载双组分药物磷酸钙骨水泥控释的研究
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摘要
磷酸钙骨水泥(calcium phosphate cements, CPC)的制备避免了高温烧结的过程,适合作为多种药物的载体材料。目前已有大量载药CPC的研究报道,但主要研究的是载单组分药物的CPC的理化性质和释药行为以及释药机理等,然而临床治疗骨科疾病常需要联合用药,通过多组分药物的协同作用,增强疗效,降低毒副作用。因此仅载单组分药物的CPC难以满足临床的应用。但是载入多种药物是否会影响CPC的凝固性能、组成结构以及多组分药物体外释放的行为以及释放机理尚不清楚。
其次,骨科疾病的治疗是一个长期的过程。药物载入CPC之后,特别是具有较高溶解性的药物会很快的释放出来,不能够达到长期治疗疾病以及在骨修复的不同阶段需要不同药物的目的。另一方面,由于人体的骨骼和牙齿可看作是由胶原等天然高分子材料所构成的连续相和弥散于其中的羟基磷灰石(HA)晶粒复合而成的复合材料,因此向HA中加入明胶(Gel)等高分子材料的研究受到关注,其中包括将这种复合材料作为药物释放的载体。因此,本论文的目的之一是将两种药物PC与CAP与CPC的固相成分直接共混的方式载入CPC,研究两种药物对CPC理化性质的影响、释药行为以及释药机理；目的之二是合成载药的羟基磷灰石明胶复合材料,并通过PLGA对此复合材料进行包裹,减缓药物的释放速率,使一种药物较快释放,另一种药物缓慢释放,实现双组分药物的不同步释放。
本论文以Biocement D磷酸钙骨水泥为载体,以镇痛药对乙酰氨基酚(paracetamol,PC)和抗生素氯霉素(chloramphenicol, CAP)为药物模型,将实验分为三组,第1组和第2组分别为载PC和CAP的CPC,载药量分别为1%、3%和5%；第3组为载PC+CAP的CPC,其中PC、CAP各为1%、3%和5%,以磷酸缓冲液(PBS)为液相,液固比为0.30 ml／g,制备载一种和两种药物的CPC,并通过Gillmore双针法、X-射线衍射(XRD)、红外光谱分析(FTIR)、紫外可见光谱(UV-vis)以及力学性能实验机等对载药CPC的凝固时间、水化机理、基团变化、释药行为以及抗压强度进行检测。Gillmore双针法的结果表明PC以及CAP的载入将延迟CPC的凝固时间,并且CPC的初凝和终凝时间均随着PC和CAP载药量的增加而增加；抗压强度实验的结果显示PC能够提高CPC的抗压强度,而CAP则使CPC的抗压强度降低,对于同时载有PC和CAP的CPC而言,抗压强度随着药物含量的增加而降低,CAP对抗压强度起着主要作用；XRD和FTIR的结果说明了药物的载入没有影响CPC的相成分,并且在药物释放过程中,CPC的固相成分逐渐向HA转化,但磷酸钙盐和药物的基团没有发生变化；药物释放结果表明,将药物直接与CPC粉末共混载入CPC中,两种药物的释放是同时进行的,载单组分和双组分药物的CPC中药物在释放前期(约24 h)都存在着突释效应,并且在药物释放后期,载单组分药物的释药速率要和释药总量上均存要高于载双组分药物,这与载体材料以及药物的性质等有关,但其释放均满足Higuchi药物扩散释放模型。
本论文采用湿法合成载有丹酚酸B (Sal B)的羟基磷灰石浆料(mSal B：mHA=0.1：1),然后通过共混的方式加入不同含量的明胶(mGel：mHA=5%,10%,15%),制备载药羟基磷灰石明胶复合材料并对复合材料中的明胶进行交联,通过XRD,扫描电镜(SEM),透射电镜(TEM)等对复合材料的结晶度以及形貌进行分析。XRD结果表明SalB的加入能够降低羟基磷灰石的结晶度以及晶粒尺寸；SEM和TEM结果表明当复合材料中的明胶的含量高于5%后,对其中的明胶进行交联能显著的改变复合材料的微观形貌；药物释放结果表明在药物突释阶段,载有Sal B羟基磷灰石的药物突释量要高于其它组,在药物稳定释放阶段,随着明胶含量的增加以及进行交联,Sal B的释药速率逐渐降低,释药速率顺序为HA/Sal B> 10%Gel> 15%Gel> 10%Gel crosslinked > 15%Gel crosslinked。
虽然明胶和通过对复合材料中的明胶进行交联可以延长药物释放的时间,但是始终存在着药物突释和明胶量过大容易发生溶胀等问题。若降低明胶的含量则达不到较好的缓释效果。因此,采用聚乳酸-羟基乙酸共聚物(PLGA)对载Sal B的羟基磷灰石明胶复合材料进行包裹(mPLGA:mHA/Gel=0.08:1),选用HA/α-TCP磷酸钙骨水泥作为药物释放的载体[所选用的HA分别为前面实验所制的HA/Gel、PLGA (HA/Gel)、HA/Gel+10%Sal B和PLGA (HA/Gel+10%Sal B)],将实验分为四组,第1组是以HA和PLGA (HA/Gel)固相成分之一的空白组[CPC, PLGA/(CPC)];第2组是以HA和PLGA (HA/Gel)固相成分之一的载PC磷酸钙骨水泥[PC/CPC, PLGA/(CPC/PC)];第3组为载有Sal B包裹PLGA和未包裹PLGA的磷酸钙骨水泥[CPC/Sal B, PLGA/(CPC/Sal B)];第4组为载PC+Sal B包裹PLGA和未包裹PLGA的磷酸钙骨水泥CPC/PC,SalB, PLGA/(CPC/PC,Sal B)],其中PC的含量为5%,Sal B的含量为10%,以PBS为液相,液固比为0.3 ml／g,制备载一种和两种药物的CPC。同样采用Gillmore双针法等表征手段对载药CPC的各种性能进行检测,此外还通过细胞培养的方法检测材料以及药物对成骨细胞的增殖情况。Gillmore双针法表明药物以及PLGA的加入能够延长CPC的凝固时间；抗压强度实验说明了PC以及Sal B的加入能够增加CPC的抗压强度,并且加入PLGA,明胶后,CPC的断裂表现为一定的塑性变形；XRD以及FTIR结果显示药物以及PLGA的载入没有影响CPC的相成分,并且在药物释放过程中,CPC的固相成分逐渐向HA转化；药物释放结果表明,通过将PC直接与CPC固相粉末共混,而采用包裹有PLGA的载有SalB的羟基磷灰石明胶复合材料作为CPC的固相成分之一,制备载有两种药物的CPC,其中PC能够较快的释放,而Sal B的释放较缓慢。载单组分和双组分药物的CPC中药物的释放可以分成突释和药物稳定释放阶段。对比载单组分和双组分CPC药物的释放,都存在着突释效应,并且载单组分和双组分药物CPC中药物的释放在释药速率以及释药总量上均存在差异,双组分药物的释药速率低于单组分的,并且在趋于平衡的时候,双组分药物释药总量低于单组分的释药总量,细胞实验表明Sal B的加入能够显著的促进细胞的增殖,而PC的加入则在一定程度上抑制了细胞的增殖,同时加入PC和Sal B仍然能够促进细胞的增殖。
本研究通过两种不同制备工艺,制备了载双组分的CPC。将PC和CAP通过共混的方式直接载入CPC中,两种药物同时释放,药物的释放符合Higuchi药物扩散释放模型；采用PLGA将载有Sal B的羟基磷灰石明胶复合材料进行包裹,作为CPC的固相成分之一,合成载有两种药物的CPC,可实现一种药物(PC)较快的释放,另一种药物(Sal B)能够缓慢的释放,以满足临床骨修复不同阶段对不同药物的需要。
Calcium phosphate cements (CPC) has been widely used as drug carrier for the preparation of CPC due to avoiding high temperature sintering process. Although there were many research reports about CPC as drug carrier, it was focused on the physicochemical properties, release behavior and drug release mechanism of CPC loaded with only one drug. However, drug combination was always needed in the treatment of orthopedic disease in Clinical Practice, which can enhance the effect and alleviate the toxicity adverse effect. Therefore CPC loaded with one drug dissatisfy with demands of clinical requirements. But the setting time, composition structure, release behavior and drug release mechanism were still unclear when CPC loaded with one more drugs.
The treatment of orthopedic disease was a long-term course. When loaded with drugs, especially high solubility drugs always release fast and cannot reach the purpose of long-term treatment. It is well known that body skeleton and tooth can be considered as composite which composed with collagen and HA. Therefore adding polymer such as gelatin to HA have been widely researched, this includes use this composite as drug carrier. Our aim was to study the physicochemical properties, release behavior and drug release mechanism of CPC loaded with two drugs and was to regulate the drug release rate by encapsulating one of the drugs, with the hope of one drug release fast and the other release relatively slow.
Firstly, Biocement D cements was used as drug carrier and paracetamol (PC) and chJoramphenicol (CAP), which were chosen as model drugs to prepare two drug-loaded CPC. The experiment was assigned into 3 groups, the first group loaded with PC and the second group loaded with CAP, the drug loading was 1%、3%and 5%, respectively. The third group loaded with (PC+CAP), the drug loading of PC and CAP was 1％、3%and 5%, respectively. The influence of the drugs on setting time, phase composition of CPC, drug release behavior and compressive strength were characterized by Gilmore Needle, XRD, FTIR, UV-vis and mechanical property tester. Gilmore Needle results showed that drugs could increase the setting time and increase with drug content. Mechanical results showed that PC can increase the compressive strength of CPC. but CAP decreased the compressive strength of CPC, PC and CAP decreased the compressive strength of CPC. XRD and FTIR results showed that during the drug release process, the composition of CPC was conversed to hydroxyapatite (HA) gradually, but had no influence on the group of phosphate radical. The release results showed that the release of PC and CAP blended was carried out simultaneously. The release rate and total amount of releasing of CPC loaded with two-component drugs was different with CPC loaded with one drug, but the release kinetics of the drugs followed the Higuchi diffusion equation independently.
Secondly, HA/gelatin (HA/Gel) composites was used as drug carrier and Salvianolic acid B (Sal B), whcih was chosen as model drugs to prepare drug-loaded CPC. Results showed that added gelatin into HA and cross linked gelatin can increase release time, and the order of drug release rate was HA/Sal B> 10%Gel> 15%Gel> 10%Gel crosslinked> 15%Gel crosslinked, but there was still exit the burst release and swelle of gelatin in solution if the content of gelatin was large and it cannot achieve slow release effect if decreased the content of gelatin.
PLGA was used to encapsulate the HA/Gel. which was loaded with Sal B, then used this composites as one of composition of CPC (40%HA+60%α-TCP) and PC as well as Sal B to prepare drug-loaded CPC. The experiment was assigned into 4 groups; these groups were blank control group [CPC. PLGA/(CPC)], loaded with PC [PC/CPC, PLGA/(CPC/PC)], loaded with Sal B[CPC/Sal B, PLGA/(CPC/Sal B)] and loaded with PC+Sal B [CPC/PC,Sal B, PLGA/(CPC/PC,Sal B)], respectively. Gilmore Needle results showed that drugs and PLGA could increase the setting time. Mechanical results showed that PC and Sal B could increase the compressive strength of CPC; moreover, plastic deformation was existed in CPC when PLGA and gelatin was added into CPC. XRD and FTIR results showed that the composition of CPC conversed to HA gradually, but had no influence on the group of phosphate radical. Release results illuminated that the release rate and total amount of releasing of CPC loaded with two-component drugs was different with CPC loaded with one drug, the release of Sal B was slower for the HA/Gel was encapsulated with PLGA, the release of PC was faster:the results of cell culture showed that Sal B could significantly promote the cell proliferation, but PC could inhibit the cell proliferation in some degree.
The release of PC and CAP were carried out simultaneously, when PC and CAP were blended with CPC, and the release kinetics of the drugs followed the Higuchi diffusion equation independently. However, the release behavior was changed when HA/Gel used as composition of CPC which was encapsulated with PLGA. PC can release faster than CAP.
其次,骨科疾病的治疗是一个长期的过程。药物载入CPC之后,特别是具有较高溶解性的药物会很快的释放出来,不能够达到长期治疗疾病以及在骨修复的不同阶段需要不同药物的目的。另一方面,由于人体的骨骼和牙齿可看作是由胶原等天然高分子材料所构成的连续相和弥散于其中的羟基磷灰石(HA)晶粒复合而成的复合材料,因此向HA中加入明胶(Gel)等高分子材料的研究受到关注,其中包括将这种复合材料作为药物释放的载体。因此,本论文的目的之一是将两种药物PC与CAP与CPC的固相成分直接共混的方式载入CPC,研究两种药物对CPC理化性质的影响、释药行为以及释药机理；目的之二是合成载药的羟基磷灰石明胶复合材料,并通过PLGA对此复合材料进行包裹,减缓药物的释放速率,使一种药物较快释放,另一种药物缓慢释放,实现双组分药物的不同步释放。
本论文以Biocement D磷酸钙骨水泥为载体,以镇痛药对乙酰氨基酚(paracetamol,PC)和抗生素氯霉素(chloramphenicol, CAP)为药物模型,将实验分为三组,第1组和第2组分别为载PC和CAP的CPC,载药量分别为1%、3%和5%；第3组为载PC+CAP的CPC,其中PC、CAP各为1%、3%和5%,以磷酸缓冲液(PBS)为液相,液固比为0.30 ml／g,制备载一种和两种药物的CPC,并通过Gillmore双针法、X-射线衍射(XRD)、红外光谱分析(FTIR)、紫外可见光谱(UV-vis)以及力学性能实验机等对载药CPC的凝固时间、水化机理、基团变化、释药行为以及抗压强度进行检测。Gillmore双针法的结果表明PC以及CAP的载入将延迟CPC的凝固时间,并且CPC的初凝和终凝时间均随着PC和CAP载药量的增加而增加；抗压强度实验的结果显示PC能够提高CPC的抗压强度,而CAP则使CPC的抗压强度降低,对于同时载有PC和CAP的CPC而言,抗压强度随着药物含量的增加而降低,CAP对抗压强度起着主要作用；XRD和FTIR的结果说明了药物的载入没有影响CPC的相成分,并且在药物释放过程中,CPC的固相成分逐渐向HA转化,但磷酸钙盐和药物的基团没有发生变化；药物释放结果表明,将药物直接与CPC粉末共混载入CPC中,两种药物的释放是同时进行的,载单组分和双组分药物的CPC中药物在释放前期(约24 h)都存在着突释效应,并且在药物释放后期,载单组分药物的释药速率要和释药总量上均存要高于载双组分药物,这与载体材料以及药物的性质等有关,但其释放均满足Higuchi药物扩散释放模型。
本论文采用湿法合成载有丹酚酸B (Sal B)的羟基磷灰石浆料(mSal B：mHA=0.1：1),然后通过共混的方式加入不同含量的明胶(mGel：mHA=5%,10%,15%),制备载药羟基磷灰石明胶复合材料并对复合材料中的明胶进行交联,通过XRD,扫描电镜(SEM),透射电镜(TEM)等对复合材料的结晶度以及形貌进行分析。XRD结果表明SalB的加入能够降低羟基磷灰石的结晶度以及晶粒尺寸；SEM和TEM结果表明当复合材料中的明胶的含量高于5%后,对其中的明胶进行交联能显著的改变复合材料的微观形貌；药物释放结果表明在药物突释阶段,载有Sal B羟基磷灰石的药物突释量要高于其它组,在药物稳定释放阶段,随着明胶含量的增加以及进行交联,Sal B的释药速率逐渐降低,释药速率顺序为HA/Sal B> 10%Gel> 15%Gel> 10%Gel crosslinked > 15%Gel crosslinked。
虽然明胶和通过对复合材料中的明胶进行交联可以延长药物释放的时间,但是始终存在着药物突释和明胶量过大容易发生溶胀等问题。若降低明胶的含量则达不到较好的缓释效果。因此,采用聚乳酸-羟基乙酸共聚物(PLGA)对载Sal B的羟基磷灰石明胶复合材料进行包裹(mPLGA:mHA/Gel=0.08:1),选用HA/α-TCP磷酸钙骨水泥作为药物释放的载体[所选用的HA分别为前面实验所制的HA/Gel、PLGA (HA/Gel)、HA/Gel+10%Sal B和PLGA (HA/Gel+10%Sal B)],将实验分为四组,第1组是以HA和PLGA (HA/Gel)固相成分之一的空白组[CPC, PLGA/(CPC)];第2组是以HA和PLGA (HA/Gel)固相成分之一的载PC磷酸钙骨水泥[PC/CPC, PLGA/(CPC/PC)];第3组为载有Sal B包裹PLGA和未包裹PLGA的磷酸钙骨水泥[CPC/Sal B, PLGA/(CPC/Sal B)];第4组为载PC+Sal B包裹PLGA和未包裹PLGA的磷酸钙骨水泥CPC/PC,SalB, PLGA/(CPC/PC,Sal B)],其中PC的含量为5%,Sal B的含量为10%,以PBS为液相,液固比为0.3 ml／g,制备载一种和两种药物的CPC。同样采用Gillmore双针法等表征手段对载药CPC的各种性能进行检测,此外还通过细胞培养的方法检测材料以及药物对成骨细胞的增殖情况。Gillmore双针法表明药物以及PLGA的加入能够延长CPC的凝固时间；抗压强度实验说明了PC以及Sal B的加入能够增加CPC的抗压强度,并且加入PLGA,明胶后,CPC的断裂表现为一定的塑性变形；XRD以及FTIR结果显示药物以及PLGA的载入没有影响CPC的相成分,并且在药物释放过程中,CPC的固相成分逐渐向HA转化；药物释放结果表明,通过将PC直接与CPC固相粉末共混,而采用包裹有PLGA的载有SalB的羟基磷灰石明胶复合材料作为CPC的固相成分之一,制备载有两种药物的CPC,其中PC能够较快的释放,而Sal B的释放较缓慢。载单组分和双组分药物的CPC中药物的释放可以分成突释和药物稳定释放阶段。对比载单组分和双组分CPC药物的释放,都存在着突释效应,并且载单组分和双组分药物CPC中药物的释放在释药速率以及释药总量上均存在差异,双组分药物的释药速率低于单组分的,并且在趋于平衡的时候,双组分药物释药总量低于单组分的释药总量,细胞实验表明Sal B的加入能够显著的促进细胞的增殖,而PC的加入则在一定程度上抑制了细胞的增殖,同时加入PC和Sal B仍然能够促进细胞的增殖。
本研究通过两种不同制备工艺,制备了载双组分的CPC。将PC和CAP通过共混的方式直接载入CPC中,两种药物同时释放,药物的释放符合Higuchi药物扩散释放模型；采用PLGA将载有Sal B的羟基磷灰石明胶复合材料进行包裹,作为CPC的固相成分之一,合成载有两种药物的CPC,可实现一种药物(PC)较快的释放,另一种药物(Sal B)能够缓慢的释放,以满足临床骨修复不同阶段对不同药物的需要。
Calcium phosphate cements (CPC) has been widely used as drug carrier for the preparation of CPC due to avoiding high temperature sintering process. Although there were many research reports about CPC as drug carrier, it was focused on the physicochemical properties, release behavior and drug release mechanism of CPC loaded with only one drug. However, drug combination was always needed in the treatment of orthopedic disease in Clinical Practice, which can enhance the effect and alleviate the toxicity adverse effect. Therefore CPC loaded with one drug dissatisfy with demands of clinical requirements. But the setting time, composition structure, release behavior and drug release mechanism were still unclear when CPC loaded with one more drugs.
The treatment of orthopedic disease was a long-term course. When loaded with drugs, especially high solubility drugs always release fast and cannot reach the purpose of long-term treatment. It is well known that body skeleton and tooth can be considered as composite which composed with collagen and HA. Therefore adding polymer such as gelatin to HA have been widely researched, this includes use this composite as drug carrier. Our aim was to study the physicochemical properties, release behavior and drug release mechanism of CPC loaded with two drugs and was to regulate the drug release rate by encapsulating one of the drugs, with the hope of one drug release fast and the other release relatively slow.
Firstly, Biocement D cements was used as drug carrier and paracetamol (PC) and chJoramphenicol (CAP), which were chosen as model drugs to prepare two drug-loaded CPC. The experiment was assigned into 3 groups, the first group loaded with PC and the second group loaded with CAP, the drug loading was 1%、3%and 5%, respectively. The third group loaded with (PC+CAP), the drug loading of PC and CAP was 1％、3%and 5%, respectively. The influence of the drugs on setting time, phase composition of CPC, drug release behavior and compressive strength were characterized by Gilmore Needle, XRD, FTIR, UV-vis and mechanical property tester. Gilmore Needle results showed that drugs could increase the setting time and increase with drug content. Mechanical results showed that PC can increase the compressive strength of CPC. but CAP decreased the compressive strength of CPC, PC and CAP decreased the compressive strength of CPC. XRD and FTIR results showed that during the drug release process, the composition of CPC was conversed to hydroxyapatite (HA) gradually, but had no influence on the group of phosphate radical. The release results showed that the release of PC and CAP blended was carried out simultaneously. The release rate and total amount of releasing of CPC loaded with two-component drugs was different with CPC loaded with one drug, but the release kinetics of the drugs followed the Higuchi diffusion equation independently.
Secondly, HA/gelatin (HA/Gel) composites was used as drug carrier and Salvianolic acid B (Sal B), whcih was chosen as model drugs to prepare drug-loaded CPC. Results showed that added gelatin into HA and cross linked gelatin can increase release time, and the order of drug release rate was HA/Sal B> 10%Gel> 15%Gel> 10%Gel crosslinked> 15%Gel crosslinked, but there was still exit the burst release and swelle of gelatin in solution if the content of gelatin was large and it cannot achieve slow release effect if decreased the content of gelatin.
PLGA was used to encapsulate the HA/Gel. which was loaded with Sal B, then used this composites as one of composition of CPC (40%HA+60%α-TCP) and PC as well as Sal B to prepare drug-loaded CPC. The experiment was assigned into 4 groups; these groups were blank control group [CPC. PLGA/(CPC)], loaded with PC [PC/CPC, PLGA/(CPC/PC)], loaded with Sal B[CPC/Sal B, PLGA/(CPC/Sal B)] and loaded with PC+Sal B [CPC/PC,Sal B, PLGA/(CPC/PC,Sal B)], respectively. Gilmore Needle results showed that drugs and PLGA could increase the setting time. Mechanical results showed that PC and Sal B could increase the compressive strength of CPC; moreover, plastic deformation was existed in CPC when PLGA and gelatin was added into CPC. XRD and FTIR results showed that the composition of CPC conversed to HA gradually, but had no influence on the group of phosphate radical. Release results illuminated that the release rate and total amount of releasing of CPC loaded with two-component drugs was different with CPC loaded with one drug, the release of Sal B was slower for the HA/Gel was encapsulated with PLGA, the release of PC was faster:the results of cell culture showed that Sal B could significantly promote the cell proliferation, but PC could inhibit the cell proliferation in some degree.
The release of PC and CAP were carried out simultaneously, when PC and CAP were blended with CPC, and the release kinetics of the drugs followed the Higuchi diffusion equation independently. However, the release behavior was changed when HA/Gel used as composition of CPC which was encapsulated with PLGA. PC can release faster than CAP.
引文
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