利培酮注射型原位凝胶植入剂的研究
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摘要
注射型原位凝胶植入剂(injectable in -situ forming implant)是近年来缓控型注射剂领域的研究热点,是将药物和生物可降解高分子聚合物溶于适宜的有机溶剂中,制成的液体制剂,局部皮下或肌肉注射进体内以后,溶剂迅速扩散到周围的组织水分中,聚合物则不溶于水,在给药部位凝固,包裹药物而形成半固体或固体药物贮库,并通过聚合物不断降解,药物不断的释放出来,达到长效缓释作用。利培酮(ziprasidone)是新型非典型抗精神病药,对精神病的阴性症状和阳性症状均有效,不良反应少且用药剂量小。精神疾病是一种需要较长时间用药维持治疗的慢性病,开发安全有效的抗精神病长效制剂,能够减少患者一日需多次用药的麻烦、减少药物的不良反应以及提高用药依从性,对改善精神卫生状况具有重要意义。
高分子载体PLGA在人体内具有良好的生物降解性和相容性,N-甲基吡咯烷酮(NMP)为两性溶剂,可以同时溶解亲水性的生物大分子药物和亲油性的高分子材料,制备利培酮长效注射型原位凝胶植入剂,考察不同处方的原位凝胶植入剂在一个月内释放行为和突释效应,并优选出最佳处方。对利培酮注射型原位凝胶植入剂在动物体内的滞留时间和刺激性进行考察。
第一部分利培酮注射型原位凝胶植入剂的制备及处方筛选
建立利培酮的高效液相检测方法,其精密度、回收率、专属性均符合方法学的要求,辅料PLGA和溶剂NMP均对利培酮的测定无干扰,利培酮在0.1-2mg/mL的范围,以浓度和峰面积为坐标作标准曲线,其线性关系良好。选用聚乳酸乙醇酸共聚物(PLGA)为载体和N-甲基吡咯烷酮(NMP)为共溶剂,采用无膜释放的方法对利培酮注射型原位凝胶植入剂进行释放行为的考察,使用旋转黏度计对制得的凝胶溶液进行黏度的测定。以投药量、药物与PLGA用量之比和PLGA与NMP用量为三因素,每个因素设5个水平,以注射型原位凝胶植入剂的黏度,前24小时突释和体外30天累积释放度为考察指标,通过星点设计—效应面法进行处方筛选,确立最佳处方为投药量与PLGA的用量比为41.55%,PLGA与溶剂NMP的用量比为18.48%,投药量为77.32mg。
第二部分利培酮注射型原位凝胶植入剂体外释放特性
以优化处方制备三批样品,对其进行含量测定,释放均一性和体外稳定性考察,结果显示三批样品的标示量均在97%左右,每批样品的释放均一性良好,30天内释放曲线平稳,且突释效应较小;以凝胶的外观颜色、含量、黏度以及释放度的变化为指标考察其稳定性,结果显示其在高温、高湿、光照条件下均不稳定,根据PLGA高温下易降解的特性以及稳定性试验的结果,因此该剂型需要在避光、干燥和低温保存,适合放置于10°C的冰箱中。建立PLGA的分子量的检测方法,用以考察降解过程中分子量的变化情况。在光镜下观察固体聚合物在降解过程表面孔径的变化情况。运用差示扫描仪检测其在释放期间熔点的变化情况,以保证其在体温条件下不会熔解。
第三部分利培酮注射型原位凝胶植入剂体内滞留情况
给实验动物新西兰大白兔颈部注射利培酮注射型原位凝胶植入剂,通过X射线系统对其颈部于1天、15天、30天进行观察,并进行图像采集,并以未注射的兔子进行对比。图像结果显示,注射1天后颈部有明显的弥散物质,使得颈部骨骼较模糊,15天后经过一段时间降解后,这种弥散状变浅,颈部骨骼较之前清晰,30天后药物聚合物降解后,弥散状几乎全部消失,颈部骨骼清晰可见。
第四部分利培酮注射型原位凝胶植入剂的刺激性
给注射了利培酮注射型原位凝胶植入剂的新西兰大白兔于1天、10天和30天后取颈部皮肤及皮下结缔组织,先进行肉眼观察,均色泽红润、无积水化脓现象并与周围组织无粘连。然后进行组织切片HE染色,除了1天后的组织有轻微的炎症反应,10天和30天的组织结构清晰可见、无慢性炎症细胞浸湿现象。结果表明,该制剂的体内相容性较好,无刺激性反应。
本研究选用非典型抗精神病药利培酮为模型药物,根据其每日用药剂量较小的特点将其制备成长效给药系统。选用聚乳酸乙醇酸共聚物PLGA为载体和N-甲基吡咯烷酮(NMP)为共溶剂,制备利培酮可生物可降解注射型原位凝胶植入剂。利培酮制成该剂型选用的载药材料,处方筛选方法在国内外均属首例,为将抗精神类疾病药物制备成长效的植入给药系统提供了一定的理论和实验依据。
In recent years, in situ forming implant is hot and researchful drug system in field of sustained or controlled release dosage forms.. Drug and high molecular polymer dissolved in a biocompatible solvent ,which are injected subcutaneously or intramuscularly and deform solid or semisolid matrices under physiological condition, then drug will be released from matrices steadily by degradation of polymer molecμLar weight in following long term. Risperidone is one of atypical antipsychotic drugs with fewer side affect and low dosage in treatment .It has good effects in positive and negative symptoms of schizophrenia that needs long term treatment because of being a chonic disease. Development of long term drug system are significant in the field of schizophrenia because that are convenient of patients and can reduce side affects and PLGA is copolymer of l-lactide and glycolid ,it can not accumulate because the characteristics of biocompatibility and biodegradability are comfortable in body .To select NMP as solvent that can dissolve not only drugs but also high molecular materials.
To adopt risperidone as model drug which was used to prepare a injectable implant with long-action in this study .To investigate release behavior and burst effect to optimize the preparation for implant. Meantime, residence time and irritation of that were studied in vivo.
Part 1 Preparation and optimization of risperidone Biodegradable In-situ Forming Implant
HPLC method was establish to for implant. Recovery, precision, specificity all met the requirement of technology, and determination of risperidone was not interfered by excipents of PLAG and solvent . Risperidone standard curve was linear over the range of o.1～2g·ml-1. PLAG and NMP were chosen for carrier and solvent respectively,and release method without membrane was used to examine release rate. Viscosity was measured by rotating cylinder viscometer.To optimize preparation by central composite design and response surface methodology depending on these facter :weight of drug, drug/PLAG(%) and PLGA/NMP(%), and every facter was designed for five levels. Viscosity , burst effect and cumulative release in 30 days in vertrowere major indexes to select best preparation was following:risperidone content was 77.32mg, drug/PLGA was 41.55% and PLGA/NMP was 18.48%.
Part 2 The characteristic of release of risperidone injectable In-situ Forming Implant in vitro
To make three groups of sample products by optimal preparation ,and to test their contents , release homogenicity and stability in vitro.The results showed that labelled amount was almost 97%,e release homogenicity was fine and release curve was steady with small burst.To investigate stability of implant by shape,content and changes of release.The results indicated it was not stable under conditions of high temperature,high humidity and light. So it was necessary to be preserved under cool and dry environment without light like refrigerator.To establish a measure to examine PLGA molecular weight and observe the changes of it in degradative phase. In addition, pore sizes on the surface of matrix were observed by light microscope. Differential scanning calorimetry was used to test melting points bo guarantee that the matrix could not melt at temperature of body.
Part 3 Residence state of risperidone injectable In-situ Forming Implant in vivo
The experimental rabbits were injected with risperidone injectable and Biodegradable In-situ Forming Implant,and X radication system was used to observe it incervicum after 1,15,and 30 days,then catched images which were compare with rabbits without injection.The images showed the diffused sediment in cervicum because of blurry cervical vetebrae after 1 day.After degradation for 15 days, it became clearer than before.Then,it almostly disappeared after 30 days,thus the cervical vertebrae was clear.
Part 4 Irritation of injectable In-situ Forming Implant in vivo the Skin and subcutaneous connective tissue were obtained from experimental rabbits received injection after 1,15,and 30 days ,and the color of them were rosy without phenomenon of hydrops and diapyesis. They were made into slices and dyed with haematoxylin and eosin and then observed in light microscope. No phenomenons of tissue damage or inflammatory cells were seen.The results showed it was biocompatible in body.
In this study, to select risperdione that is antipsychotic drug can be used to prepare long-action drug delivery system depending on advantage of low dosage in every day. PLGA and NMP were chose for excipents in this system. The preparation of Risperidone injectable and Biodegradable In-situ Forming Implant can lay practical and theoretical foundations for long action drug delivery system.
高分子载体PLGA在人体内具有良好的生物降解性和相容性,N-甲基吡咯烷酮(NMP)为两性溶剂,可以同时溶解亲水性的生物大分子药物和亲油性的高分子材料,制备利培酮长效注射型原位凝胶植入剂,考察不同处方的原位凝胶植入剂在一个月内释放行为和突释效应,并优选出最佳处方。对利培酮注射型原位凝胶植入剂在动物体内的滞留时间和刺激性进行考察。
第一部分利培酮注射型原位凝胶植入剂的制备及处方筛选
建立利培酮的高效液相检测方法,其精密度、回收率、专属性均符合方法学的要求,辅料PLGA和溶剂NMP均对利培酮的测定无干扰,利培酮在0.1-2mg/mL的范围,以浓度和峰面积为坐标作标准曲线,其线性关系良好。选用聚乳酸乙醇酸共聚物(PLGA)为载体和N-甲基吡咯烷酮(NMP)为共溶剂,采用无膜释放的方法对利培酮注射型原位凝胶植入剂进行释放行为的考察,使用旋转黏度计对制得的凝胶溶液进行黏度的测定。以投药量、药物与PLGA用量之比和PLGA与NMP用量为三因素,每个因素设5个水平,以注射型原位凝胶植入剂的黏度,前24小时突释和体外30天累积释放度为考察指标,通过星点设计—效应面法进行处方筛选,确立最佳处方为投药量与PLGA的用量比为41.55%,PLGA与溶剂NMP的用量比为18.48%,投药量为77.32mg。
第二部分利培酮注射型原位凝胶植入剂体外释放特性
以优化处方制备三批样品,对其进行含量测定,释放均一性和体外稳定性考察,结果显示三批样品的标示量均在97%左右,每批样品的释放均一性良好,30天内释放曲线平稳,且突释效应较小;以凝胶的外观颜色、含量、黏度以及释放度的变化为指标考察其稳定性,结果显示其在高温、高湿、光照条件下均不稳定,根据PLGA高温下易降解的特性以及稳定性试验的结果,因此该剂型需要在避光、干燥和低温保存,适合放置于10°C的冰箱中。建立PLGA的分子量的检测方法,用以考察降解过程中分子量的变化情况。在光镜下观察固体聚合物在降解过程表面孔径的变化情况。运用差示扫描仪检测其在释放期间熔点的变化情况,以保证其在体温条件下不会熔解。
第三部分利培酮注射型原位凝胶植入剂体内滞留情况
给实验动物新西兰大白兔颈部注射利培酮注射型原位凝胶植入剂,通过X射线系统对其颈部于1天、15天、30天进行观察,并进行图像采集,并以未注射的兔子进行对比。图像结果显示,注射1天后颈部有明显的弥散物质,使得颈部骨骼较模糊,15天后经过一段时间降解后,这种弥散状变浅,颈部骨骼较之前清晰,30天后药物聚合物降解后,弥散状几乎全部消失,颈部骨骼清晰可见。
第四部分利培酮注射型原位凝胶植入剂的刺激性
给注射了利培酮注射型原位凝胶植入剂的新西兰大白兔于1天、10天和30天后取颈部皮肤及皮下结缔组织,先进行肉眼观察,均色泽红润、无积水化脓现象并与周围组织无粘连。然后进行组织切片HE染色,除了1天后的组织有轻微的炎症反应,10天和30天的组织结构清晰可见、无慢性炎症细胞浸湿现象。结果表明,该制剂的体内相容性较好,无刺激性反应。
本研究选用非典型抗精神病药利培酮为模型药物,根据其每日用药剂量较小的特点将其制备成长效给药系统。选用聚乳酸乙醇酸共聚物PLGA为载体和N-甲基吡咯烷酮(NMP)为共溶剂,制备利培酮可生物可降解注射型原位凝胶植入剂。利培酮制成该剂型选用的载药材料,处方筛选方法在国内外均属首例,为将抗精神类疾病药物制备成长效的植入给药系统提供了一定的理论和实验依据。
In recent years, in situ forming implant is hot and researchful drug system in field of sustained or controlled release dosage forms.. Drug and high molecular polymer dissolved in a biocompatible solvent ,which are injected subcutaneously or intramuscularly and deform solid or semisolid matrices under physiological condition, then drug will be released from matrices steadily by degradation of polymer molecμLar weight in following long term. Risperidone is one of atypical antipsychotic drugs with fewer side affect and low dosage in treatment .It has good effects in positive and negative symptoms of schizophrenia that needs long term treatment because of being a chonic disease. Development of long term drug system are significant in the field of schizophrenia because that are convenient of patients and can reduce side affects and PLGA is copolymer of l-lactide and glycolid ,it can not accumulate because the characteristics of biocompatibility and biodegradability are comfortable in body .To select NMP as solvent that can dissolve not only drugs but also high molecular materials.
To adopt risperidone as model drug which was used to prepare a injectable implant with long-action in this study .To investigate release behavior and burst effect to optimize the preparation for implant. Meantime, residence time and irritation of that were studied in vivo.
Part 1 Preparation and optimization of risperidone Biodegradable In-situ Forming Implant
HPLC method was establish to for implant. Recovery, precision, specificity all met the requirement of technology, and determination of risperidone was not interfered by excipents of PLAG and solvent . Risperidone standard curve was linear over the range of o.1～2g·ml-1. PLAG and NMP were chosen for carrier and solvent respectively,and release method without membrane was used to examine release rate. Viscosity was measured by rotating cylinder viscometer.To optimize preparation by central composite design and response surface methodology depending on these facter :weight of drug, drug/PLAG(%) and PLGA/NMP(%), and every facter was designed for five levels. Viscosity , burst effect and cumulative release in 30 days in vertrowere major indexes to select best preparation was following:risperidone content was 77.32mg, drug/PLGA was 41.55% and PLGA/NMP was 18.48%.
Part 2 The characteristic of release of risperidone injectable In-situ Forming Implant in vitro
To make three groups of sample products by optimal preparation ,and to test their contents , release homogenicity and stability in vitro.The results showed that labelled amount was almost 97%,e release homogenicity was fine and release curve was steady with small burst.To investigate stability of implant by shape,content and changes of release.The results indicated it was not stable under conditions of high temperature,high humidity and light. So it was necessary to be preserved under cool and dry environment without light like refrigerator.To establish a measure to examine PLGA molecular weight and observe the changes of it in degradative phase. In addition, pore sizes on the surface of matrix were observed by light microscope. Differential scanning calorimetry was used to test melting points bo guarantee that the matrix could not melt at temperature of body.
Part 3 Residence state of risperidone injectable In-situ Forming Implant in vivo
The experimental rabbits were injected with risperidone injectable and Biodegradable In-situ Forming Implant,and X radication system was used to observe it incervicum after 1,15,and 30 days,then catched images which were compare with rabbits without injection.The images showed the diffused sediment in cervicum because of blurry cervical vetebrae after 1 day.After degradation for 15 days, it became clearer than before.Then,it almostly disappeared after 30 days,thus the cervical vertebrae was clear.
Part 4 Irritation of injectable In-situ Forming Implant in vivo the Skin and subcutaneous connective tissue were obtained from experimental rabbits received injection after 1,15,and 30 days ,and the color of them were rosy without phenomenon of hydrops and diapyesis. They were made into slices and dyed with haematoxylin and eosin and then observed in light microscope. No phenomenons of tissue damage or inflammatory cells were seen.The results showed it was biocompatible in body.
In this study, to select risperdione that is antipsychotic drug can be used to prepare long-action drug delivery system depending on advantage of low dosage in every day. PLGA and NMP were chose for excipents in this system. The preparation of Risperidone injectable and Biodegradable In-situ Forming Implant can lay practical and theoretical foundations for long action drug delivery system.
引文
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