吲达帕胺几乎能定量降解为其母体药物吲达帕胺，转化率在90％以上，而且月桂酰吲达帕胺降解百分率和吲达帕胺的生成百分率之间存在良好的线性相关性。
大鼠肌肉注射体温敏感月桂酰吲达帕胺脂质体凝胶剂后，在大鼠体内能同时监测到吲达帕胺和月桂酰吲达帕胺，它们的消除半衰期分别为15.298h和21.19h，相对于单纯的月桂酰吲达帕胺脂质体大鼠肌肉注射而言，它们的半衰期分别延长3.37倍和4.48倍，达峰时间分别延长了8.94和7.09倍，AUC也分别增大近7.95倍和6.58倍，并且能持续192h缓慢释放月桂酰吲达帕胺和吲达帕胺。
体温敏感月桂酰吲达帕胺脂质体凝胶剂主要通过脂质体凝胶在肌肉组织体液中缓慢地溶蚀而释放脂质体，释放出来的脂质体进入血液中并迅速破坏，释放包封的药物，药物在血液中断链降解为母体药物吲达帕胺。通过上面的实验，总体看来体温敏感月桂酰吲达帕胺脂质体凝胶剂在机体内能按预期的目标缓慢地释放吲达帕胺，以达到长效利尿降压的目的。
Indapamide is an effective antihypertensive diuretic agent with little side effect, mainly used to treat mild or moderate hypertension. The patient often need long time administration of drug to relieve the symptoms. Currently, Indapamide is only available in its oral dosage form. In order to reduce the frequency of its administration, we brought forward liposomal encapsulation of lauroyl-indapamide, the prodrug of indapamide, which was then incorporated into temperature-sensitive hydrogel to obtain a long-term sustained release of indapamide after its i.m. administration. According to this aim, a series of experiments were conducted.Indapamide is a water-insoluble highly lipophilic drug, which is difficult to be encapsulated into liposomes with its entrapment efficiency much lower. In order to encapsulate it into liposomes, a modified indapamide substituted at the free amino with a long carbonic chain, lauroyl-indapamide, was synthesized, whose structure was confirmed by FTIR, ~1H-NMR and UV after its purification with silica column.The pKa values of lauroyl-indapamide at different concentrations were determined when lauroyl-indapamide were dissolved in a mixed acetone/buffer solutions at different ratios, they were then extrapolated to obtain the characteristic pKa. value of the drug at extremely diluted concentration in purified water. The w/o partition coefficient of lauroyl-indapamide between butyl alcohol and water was determined with bottle shaking method. The results proved that the pKa value is 3.87 and lgP is 2.588 respectively, which demonstrate that the drug is a lipophilic weak acid. The degradation kinetic parameters of drug in mixture of acetone/buffer solution (9:1, v/v) at different pH were determined, and the results proved that lauroyl-indapamide is most stable at pH6.8, and a good correlation of the degradation rates of free drug and that encapsulated in liposomes was showed.Lauroyl-indapamide is a highly lipophilic drug, but showed much lower entrapment efficiency in liposomes when prepared with ethanol injection method, only in the presence of divalent, trivalent or higher valent cations can it be encapsulated in liposomes, and obtained a much higher entrapment efficiency (more than 90%). It was demonstrated by ~(15)N-NMR, ~1H-NMR and ~1H-~(15)N-NMR(HMBC) that Ca~(2+) can eliminate the adsorption of solvent molecule on drug molecule and the hydrogen bond between them. The hydrogen at the N linked with lauroyl group substituted by Ca~(2+) may also favor the liposomal encapsulation of drug lauroyl-indapamide.The temperature-sensitive hydrogel was prepared with cold method, and the factors that may influence the gel temperature have been explored, and proved that gel temperature decreased with the concentration of PF127 increased, and the addition of PF68 and PEG could increase the gel temperature, while the addition of sodium chloride and Tris buffer solution showed an opposite effect. Based on the formulation of temperature-sensitive hydrogel, a liposomal lauroyl-indapamide hydrogel was prepared, which also showed reversible gel properties, and the liposomal lauroyl-indapamide was imbedded in the semisolid gel when its temperature rose, and the gel process has little influence on the liposomes size and entrapment efficiency of drug.The membraneless-dissolution model was used to explore the release behavior of drug in dissolution apparatus, and the results proved that the drug was released in liposome rather than in free form from the liposomal hydrogel with its size and entrapment efficiency of drug changing little, and the morphologies of liposomes have also been observed under Transmission Electronic Micrograph (TEM). Both drug release and liposomal hydrogel dissolution rates were followed zero-order kinetics, the later controlled the former and a good correlation between them was showed. Both drug release and liposomal hydrogel dissolution rate were influenced by such as the stirring speed and the height from the bottom of vessel of the stirring peddles, release area, sort of buffer solution, osmotic pressure and composition of the formulation and so on. The boundary layer thickness and mass transfer coefficient of liposomes across this boundary layer were the determinants that controlled the liposomal hydrogel dissolution and drug release.
The diffusion of drug in the gel was measure by a free-diffusion model, and found that the drug is always diffused, following a Fickian law, in liposome rather than in free form in the hydrogel, which was demonstrated by the near constant molar ratios of drug to lipid in each gel slice. And also found the more flexible the liposomal membrane was, the faster the drug diffused, the smaller the liposome was the fast the drug diffused. The drug diffused fast with water channel increased in the liposomal hydrogel, while the diffusivity decreased when the polymer concentration was increased, due to the distorted aqueous channels and higher microviscosity.
The results of liposomal lauroyl-indapamide incubated with rat blood at 37℃proved that lauroyl-indapamide degraded into indapamide almost quantitatively (more than 90%), and the correlation between the percentage of lauroyl-indapamide degraded and that of indapamide produced showed a good linearity.
The concentrations of lauroyl-indapamide and indapamide afterⅰ.m. administration of the temperature-sensitive liposomal lauroyl-indapamide hydrogel can be followed simultaneous, and found that their half-lives were 15.298h and 21.19h respectively, compared withⅰ.m. administration of liposomal lauroyl-indapamide, their half-lives were extended 3.37 times and 4.49 times, and their peak times were extended 8.94 times and 7.09 times, their AUC(area under the curve) were increased 7.95 times and 6.58 times respectively, and the formulation can sustained-release lauroyl-indapamide and indapamide for 192h.
Temperature-sensitive liposomal lauroyl-indapamide hydrogel can sustained-release liposomes mainly through the slowly dissolution of the liposomal hydrogel by biological fluids in muscle, the released liposomes then quickly enter blood stream where they are not stable and disrupted, and followed by the release of lauroyl-indapamide that they contained, which is then experienced chain broken and degraded into its parent drug indapamide in blood.
The overall result is that the temperature-sensitive liposomal lauroyl-indapamide hydrogel can release indapamide in a sustained manner to exert its long-term antihypertensive diuretic activity.
引文
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