RFP-PLGA骨缓释复合体的初步实验研究
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摘要
目的：①拟通过O/w乳化溶剂挥发法制备RFP-PLGA微球,以形态、粒径分布、包封率和载药量为指标考察各处方因素的影响,并筛选出最优工艺；②拟采用前期优化处方制备缓释微球,与骨支架结合,并观察微球的骨填充情况及体外释放行为；③采用新西兰大白兔作为动物模型,对RFP-PLGA骨缓释复合体中RFP在体内的分布及缓释行为进行了相关研究,同时考察了该复合物在体内的相容性。为探讨术后脊柱结核患者抗结核治疗,减少其副作用提供实验依据。
方法：①通过乳化-溶剂挥发法制备缓释微球,以粒径、载药量、包封率为考察指标对处方中的不同因素如PLGA浓度,表面活性剂的种类及浓度,油水比,药载比进行了单因素考察。并选取重要的影响因素进行正交实验对处方进一步优化,得出各影响因素对制备过程影响强度,并筛选出最优处方；②采用超声振荡法将RFP-PLGA缓释微球灌入异体骨内,再浇盖一层壳聚糖溶液,真空干燥喷金后,用电子扫描显微镜和骨密度仪分别观察RFP-PLGA缓释复合体的填充状态、外观表面形态及灌注前后骨密度的变化；体外释放实验分成三组：A组RFP晶体、B组RFP缓释微球及C组RFP-PLGA骨缓释复合体,并采用透析袋法进行体外释放研究；③体内药动学研究分成A组RFP口服给药组、B组RFP-PLGA骨缓释复合体组、C组RFP晶体-骨复合体组,后两组植入兔腰椎骨性缺损处,并通过大体观察、影像学观察、骨密度观察、组织分布结果、生化指标检测、组织形态学观察六个方面进行对比。采用HPLC-UV法测定血浆及各组织中的药物浓度。采用SPSS17.0软件包进行分析,结果以均数±标准差即x±S表示,采用多种统计学分析方法,如t检验、方差分析及组间比较的SNK-q检验、LSD-t检验等,检验水准a=0.05,P值<0.05为差异有显著性意义。
结果：①通过单因素考察得知对考察指标具有较大影响的处方因素,在此基础上对处方进行了优化,结果中各处方因素的影响强度如下：药载比>PVA浓度>PLGA浓度>油水比,并确定较优工艺为：PLGA浓度15mg·ml-1、药载比1：2、PVA浓度2%、油水比1：5；平行制得3批微球粒径为12.23±0.98μ m；载药量、包封产率分别为(19.63±0.62)%、(59.49±2.62)%,微球冷冻干燥后,再分散性及外观良好；
②体外释放显示：A组RFP晶体在24h内释放基本完全,B组RFP缓释微球组及C组RFP.PLGA骨缓释复合体组释药平缓,其中RFP缓释微球组31d累计释药率达到近95%,释放进行动力学方程拟合,显示符合零级动力学方程F=0.168*t;RFP-PLGA骨缓释复合体组约31d累计释药率达到近92.31%,未见无明显的突释,进行动力学方程拟合,显示符合零级动力学方程F=0.15*t；骨密度检测：三组灌注前后及B、C组骨密度无明显统计学差异(P>0.05)；
③体内实验表明：A组即口服给药组虽然在局部腰椎体组织中能维持较高的有效浓度,但其在肝、脾、心、肺等脏器中也存在较高的浓度;C组即RFP晶体-骨复合体植入组,尽管在维持靶组织有效浓度的同时减小药物在其他脏器中的分布,但维持时间甚短,15天后已低于最低检测浓度；相对而言,B组RFP-PLGA骨缓释复合体植入新西兰大兔给药后,3天时RFP浓度为11±0.7μg/ml-1,在7天时RFP浓度为13.3±0.4μg/ml-1,在15天时RFP浓度为8.5±1.6μg/ml-1,在30天时RFP浓度为1.6±0.4μg/ml-1,在40天时RFP浓度为0.45±0.21μg/ml-1,均明显高于有效抑菌浓度,在体内组织中缓慢下降,不仅其他脏器中的药物浓度低,而且40天时腰椎椎体RFP浓度仍可维持有效抑菌浓度,相对于C组在局部腰椎椎体组织中RFP的有效浓度持续时间较长；骨密度检测：a.术后第7天：三组统计学比较分析：P>0.05,无明显统计学意义；b.术后第30天：A组与B、C组比较：P<0.05,有明显统计学意义；B组与C组比较：P>0.05,无明显统计学意义；c.术后第7天与第30天不同组别比较：A7组与A30组比较：P>0.05,无明显统计学意义,B7组与B30组比较：P<0.05,有明显统计学意义,C7组与C30组比较：P<0.05,有明显统计学意义；肝毒性检测：三组给药前后比较未见明显统计学差异；RFP-PLGA骨缓释复合体行内植入腰椎骨性组织后,腰椎和腰大肌组织均未见明显炎症反应,亦未见相关正常组织的破坏或形态异常。
结论：
①1、乳化-溶剂挥发法中诸多因素对微球成形和质量具有明显影响；2、筛选出最优处方即PLGA浓度15mg·mL-1、PVA浓度2%、药载比1：2及油水比1：5。
②RFP微球形态良好,粒径分布均匀,超声波振荡的方法可以与多孔隙的骨制备成RFP-PLGA骨缓释复合体,其填充效果好,三组灌注前后骨密度无明显统计学差异,具有良好的体外缓释释放性能,检测各时间点的浓度均在有效抑菌浓度以上。
③RFP-PLGA骨缓释复合体体内椎旁植入后,局部组织内RFP抗结核有效浓度可维持在持续到约40天以上,无明显心、肝、肺及脾等组织蓄积作用及毒性,骨密度无明显影响,组织相容性良好。
Objective:①To achieve the optimal method of preparation of RFP-PLGA microspheres(Ms) by O/W emulsion-solvent evaporation techniques through observation of the morphology, particle size and distribution,encapsulation and loading efficiency of Ms.(2)To observe the filling state and releasing of sustained-release Ms when combining it with allografted bone scaffold in vitro.③To observe the distribution pharmacokinetics and compatibility of RFP-PLGA-allograft bone complex in animal model to provide experimental basis for antituberculosis therapy after spinal surgery.
Methods:①The O/W emulsion solvent evaporation method was used to prepare sustained-release Ms. Particle size, drug loading and entrapment efficiency were used as the evaluation index.The PLGA concentration,O/W rate,and the type and concentration of surfactant were investigated as single factor respectively.Some important influencing factors were chose to go through orthogonal experiment to figure out their impact for optimal procedure.②The RFP-PLGA Ms was placed into allografted bone by using ultrasonic vibration,covered with a chitosan membrane.The bone densitometer and electron scanning microscope were used to observe the filling state and the morphology of the Ms as well as the change of BMD (Bone mineral density)after vacuum drying and metal spraying.The vitro releasing experiments were divided into three groups: Group A:RFPcrystal,Group B:RFP Ms;and Group C:RFP-PLGA-allograft bone complex.Three groups were investigated with bag filter method.③The pharmacokinetics in vivo experiments were divided into3groups:Group A:RFP oral dosing,Group B:RFP-PLGA-allograft bone complex and,Group C:RFP crystal-allograft bone.Group B and C were embedded into the rabbit's lumbar vertebral defect site and compared them in six aspects including observation of general condition,imaging feature,BMD,tissue distribution,biochemistry index and histomorphology.HPLC-UV method was used to detect the drug concentration in blood plasma and other tissues.The results were showed as the(x±S)and multiple statistical methods including the T test, ANOVA, SNK-q test of group comparison and LSD-t test by using the SPSS17.0.The setting, size of test was a=0.05and,p<0.05was considered the significant difference.
Results:①On the basis of the single factor exploration we knew the important influential factor and grading-up the method, the conclusion of effect intensity of each factor was:Drug/Copolymer composition> PVA concentration> PLGA concentration> O/W rate.Optimal method was:PLGA concentration15mg·ml-1,RFP/PLGA1:2,PVA concentration2%, O/W rate1:5.The mean diameter of Ms was12.33±0.98μm,with the drug loading and entrapment efficiency was (19.63±0.62)%and (59.49±2.62)%,repectively.After the cryodesiccate of Ms,the redispersibility and appearance was well.②The release in vitro showed: the RFP crystal of Group A was almost released completely in24hours;the Ms of Group B and Ms-bone complex of Group C was sustainsably released. The releasing rate of Group B was approximately up to95%totally in31days,consistent with the zero-order elimination kinetics equation:F=0.168*t.RFP-PLGA-allograft bone complex rate was approximately up to92.31%totally in31days without apparent burst release.With the zero-order elimination kinetics equation:F=0.15*t;the BMD test showed:the BMD of Group B and C showed no apparently statistical difference after filling in three groups,(p>0.05).③In vivo kinetics showed group A(oral dosing) had high drug concentration in both local lumbar vertebra and other organs like heart, liver and spleen. Group C (RFP crystal-allograft bone),although maintaining the effective concentration in target tissue and diminishing the drug concentration in other organ,its duration was short,under the minimal detectable concentration after15d.By comparison,Group B:after the RFP-PLGA-allograft bone complex inserted into New Zealand white rabbits,RFP concentration was11±0.7μg/ml-1in the3rd day,RFP concentration was13.3±0.4μg/ml-1in the7th day and RFP concentration was8.5±1.6μg/ml-1in the15th day,RFP concentration was1.6±0.4μ/ml-1in the30th day,RFP concentration was0.45±0.21μg/ml-1in the40th day,which were apparently higher than MIC.Slowly releasing in vivo tissue,the drug concentration was lower in other organ but could reach the effective sterilization concentrations in lumbar vertebra in the40th day.Compared to Group C,it maintained longer effective sterilization concentrations in local lumbar vertebra.BMD test showed:a.There were no statistical significance after the surgery for7days in three groups: three groups have no statistical difference:P>0.05;b.30days after the surgery:Group A compared with Group B and C:P<0.05;Group B compared with Group C:P>0.05;c.7d and30d after the surgery:A'group compare with A30group:P>0.05;B7group compared with B30group:P<0.05;C group compared with C30group:P<0.05; Hepatotoxicity test:the3groups showed no apparently statistical difference after the dose; After the RFP-PLGA-allograft bone complex had been embedded into lumbar vertebra,lumbar vertebra and psoas tissue didn't show any apparently inflammatory reaction and no normal tissue damage or paramorphia.
Conclusion:①A variety of factors in O/W emulsion solvent evaporation method have significant influence on morphology and quality of Ms. The optimal scheme was screened that the concentration of PLGA was15mg-mL-1;concentration of PVA was2%;RFP/PLGA1:2and O/W rate was1:5.②The RFP Ms was well shaped and,particle diameter distributed evenly.Ultrasonic oscillation worked with the poriferous allograft bone could make up RFP-PLGA-allograft bone complex,to be filled well.The BMD show no significant statistical difference after the filling.Among the three groups and with good slowly-releasing function in vitro. The drug concentration in different time point was above the MIC.③After the RFP-PLGA-allograft bone complex was implanted into para-vertebrae, the RFP concentration in local tissue could maintain above MIC over40d without apparent toxicity and no drug accumulation was found in heart,liver and spleen.No abnormality was found in BMD and histocompatibility.
方法：①通过乳化-溶剂挥发法制备缓释微球,以粒径、载药量、包封率为考察指标对处方中的不同因素如PLGA浓度,表面活性剂的种类及浓度,油水比,药载比进行了单因素考察。并选取重要的影响因素进行正交实验对处方进一步优化,得出各影响因素对制备过程影响强度,并筛选出最优处方；②采用超声振荡法将RFP-PLGA缓释微球灌入异体骨内,再浇盖一层壳聚糖溶液,真空干燥喷金后,用电子扫描显微镜和骨密度仪分别观察RFP-PLGA缓释复合体的填充状态、外观表面形态及灌注前后骨密度的变化；体外释放实验分成三组：A组RFP晶体、B组RFP缓释微球及C组RFP-PLGA骨缓释复合体,并采用透析袋法进行体外释放研究；③体内药动学研究分成A组RFP口服给药组、B组RFP-PLGA骨缓释复合体组、C组RFP晶体-骨复合体组,后两组植入兔腰椎骨性缺损处,并通过大体观察、影像学观察、骨密度观察、组织分布结果、生化指标检测、组织形态学观察六个方面进行对比。采用HPLC-UV法测定血浆及各组织中的药物浓度。采用SPSS17.0软件包进行分析,结果以均数±标准差即x±S表示,采用多种统计学分析方法,如t检验、方差分析及组间比较的SNK-q检验、LSD-t检验等,检验水准a=0.05,P值<0.05为差异有显著性意义。
结果：①通过单因素考察得知对考察指标具有较大影响的处方因素,在此基础上对处方进行了优化,结果中各处方因素的影响强度如下：药载比>PVA浓度>PLGA浓度>油水比,并确定较优工艺为：PLGA浓度15mg·ml-1、药载比1：2、PVA浓度2%、油水比1：5；平行制得3批微球粒径为12.23±0.98μ m；载药量、包封产率分别为(19.63±0.62)%、(59.49±2.62)%,微球冷冻干燥后,再分散性及外观良好；
②体外释放显示：A组RFP晶体在24h内释放基本完全,B组RFP缓释微球组及C组RFP.PLGA骨缓释复合体组释药平缓,其中RFP缓释微球组31d累计释药率达到近95%,释放进行动力学方程拟合,显示符合零级动力学方程F=0.168*t;RFP-PLGA骨缓释复合体组约31d累计释药率达到近92.31%,未见无明显的突释,进行动力学方程拟合,显示符合零级动力学方程F=0.15*t；骨密度检测：三组灌注前后及B、C组骨密度无明显统计学差异(P>0.05)；
③体内实验表明：A组即口服给药组虽然在局部腰椎体组织中能维持较高的有效浓度,但其在肝、脾、心、肺等脏器中也存在较高的浓度;C组即RFP晶体-骨复合体植入组,尽管在维持靶组织有效浓度的同时减小药物在其他脏器中的分布,但维持时间甚短,15天后已低于最低检测浓度；相对而言,B组RFP-PLGA骨缓释复合体植入新西兰大兔给药后,3天时RFP浓度为11±0.7μg/ml-1,在7天时RFP浓度为13.3±0.4μg/ml-1,在15天时RFP浓度为8.5±1.6μg/ml-1,在30天时RFP浓度为1.6±0.4μg/ml-1,在40天时RFP浓度为0.45±0.21μg/ml-1,均明显高于有效抑菌浓度,在体内组织中缓慢下降,不仅其他脏器中的药物浓度低,而且40天时腰椎椎体RFP浓度仍可维持有效抑菌浓度,相对于C组在局部腰椎椎体组织中RFP的有效浓度持续时间较长；骨密度检测：a.术后第7天：三组统计学比较分析：P>0.05,无明显统计学意义；b.术后第30天：A组与B、C组比较：P<0.05,有明显统计学意义；B组与C组比较：P>0.05,无明显统计学意义；c.术后第7天与第30天不同组别比较：A7组与A30组比较：P>0.05,无明显统计学意义,B7组与B30组比较：P<0.05,有明显统计学意义,C7组与C30组比较：P<0.05,有明显统计学意义；肝毒性检测：三组给药前后比较未见明显统计学差异；RFP-PLGA骨缓释复合体行内植入腰椎骨性组织后,腰椎和腰大肌组织均未见明显炎症反应,亦未见相关正常组织的破坏或形态异常。
结论：
①1、乳化-溶剂挥发法中诸多因素对微球成形和质量具有明显影响；2、筛选出最优处方即PLGA浓度15mg·mL-1、PVA浓度2%、药载比1：2及油水比1：5。
②RFP微球形态良好,粒径分布均匀,超声波振荡的方法可以与多孔隙的骨制备成RFP-PLGA骨缓释复合体,其填充效果好,三组灌注前后骨密度无明显统计学差异,具有良好的体外缓释释放性能,检测各时间点的浓度均在有效抑菌浓度以上。
③RFP-PLGA骨缓释复合体体内椎旁植入后,局部组织内RFP抗结核有效浓度可维持在持续到约40天以上,无明显心、肝、肺及脾等组织蓄积作用及毒性,骨密度无明显影响,组织相容性良好。
Objective:①To achieve the optimal method of preparation of RFP-PLGA microspheres(Ms) by O/W emulsion-solvent evaporation techniques through observation of the morphology, particle size and distribution,encapsulation and loading efficiency of Ms.(2)To observe the filling state and releasing of sustained-release Ms when combining it with allografted bone scaffold in vitro.③To observe the distribution pharmacokinetics and compatibility of RFP-PLGA-allograft bone complex in animal model to provide experimental basis for antituberculosis therapy after spinal surgery.
Methods:①The O/W emulsion solvent evaporation method was used to prepare sustained-release Ms. Particle size, drug loading and entrapment efficiency were used as the evaluation index.The PLGA concentration,O/W rate,and the type and concentration of surfactant were investigated as single factor respectively.Some important influencing factors were chose to go through orthogonal experiment to figure out their impact for optimal procedure.②The RFP-PLGA Ms was placed into allografted bone by using ultrasonic vibration,covered with a chitosan membrane.The bone densitometer and electron scanning microscope were used to observe the filling state and the morphology of the Ms as well as the change of BMD (Bone mineral density)after vacuum drying and metal spraying.The vitro releasing experiments were divided into three groups: Group A:RFPcrystal,Group B:RFP Ms;and Group C:RFP-PLGA-allograft bone complex.Three groups were investigated with bag filter method.③The pharmacokinetics in vivo experiments were divided into3groups:Group A:RFP oral dosing,Group B:RFP-PLGA-allograft bone complex and,Group C:RFP crystal-allograft bone.Group B and C were embedded into the rabbit's lumbar vertebral defect site and compared them in six aspects including observation of general condition,imaging feature,BMD,tissue distribution,biochemistry index and histomorphology.HPLC-UV method was used to detect the drug concentration in blood plasma and other tissues.The results were showed as the(x±S)and multiple statistical methods including the T test, ANOVA, SNK-q test of group comparison and LSD-t test by using the SPSS17.0.The setting, size of test was a=0.05and,p<0.05was considered the significant difference.
Results:①On the basis of the single factor exploration we knew the important influential factor and grading-up the method, the conclusion of effect intensity of each factor was:Drug/Copolymer composition> PVA concentration> PLGA concentration> O/W rate.Optimal method was:PLGA concentration15mg·ml-1,RFP/PLGA1:2,PVA concentration2%, O/W rate1:5.The mean diameter of Ms was12.33±0.98μm,with the drug loading and entrapment efficiency was (19.63±0.62)%and (59.49±2.62)%,repectively.After the cryodesiccate of Ms,the redispersibility and appearance was well.②The release in vitro showed: the RFP crystal of Group A was almost released completely in24hours;the Ms of Group B and Ms-bone complex of Group C was sustainsably released. The releasing rate of Group B was approximately up to95%totally in31days,consistent with the zero-order elimination kinetics equation:F=0.168*t.RFP-PLGA-allograft bone complex rate was approximately up to92.31%totally in31days without apparent burst release.With the zero-order elimination kinetics equation:F=0.15*t;the BMD test showed:the BMD of Group B and C showed no apparently statistical difference after filling in three groups,(p>0.05).③In vivo kinetics showed group A(oral dosing) had high drug concentration in both local lumbar vertebra and other organs like heart, liver and spleen. Group C (RFP crystal-allograft bone),although maintaining the effective concentration in target tissue and diminishing the drug concentration in other organ,its duration was short,under the minimal detectable concentration after15d.By comparison,Group B:after the RFP-PLGA-allograft bone complex inserted into New Zealand white rabbits,RFP concentration was11±0.7μg/ml-1in the3rd day,RFP concentration was13.3±0.4μg/ml-1in the7th day and RFP concentration was8.5±1.6μg/ml-1in the15th day,RFP concentration was1.6±0.4μ/ml-1in the30th day,RFP concentration was0.45±0.21μg/ml-1in the40th day,which were apparently higher than MIC.Slowly releasing in vivo tissue,the drug concentration was lower in other organ but could reach the effective sterilization concentrations in lumbar vertebra in the40th day.Compared to Group C,it maintained longer effective sterilization concentrations in local lumbar vertebra.BMD test showed:a.There were no statistical significance after the surgery for7days in three groups: three groups have no statistical difference:P>0.05;b.30days after the surgery:Group A compared with Group B and C:P<0.05;Group B compared with Group C:P>0.05;c.7d and30d after the surgery:A'group compare with A30group:P>0.05;B7group compared with B30group:P<0.05;C group compared with C30group:P<0.05; Hepatotoxicity test:the3groups showed no apparently statistical difference after the dose; After the RFP-PLGA-allograft bone complex had been embedded into lumbar vertebra,lumbar vertebra and psoas tissue didn't show any apparently inflammatory reaction and no normal tissue damage or paramorphia.
Conclusion:①A variety of factors in O/W emulsion solvent evaporation method have significant influence on morphology and quality of Ms. The optimal scheme was screened that the concentration of PLGA was15mg-mL-1;concentration of PVA was2%;RFP/PLGA1:2and O/W rate was1:5.②The RFP Ms was well shaped and,particle diameter distributed evenly.Ultrasonic oscillation worked with the poriferous allograft bone could make up RFP-PLGA-allograft bone complex,to be filled well.The BMD show no significant statistical difference after the filling.Among the three groups and with good slowly-releasing function in vitro. The drug concentration in different time point was above the MIC.③After the RFP-PLGA-allograft bone complex was implanted into para-vertebrae, the RFP concentration in local tissue could maintain above MIC over40d without apparent toxicity and no drug accumulation was found in heart,liver and spleen.No abnormality was found in BMD and histocompatibility.
引文
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