酮康唑/乳酸—羟基乙酸共聚物缓释材料的制备和性能研究
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摘要
乳酸-羟基乙酸共聚物(PLGA)是已被美国FDA批准的可用于人体的生物可降解材料,在体内的最终降解产物是水和二氧化碳,无毒且具有极佳的生物相容性,可以制成微球、纤维、支架等各种形状的产品,被广泛应用于医用工程材料、制药和现代化工业领域。酮康唑(KCZ)是目前临床应用较为广泛的咪唑类抗真菌药物,可用于治疗皮肤科、妇产科、眼科、耳科等多种疾病,但是长期应用会产生恶心、呕吐、瘙痒、腹痛及嗜睡等副作用,甚至造成肝脏损坏,这在一定程度上限制了它的应用。
以降低药物副作用为切入点研究生物材料缓释技术,本文将酮康唑负载于PLGA可降解载体上,采用两种不同的方法制备了毫米和微米级的载药微球,用静电纺丝法制成了载药超细纤维膜。讨论了制备工艺中的影响因素,用光学显微镜、扫描电镜、X射线衍射仪、红外光谱仪、高效液相色谱仪等仪器对微球和纤维进行分析表征,建立了体内外酮康唑含量的测定方法,测定了微球及纤维的体外释放度,并以小鼠为动物模型研究了KCZ/PLGA微球的体内药物释放规律。主要研究内容和结果如下：
1. KCZ/PLGA缓释微球中酮康唑含量测定方法的建立。通过方法学考察,建立了用高效液相色谱仪(HPLC)测定酮康唑缓释微球的载药量和包封率的方法,选择pH=4.5和pH=7.4磷酸盐缓冲溶液为释放介质,建立了动态膜透析法测定酮康唑缓释微球体外释放度的方法。结果表明,HPLC法分离效率高、速度快,流动相可选择范围宽、灵敏度高,适用于酮康唑缓释微球中酮康唑含量的测定,为缓释微球配方筛选、工艺优化和性质表征奠定了基础。
2.用微流控装置制备了粒径均一的KCZ/PLGA缓释微球,对微球进行了表征和体外释放度的测定。结果表明,微球的形貌受分散相及流动相溶液浓度、载药量、微球粒径的影响；微球的粒径受分散相及流动相溶液的流速影响大,受载药量的影响小。通过用红外光谱(FT-IR)、热重分析(TGA)和X射线衍射分析(XRD)等方法对微球进行分析测试,证明PLGA与酮康唑之间没有发生化学反应,只是产生预期的物理性包埋,载药微球在120℃以下具有良好的热稳定性,酮康唑的存在使载药微球中PLGA的热分解温度变低了,PLGA与酮康唑分子间的相互作用降低了载药微球中酮康唑的结晶度。载药微球的体外释药结果表明相同粒径的微球随载药量的增大,药物的释放量也增大；相同载药量的微球随粒径的增大,药物的释放量减小。
3.利用乳化溶剂挥发法(O/W),选择不同的乳化搅拌速度,制备出相应粒径的KCZ/PLGA缓释微球,研究了缓释微球的粒径和包封率及其影响因素,考察了微球粒径、PLGA的性质、释放液pH值等对微球药物体外释放的影响。结果表明,采用乳化溶剂挥发法制备KCZ/PLGA缓释微球,制备工艺简便易行,包封率和载药量较高。微球粒径越小、PLGA分子量越低、GA含量越高、释放液pH值越小酮康唑的释放速度越快。微球前期释放较快,后期稳定,药物缓慢释放时间可达3周以上。
4.利用静电纺丝的方法制备KCZ/PLGA超细纤维,对纤维进行了表征和体外释放度的测定。用扫描电镜(SEM)观察纤维的形貌,确定了静电纺PLGA超细纤维的最佳工艺参数：PLGA纺丝液浓度为15wt%,纺丝电压为16kV,极距为15cm。对纤维进行SEM、FT-IR、TGA和XRD分析测试,结果表明制备的KCZ/PLGA复合纤维表面光滑,酮康唑能够均匀地分散在PLGA纺丝液中而不发生凝聚。酮康唑是以分子状态分散在PLGA纤维中的,其分散过程是物理过程,并没有与PLGA纺丝液发生化学反应,因此在KCZ/PLGA复合纤维膜中酮康唑的性能不会发生改变。酮康唑的加入改变了PLGA纤维的热性能,在温度300℃以下加快了PLGA纤维的热降解速度,在300～400℃之间却使PLGA热降解速度减慢。对纤维的体外释药研究表明,载药量越大、PLGA中GA含量越高、释放液pH值越小酮康唑的释放速度越快。纤维前期释放较快,后期稳定,药物缓慢释放时间可达3周以上。
5.建立了检测血浆中酮康唑浓度的HPLC法,以小鼠为模型,研究了KCZ/PLGA缓释微球在动物体内的降解及药物释放情况。结果显示酮康唑的绝对回收率大于87.21%,日内、日间精密度均小于3.09%,室温放置、反复冻融稳定性试验结果表明酮康唑血浆样品的稳定性良好,药物浓度的RSD均小于4.43%,符合关于生物样品分析方法的基本要求,可用于酮康唑小鼠体内药动学和生物等效性的血药浓度检测。体内降解试验说明PLGA微球有很好的缓释作用且在体内环境中可以降解完全。对比研究结果表明,微球粒径、载体分子量和载体组成对微球的降解有明显影响,其中载体组成影响最大。
Poly(lactic-co-glycolic acid)(PLGA) is a biodegradable polymeric material, which has been approved by the FDA of U.S. to be used in the human body, and it can be decomposed into water and carbon dioxide. PLGA is non-toxic and has excellent biocompatibility. Microspheres and fiber scaffolds made of PLGA are extensively used in medical engineering materials, pharmaceuticals and modern industrial fields. Ketoconazole (KCZ) has widely been used as imidazole antifungal agents such as treating many diseases of dermatology, obstetrics/gynecology, ophthalmology and otology, however, some drawbacks of using it for long term are nausea, vomiting, itching, abdominal pain and drowsiness, and in extreme cases may cause liver damage. These drawbacks limit its application.
The main goal of this research work is exploring the biological materials mitigation technology to reduce the side effects of drugs. Ketoconazole microspheres with different particle size were prepared by two different methods with PLGA as carrier material.
The composite fiber membrane was prepared by electrostatic spinning. We have discussed the influencing factors in the preparation process. The microspheres and fibers membrane were characterized by optical microscopy, scanning electron microscopy, X-ray diffraction, Fourier transform infrared (FT-IR) spectroscopy, and high performance liquid chromatography (HPLC). The determination method of the in vitro release content of KCZ in KCZ/PLGA microspheres was established, mice was chosen as the animal model and in vivo drug delivery of KCZ/PLGA microspheres was studied.
The main research contents and results are summarized as follows:
1. Establishment of determining method of the content of the KCZ in KCZ/PLGA sustained-release microspheres. The loading amount of KCZ in the sustained release microsphere and encapsulation efficiency were measured by HPLC at pH4.5and7.4using phosphate buffer solution as a release medium. Dynamic membrane dialysis method was established to determine the amount of KCZ in microspheres in vitro release. The results showed that the HPLC method has high separation efficiency, high speed, and wide range selectable mobile phase and high sensitivity. The HPLC is applicable for determining of the content of ketoconazole, which is beneficial for screening suitable sustained release microspheres formula, for optimizing preparation and characterization condition of KCZ/PLGA sustained release microspheres.
2. Uniform particle size KCZ/PLGA sustained release microspheres were prepared by using microfluidic devices, the composition of KCZ/PLGA microspheres was characterized and in vitro release of the microspheres was determined. The results showed that the morphology of the microspheres is influenced by concentration of the dispersed phase and the mobile phase solution, drug loading and the size of microspheres. The diameter of microspheres is greatly affected by the flow rate of the dispersed phase and mobile phase, while the drug loading contributes minimal effect. Microspheres are analyzed and tested by FT-IR, thermal gravimetric analysis (TGA), and X-ray diffraction (XRD). Physical packing occurred while no chemical reactions were found between PLGA and ketoconazole in the microspheres. The thermal decomposition temperature of PLGA became lower due to the exit of KCZ; meanwhile, the degree of crystallinity of microspheres became lower due to the intermolecular interactions between KCZ and PLGA. Two important results of the in vitro release of the drug-loaded microspheres were obtained. First, in the same particle size of the microspheres, increasing the drug-loading amount increased the drug release; second, in the microspheres containing same amount of KCZ, increasing the particle size, decreased the drug release.
3. Various particles size of KCZ/PLGA sustained release microspheres were prepared by emulsion solvent evaporation method (W/O) at different emulsification stirring speed. The drug release in vitro of the microspheres has been examined by different effects, such as the particle size of the microspheres, properties of PLGA and pH value of released solution. The results indicated that emulsion solvent evaporation method is a simple way to provide high encapsulation and high drug loading. The release rate of ketoconazole depends on the smaller size of microspheres, lower molecular weight of PLGA, higher amount of GA and low pH value of released solution. The drug can slowly be released up to three weeks or more.
4. KCZ/PLGA microfiber fibers were prepared by electro-spinning, the composition was characterized and in vitro release was tested. The morphology of the fibers was observed by scanning electron microscopy (SEM), the optimum parameters of electrostatic spinning PLGA microfiber were established:the concentration of PLGA spinning solution was15wt%, the spinning voltage was16kV, electrode distance was approximately15cm. The SEM, FT-IR, TGA and XRD test results show that the prepared KCZ/PLGA composite fiber are smooth, ketoconazole can be uniformly dispersed in the PLGA spinning solution without aggregation on the fiber. Ketoconazole is molecular state dispersed in the PLGA fibers, the dispersion process is a physical process, and no chemical reaction occurs between KCZ and the spinning solution of PLGA. The property of ketoconazole in KCZ/PLGA composite fiber membrane is not changed. Adding KCZ changed the thermal property of the PLGA fibers, and the speed of the thermal degradation of the PLGA fibers was accelerated below3000C and plateaued from300to4000C. The studies of fiber in vitro release indicated that the greater amount of drug loading and the higher content of GA in PLGA and the lower of pH of the release liquid results in faster release of the ketoconazole. The KCZ was released faster in the early stage, and then became stable and sustained release of the drug lasted up to three weeks or more.
5. HPLC method was established to detect the concentration of ketoconazole in plasma. Mice were used as a model to study the KCZ/PLGA sustained release microspheres degradation and drug release in vivo. The results showed that the absolute recovery of ketoconazole were greater than87.21%, intra-day precision were less than3.09%, the stability of ketoconazole plasma samples was high under the room temperature and repeated freeze-thaw test, the RSD of the concentration of the drug were less than4.43%, which is consistent with the basic requirements of the analysis of biological sample. This can be used for studying pharmacokinetic of ketoconazole in the mice and detecting the blood drug concentration of bioequivalence. The degradation test in vivo indicated that PLGA microspheres have a good sustained release effect and can be degraded completely in vivo. Comparative tests found that microsphere size, carrier molecular weight and the composition of the KCZ/PLGA microspheres have significant effects on the degradation of the microspheres, and among them, the carrier composition plays the most important role.
以降低药物副作用为切入点研究生物材料缓释技术,本文将酮康唑负载于PLGA可降解载体上,采用两种不同的方法制备了毫米和微米级的载药微球,用静电纺丝法制成了载药超细纤维膜。讨论了制备工艺中的影响因素,用光学显微镜、扫描电镜、X射线衍射仪、红外光谱仪、高效液相色谱仪等仪器对微球和纤维进行分析表征,建立了体内外酮康唑含量的测定方法,测定了微球及纤维的体外释放度,并以小鼠为动物模型研究了KCZ/PLGA微球的体内药物释放规律。主要研究内容和结果如下：
1. KCZ/PLGA缓释微球中酮康唑含量测定方法的建立。通过方法学考察,建立了用高效液相色谱仪(HPLC)测定酮康唑缓释微球的载药量和包封率的方法,选择pH=4.5和pH=7.4磷酸盐缓冲溶液为释放介质,建立了动态膜透析法测定酮康唑缓释微球体外释放度的方法。结果表明,HPLC法分离效率高、速度快,流动相可选择范围宽、灵敏度高,适用于酮康唑缓释微球中酮康唑含量的测定,为缓释微球配方筛选、工艺优化和性质表征奠定了基础。
2.用微流控装置制备了粒径均一的KCZ/PLGA缓释微球,对微球进行了表征和体外释放度的测定。结果表明,微球的形貌受分散相及流动相溶液浓度、载药量、微球粒径的影响；微球的粒径受分散相及流动相溶液的流速影响大,受载药量的影响小。通过用红外光谱(FT-IR)、热重分析(TGA)和X射线衍射分析(XRD)等方法对微球进行分析测试,证明PLGA与酮康唑之间没有发生化学反应,只是产生预期的物理性包埋,载药微球在120℃以下具有良好的热稳定性,酮康唑的存在使载药微球中PLGA的热分解温度变低了,PLGA与酮康唑分子间的相互作用降低了载药微球中酮康唑的结晶度。载药微球的体外释药结果表明相同粒径的微球随载药量的增大,药物的释放量也增大；相同载药量的微球随粒径的增大,药物的释放量减小。
3.利用乳化溶剂挥发法(O/W),选择不同的乳化搅拌速度,制备出相应粒径的KCZ/PLGA缓释微球,研究了缓释微球的粒径和包封率及其影响因素,考察了微球粒径、PLGA的性质、释放液pH值等对微球药物体外释放的影响。结果表明,采用乳化溶剂挥发法制备KCZ/PLGA缓释微球,制备工艺简便易行,包封率和载药量较高。微球粒径越小、PLGA分子量越低、GA含量越高、释放液pH值越小酮康唑的释放速度越快。微球前期释放较快,后期稳定,药物缓慢释放时间可达3周以上。
4.利用静电纺丝的方法制备KCZ/PLGA超细纤维,对纤维进行了表征和体外释放度的测定。用扫描电镜(SEM)观察纤维的形貌,确定了静电纺PLGA超细纤维的最佳工艺参数：PLGA纺丝液浓度为15wt%,纺丝电压为16kV,极距为15cm。对纤维进行SEM、FT-IR、TGA和XRD分析测试,结果表明制备的KCZ/PLGA复合纤维表面光滑,酮康唑能够均匀地分散在PLGA纺丝液中而不发生凝聚。酮康唑是以分子状态分散在PLGA纤维中的,其分散过程是物理过程,并没有与PLGA纺丝液发生化学反应,因此在KCZ/PLGA复合纤维膜中酮康唑的性能不会发生改变。酮康唑的加入改变了PLGA纤维的热性能,在温度300℃以下加快了PLGA纤维的热降解速度,在300～400℃之间却使PLGA热降解速度减慢。对纤维的体外释药研究表明,载药量越大、PLGA中GA含量越高、释放液pH值越小酮康唑的释放速度越快。纤维前期释放较快,后期稳定,药物缓慢释放时间可达3周以上。
5.建立了检测血浆中酮康唑浓度的HPLC法,以小鼠为模型,研究了KCZ/PLGA缓释微球在动物体内的降解及药物释放情况。结果显示酮康唑的绝对回收率大于87.21%,日内、日间精密度均小于3.09%,室温放置、反复冻融稳定性试验结果表明酮康唑血浆样品的稳定性良好,药物浓度的RSD均小于4.43%,符合关于生物样品分析方法的基本要求,可用于酮康唑小鼠体内药动学和生物等效性的血药浓度检测。体内降解试验说明PLGA微球有很好的缓释作用且在体内环境中可以降解完全。对比研究结果表明,微球粒径、载体分子量和载体组成对微球的降解有明显影响,其中载体组成影响最大。
Poly(lactic-co-glycolic acid)(PLGA) is a biodegradable polymeric material, which has been approved by the FDA of U.S. to be used in the human body, and it can be decomposed into water and carbon dioxide. PLGA is non-toxic and has excellent biocompatibility. Microspheres and fiber scaffolds made of PLGA are extensively used in medical engineering materials, pharmaceuticals and modern industrial fields. Ketoconazole (KCZ) has widely been used as imidazole antifungal agents such as treating many diseases of dermatology, obstetrics/gynecology, ophthalmology and otology, however, some drawbacks of using it for long term are nausea, vomiting, itching, abdominal pain and drowsiness, and in extreme cases may cause liver damage. These drawbacks limit its application.
The main goal of this research work is exploring the biological materials mitigation technology to reduce the side effects of drugs. Ketoconazole microspheres with different particle size were prepared by two different methods with PLGA as carrier material.
The composite fiber membrane was prepared by electrostatic spinning. We have discussed the influencing factors in the preparation process. The microspheres and fibers membrane were characterized by optical microscopy, scanning electron microscopy, X-ray diffraction, Fourier transform infrared (FT-IR) spectroscopy, and high performance liquid chromatography (HPLC). The determination method of the in vitro release content of KCZ in KCZ/PLGA microspheres was established, mice was chosen as the animal model and in vivo drug delivery of KCZ/PLGA microspheres was studied.
The main research contents and results are summarized as follows:
1. Establishment of determining method of the content of the KCZ in KCZ/PLGA sustained-release microspheres. The loading amount of KCZ in the sustained release microsphere and encapsulation efficiency were measured by HPLC at pH4.5and7.4using phosphate buffer solution as a release medium. Dynamic membrane dialysis method was established to determine the amount of KCZ in microspheres in vitro release. The results showed that the HPLC method has high separation efficiency, high speed, and wide range selectable mobile phase and high sensitivity. The HPLC is applicable for determining of the content of ketoconazole, which is beneficial for screening suitable sustained release microspheres formula, for optimizing preparation and characterization condition of KCZ/PLGA sustained release microspheres.
2. Uniform particle size KCZ/PLGA sustained release microspheres were prepared by using microfluidic devices, the composition of KCZ/PLGA microspheres was characterized and in vitro release of the microspheres was determined. The results showed that the morphology of the microspheres is influenced by concentration of the dispersed phase and the mobile phase solution, drug loading and the size of microspheres. The diameter of microspheres is greatly affected by the flow rate of the dispersed phase and mobile phase, while the drug loading contributes minimal effect. Microspheres are analyzed and tested by FT-IR, thermal gravimetric analysis (TGA), and X-ray diffraction (XRD). Physical packing occurred while no chemical reactions were found between PLGA and ketoconazole in the microspheres. The thermal decomposition temperature of PLGA became lower due to the exit of KCZ; meanwhile, the degree of crystallinity of microspheres became lower due to the intermolecular interactions between KCZ and PLGA. Two important results of the in vitro release of the drug-loaded microspheres were obtained. First, in the same particle size of the microspheres, increasing the drug-loading amount increased the drug release; second, in the microspheres containing same amount of KCZ, increasing the particle size, decreased the drug release.
3. Various particles size of KCZ/PLGA sustained release microspheres were prepared by emulsion solvent evaporation method (W/O) at different emulsification stirring speed. The drug release in vitro of the microspheres has been examined by different effects, such as the particle size of the microspheres, properties of PLGA and pH value of released solution. The results indicated that emulsion solvent evaporation method is a simple way to provide high encapsulation and high drug loading. The release rate of ketoconazole depends on the smaller size of microspheres, lower molecular weight of PLGA, higher amount of GA and low pH value of released solution. The drug can slowly be released up to three weeks or more.
4. KCZ/PLGA microfiber fibers were prepared by electro-spinning, the composition was characterized and in vitro release was tested. The morphology of the fibers was observed by scanning electron microscopy (SEM), the optimum parameters of electrostatic spinning PLGA microfiber were established:the concentration of PLGA spinning solution was15wt%, the spinning voltage was16kV, electrode distance was approximately15cm. The SEM, FT-IR, TGA and XRD test results show that the prepared KCZ/PLGA composite fiber are smooth, ketoconazole can be uniformly dispersed in the PLGA spinning solution without aggregation on the fiber. Ketoconazole is molecular state dispersed in the PLGA fibers, the dispersion process is a physical process, and no chemical reaction occurs between KCZ and the spinning solution of PLGA. The property of ketoconazole in KCZ/PLGA composite fiber membrane is not changed. Adding KCZ changed the thermal property of the PLGA fibers, and the speed of the thermal degradation of the PLGA fibers was accelerated below3000C and plateaued from300to4000C. The studies of fiber in vitro release indicated that the greater amount of drug loading and the higher content of GA in PLGA and the lower of pH of the release liquid results in faster release of the ketoconazole. The KCZ was released faster in the early stage, and then became stable and sustained release of the drug lasted up to three weeks or more.
5. HPLC method was established to detect the concentration of ketoconazole in plasma. Mice were used as a model to study the KCZ/PLGA sustained release microspheres degradation and drug release in vivo. The results showed that the absolute recovery of ketoconazole were greater than87.21%, intra-day precision were less than3.09%, the stability of ketoconazole plasma samples was high under the room temperature and repeated freeze-thaw test, the RSD of the concentration of the drug were less than4.43%, which is consistent with the basic requirements of the analysis of biological sample. This can be used for studying pharmacokinetic of ketoconazole in the mice and detecting the blood drug concentration of bioequivalence. The degradation test in vivo indicated that PLGA microspheres have a good sustained release effect and can be degraded completely in vivo. Comparative tests found that microsphere size, carrier molecular weight and the composition of the KCZ/PLGA microspheres have significant effects on the degradation of the microspheres, and among them, the carrier composition plays the most important role.
引文
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