载药磷酸钙骨水泥研究
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摘要
磷酸钙骨水泥在体内环境下可自凝结固化,可根据需要的形状任意塑型,是一种优良的骨填充材料。但在进行骨填充的同时,常常需给予药物预防、治疗感染,或进一步促进骨折愈合,而且在治疗的不同时期可能需要给予不同的药物进行治疗。磷酸钙骨水泥因制备过程不需要高温加热,允许多种药物和生物活性分子的载入,同时保持药物的活性和性质不变。因此磷酸钙骨水泥不仅可作为骨填充材料,而且可作为药物局部释放和控制释放的载体,应用于不同骨骼疾病的填充和治疗。本论文对符合不同临床需要的三种载药磷酸钙骨水泥进行研究。
本论文采用Biocement D配方,即固相由α—磷酸三钙、二水磷酸氢钙、羟基磷灰石和碳酸钙按58：25：8.5：8.5的质量比混合而成,液相为磷酸氢二钠和磷酸二氢钠浓度均为0.2 mol／L的等体积混合水溶液,液固混合制备磷酸钙骨水泥。
为促进骨愈合,本论文选用具有活血和促进骨愈合作用的香丹注射液(简称香丹)载入磷酸钙骨水泥。通过比较不同加载工艺优劣发现,香丹与原材料磷酸氢钙混合后,在70℃条件下烘干制备载香丹磷酸氢钙,这种工艺可以在较大范围调节香丹的载入量。故采用不同比例的香丹与磷酸氢钙混合烘干粉末作为磷酸钙骨水泥的起始原料之一,制备载不同浓度香丹磷酸钙骨水泥。并对载不同浓度香丹磷酸钙骨水泥进行表征和微观形貌观察,同时测定载不同浓度香丹磷酸钙骨水泥的药物释放行为。研究结果表明,磷酸钙骨水泥凝结时间随香丹浓度的增加而延长,浓度不高于0.2 mL／g的磷酸钙骨水泥凝结时间符合临床要求；抗压强度随香丹含量的增加而增加；香丹载入对磷酸钙骨水泥转化没有明显影响；但导致水化产物晶体形貌从颗粒状松散搭接转化为片状交织,且浓度越高片状晶体越多。在药物释放的最初4h,载入香丹浓度范围为0.1-0.5 mL／g的磷酸钙骨水泥释药量符合临床需要。因此,载入香丹浓度范围为0.1-0.2 mL／g的磷酸钙骨水泥凝结时间符合临床要求,比空白磷酸钙骨水泥具有更高的抗压强度,在初阶段药物释放量符合治疗需求。同时研究了香丹对磷酸钙骨水泥性能影响的机理,研究结果表明香丹载入会导致pH值下降,Zeta电位降低,钙元素与其它离子的键接作用增强。根据上述结果推测香丹导致磷酸钙骨水泥凝结时间延长的主要原因是：部分反应活性中心被覆盖和香丹中的极性基团导致流动性增强；香丹导致强度增强的原因可能是：香丹载入导致微观结构发生变化、香丹与部分钙发生键接。
为防止磷酸钙骨水泥中抗生素长期残留而导致耐药性发生,通过添加易溶物制备快释型磷酸钙骨水泥。考察了易溶物及其含量对磷酸钙骨水泥凝结时间、抗压强度、转化程度等的影响,欲改进磷酸钙骨水泥制备快释型磷酸钙骨水泥。同时研究添加不同量易溶物对载药磷酸钙骨水泥药物释放行为的影响。通过研究发现,随易溶物添加量的增加,其凝结时间延长,抗压强度降低,药物释放速度加快；由药物释放7d后的扫描电镜照片可观察到,随易溶物添加量的增加,磷酸钙骨水泥的孔隙率和孔径增大。含20%易溶物的磷酸钙骨水泥其凝结时间基本符合临床需要。虽然其抗压强度略微偏低,但可通过一定的方法进行改进；而且药物可在7d内完全释放。故以其为例研究快释型磷酸钙骨水泥加快药物释放的机理。主要是采用沉淀滴定法和X-射线衍射考察易溶物随药物释放进行不同时间的溶出情况,并考察随药物释放进行磷酸钙骨水泥孔隙率和孔径的变化情况。通过研究发现快释型磷酸钙骨水泥中易溶物迅速溶出,其孔隙率和孔径均比普通磷酸钙骨水泥大,药物释放速率也比普通磷酸钙骨水泥中药物释放加快。通过对快释型磷酸钙骨水泥的药物释放动力学进行拟合,发现其释放机理仍然符合基质扩散型载体的药物释放模型即Higuchi模型。上述结果表明,此快释型磷酸钙骨水泥通过易溶物溶出增大其孔隙率和孔径加速了药物的扩散释放,可防止耐药性的发生,有望应用于临床。
为实现在不同时期采用不同药物治疗的需要,本论文将载药明胶微球、另一组分药物、骨水泥原材料混合制备载双组分药物的磷酸钙骨水泥／明胶复合载体,期望实现双组分药物的先后释放。研究发现改进的乳化交联法能获得载药量较高的明胶微球。采用双波长分光光度法结合解方程的方法学可准确测定双组分药物含量。考察液／固比对载双组分药物磷酸钙骨水泥／明胶复合载体凝结成型的影响,以及不发生崩解所需液／固比。并考察载药微球加载对磷酸钙骨水泥抗压强度和转化的影响,并用双波长分光光度法测定双组分药物的释放。考察用此种方式是否可实现双组分药物的先后释放。实验结果表明,液／固比为0.85 mL／g的载双组分药物的磷酸钙骨水泥／明胶复合载体可凝结成型,置入磷酸盐缓冲溶液中也不会发生崩解,而且具有较高的抗压强度,并且微球内包裹的药物可实现进一步延迟释放,即可在一定程度上达到双组分药物先后释放的目的。
Calcium phosphate cements (CPCs) present various advantages in the repair of hard tissues, such as in vivo self-setting and the perfect fit with the implantation bed, which ensures good bone-material contact even in geometrically complex defects. In the clinical setting, at different stages after the filling of bone defects drugs are often administered at the filled site for various purposes. Antibiotics are usually administered at sufficient concentrations to prevent potential infections. Osteogenic drugs may also be administered to accelerate bone repair. The low-temperature setting of CPC allows the incorporation of a variety of drugs and biologically active molecules without deactivation or denaturalization. Therefore, in addition to serving as bone substitutes, the possibilities of using CPC as carriers for local controlled release of drugs provides attractive opportunities in the treatment of skeletal disorders. In this work, three types of drug-containing CPCs designed for different clinical requirements were studied.
The Biocement D composition was adapted for the work in this study. The solid phase contained a-tricalcium phosphate (a-TCP, a-Ca3(PO4)2), dicalcium phosphate dehydrate (DCPD, CaHPO4.2H2O), sintered hydroxyapatite (HA, Ca5(PO4)3OH) and calcium carbonate (CaCO3) in the ratio of 58/25/8.5/8.5 (w/w/w/w). The liquid phase contained equivalent volume of disodium hydrogen phosphate (0.2 mol/L Na2HPO4) and sodium dihydrogen phosphate (0.2 mol/L NaH2PO4).
The incorporation of Xiangdan injection (Xiangdan), an accelerator of bone healing, was studied. Different incorporating techniques were compared. It was found that Xangdan could be mixed with DCPD and dried with denaturalization at 70℃. Then, the concentration of incorporated Xiangdan was extended to a relatively wide range. Xiangdan was mixed with DCPD at different ratios and dried into Xiangdan-loaded DCPD, which was then used as a raw material in the subsequent preparation of Xiangdan-loaded CPCs. The physicochemical properties of CPCs containing various Xiangdan concentrations were characterized, including the microstructures and in vitro drug release kinetics. The setting time increased with increasing Xiangdan concentration in CPC, and could meet the clinic requirement at a concentration of or below 0.2mL/g. The compressive strength also increased with increasing Xiangdan concentration. No difference in phase conversion degree was observed between hydrated CPCs with and without Xiangdan. SEM found that the morphology of crystals changed from particles to plates with the increase in Xiangdan concentration. In the first 4 h, the in vitro release of Xiangdan from CPCs with a Xiangdan concentration of 0.1-0.5ml/g could satisfy with the clinic requirement. It was concluded that both the setting time and in vitro Xiangdan release from CPC with Xiangdan concentrations of 0.1-0.2ml/g could meet the requirement of clinical applications in the initial stage. In addition, the effect of Xiangdan on the Zeta potential, pH and raw materials was studied to understand the mechanisms of the influence of Xiangdan on the properties of CPCs. The addition of Xiangdan was found to result in decreased Zeta potential, pH, and the ratio of calcium ions in the fragment ions. These findings suggested that the prolonged setting time was attributed to the coverage of reaction active center of CPC as well as the polar groups of Xiangdan, which resulted in increased CPC fluidity. The increased compressive strength was attributed to the change of microstructure of CPC and the bonding between calcium and Xiangdan.
The long-retention of antibiotics in CPCs may induce the development of drug resistance. Fast-releasing CPC containing antibiotics (FRCPC) was proposed as a solution to this problem and studied in this work. The FRCPC containing different proportions of soluble component were prepared and characterized. The setting time, compressive strength, degree of the conversion, in vitro antibiotic release, and fractography of FRCPC were studied. The results showed that the setting time increased, the compressive strength decreased, the in vitro antibiotic release accelerated with increasing fraction of soluble component in FRCPC. SEM showed that the porosity and pore size increased with increasing fraction of soluble component. The setting time and compressive strength of FRCPCs containing 20 wt% soluble component were close to the requirements of clinic applications, and the in vitro release was completed within 7 d. The FRCPCs containing 20 wt% may be useful in clinical applications after appropriate modifications. The mechanisms of in vitro antibiotic release from these FRCPCs were studied. X-ray diffraction and titration revealed a rapid dissolution of the soluble component during the in vitro release, and SEM showed a higher porosity and larger pore size compared with the control CPC at the same time points. These findings explained an accelerated drug release. The release kinetics followed the Higuchi's diffusion-controlled model. These FRCPCs may prevent the development of drug resistance and may find applications in clinics.
To address the different requirements of treatment at different clinical stages, gelatin /CPCs composite containing two drug components, paracetamol and chloromycetin, were prepared to realize the temporally-ordered release of two drugs. The drug intended to be released at the late stage was encapsulated in gelatin microspheres. The drug load in microspheres was enhanced by a modified emulsion crosslink method. The concentrations of released drugs were assayed by dual-wavelength spectrophotometry. The assay was confirmed to have a high recovery, ensuring an excellent accuracy. Gelatin/CPCs composite containing two drug components were prepared by mixing CPC, free chloromycetin, and paracetamol-containing microspheres. The optimum powder:liquid ratio for the formation of CPC was studied to prevent the disintegration of gelatin/CPCs composite. The result showed that the gelatin/CPCs composite design realized the temporally-ordered release of the two drugs. At the powder:liquid ratio of 0.85g/mL, gelatin/CPCs composite containing two drug components were readily formed and could resist disintegration in aqueous solution; the compressive strength obtained at this powder:liquid ratio was within the range of the clinic applications. The delayed release of drug was realized by encapsulation in microspheres, thus successfully achieving a temporally-ordered release of two drugs from gelatin/CPCs composite.
本论文采用Biocement D配方,即固相由α—磷酸三钙、二水磷酸氢钙、羟基磷灰石和碳酸钙按58：25：8.5：8.5的质量比混合而成,液相为磷酸氢二钠和磷酸二氢钠浓度均为0.2 mol／L的等体积混合水溶液,液固混合制备磷酸钙骨水泥。
为促进骨愈合,本论文选用具有活血和促进骨愈合作用的香丹注射液(简称香丹)载入磷酸钙骨水泥。通过比较不同加载工艺优劣发现,香丹与原材料磷酸氢钙混合后,在70℃条件下烘干制备载香丹磷酸氢钙,这种工艺可以在较大范围调节香丹的载入量。故采用不同比例的香丹与磷酸氢钙混合烘干粉末作为磷酸钙骨水泥的起始原料之一,制备载不同浓度香丹磷酸钙骨水泥。并对载不同浓度香丹磷酸钙骨水泥进行表征和微观形貌观察,同时测定载不同浓度香丹磷酸钙骨水泥的药物释放行为。研究结果表明,磷酸钙骨水泥凝结时间随香丹浓度的增加而延长,浓度不高于0.2 mL／g的磷酸钙骨水泥凝结时间符合临床要求；抗压强度随香丹含量的增加而增加；香丹载入对磷酸钙骨水泥转化没有明显影响；但导致水化产物晶体形貌从颗粒状松散搭接转化为片状交织,且浓度越高片状晶体越多。在药物释放的最初4h,载入香丹浓度范围为0.1-0.5 mL／g的磷酸钙骨水泥释药量符合临床需要。因此,载入香丹浓度范围为0.1-0.2 mL／g的磷酸钙骨水泥凝结时间符合临床要求,比空白磷酸钙骨水泥具有更高的抗压强度,在初阶段药物释放量符合治疗需求。同时研究了香丹对磷酸钙骨水泥性能影响的机理,研究结果表明香丹载入会导致pH值下降,Zeta电位降低,钙元素与其它离子的键接作用增强。根据上述结果推测香丹导致磷酸钙骨水泥凝结时间延长的主要原因是：部分反应活性中心被覆盖和香丹中的极性基团导致流动性增强；香丹导致强度增强的原因可能是：香丹载入导致微观结构发生变化、香丹与部分钙发生键接。
为防止磷酸钙骨水泥中抗生素长期残留而导致耐药性发生,通过添加易溶物制备快释型磷酸钙骨水泥。考察了易溶物及其含量对磷酸钙骨水泥凝结时间、抗压强度、转化程度等的影响,欲改进磷酸钙骨水泥制备快释型磷酸钙骨水泥。同时研究添加不同量易溶物对载药磷酸钙骨水泥药物释放行为的影响。通过研究发现,随易溶物添加量的增加,其凝结时间延长,抗压强度降低,药物释放速度加快；由药物释放7d后的扫描电镜照片可观察到,随易溶物添加量的增加,磷酸钙骨水泥的孔隙率和孔径增大。含20%易溶物的磷酸钙骨水泥其凝结时间基本符合临床需要。虽然其抗压强度略微偏低,但可通过一定的方法进行改进；而且药物可在7d内完全释放。故以其为例研究快释型磷酸钙骨水泥加快药物释放的机理。主要是采用沉淀滴定法和X-射线衍射考察易溶物随药物释放进行不同时间的溶出情况,并考察随药物释放进行磷酸钙骨水泥孔隙率和孔径的变化情况。通过研究发现快释型磷酸钙骨水泥中易溶物迅速溶出,其孔隙率和孔径均比普通磷酸钙骨水泥大,药物释放速率也比普通磷酸钙骨水泥中药物释放加快。通过对快释型磷酸钙骨水泥的药物释放动力学进行拟合,发现其释放机理仍然符合基质扩散型载体的药物释放模型即Higuchi模型。上述结果表明,此快释型磷酸钙骨水泥通过易溶物溶出增大其孔隙率和孔径加速了药物的扩散释放,可防止耐药性的发生,有望应用于临床。
为实现在不同时期采用不同药物治疗的需要,本论文将载药明胶微球、另一组分药物、骨水泥原材料混合制备载双组分药物的磷酸钙骨水泥／明胶复合载体,期望实现双组分药物的先后释放。研究发现改进的乳化交联法能获得载药量较高的明胶微球。采用双波长分光光度法结合解方程的方法学可准确测定双组分药物含量。考察液／固比对载双组分药物磷酸钙骨水泥／明胶复合载体凝结成型的影响,以及不发生崩解所需液／固比。并考察载药微球加载对磷酸钙骨水泥抗压强度和转化的影响,并用双波长分光光度法测定双组分药物的释放。考察用此种方式是否可实现双组分药物的先后释放。实验结果表明,液／固比为0.85 mL／g的载双组分药物的磷酸钙骨水泥／明胶复合载体可凝结成型,置入磷酸盐缓冲溶液中也不会发生崩解,而且具有较高的抗压强度,并且微球内包裹的药物可实现进一步延迟释放,即可在一定程度上达到双组分药物先后释放的目的。
Calcium phosphate cements (CPCs) present various advantages in the repair of hard tissues, such as in vivo self-setting and the perfect fit with the implantation bed, which ensures good bone-material contact even in geometrically complex defects. In the clinical setting, at different stages after the filling of bone defects drugs are often administered at the filled site for various purposes. Antibiotics are usually administered at sufficient concentrations to prevent potential infections. Osteogenic drugs may also be administered to accelerate bone repair. The low-temperature setting of CPC allows the incorporation of a variety of drugs and biologically active molecules without deactivation or denaturalization. Therefore, in addition to serving as bone substitutes, the possibilities of using CPC as carriers for local controlled release of drugs provides attractive opportunities in the treatment of skeletal disorders. In this work, three types of drug-containing CPCs designed for different clinical requirements were studied.
The Biocement D composition was adapted for the work in this study. The solid phase contained a-tricalcium phosphate (a-TCP, a-Ca3(PO4)2), dicalcium phosphate dehydrate (DCPD, CaHPO4.2H2O), sintered hydroxyapatite (HA, Ca5(PO4)3OH) and calcium carbonate (CaCO3) in the ratio of 58/25/8.5/8.5 (w/w/w/w). The liquid phase contained equivalent volume of disodium hydrogen phosphate (0.2 mol/L Na2HPO4) and sodium dihydrogen phosphate (0.2 mol/L NaH2PO4).
The incorporation of Xiangdan injection (Xiangdan), an accelerator of bone healing, was studied. Different incorporating techniques were compared. It was found that Xangdan could be mixed with DCPD and dried with denaturalization at 70℃. Then, the concentration of incorporated Xiangdan was extended to a relatively wide range. Xiangdan was mixed with DCPD at different ratios and dried into Xiangdan-loaded DCPD, which was then used as a raw material in the subsequent preparation of Xiangdan-loaded CPCs. The physicochemical properties of CPCs containing various Xiangdan concentrations were characterized, including the microstructures and in vitro drug release kinetics. The setting time increased with increasing Xiangdan concentration in CPC, and could meet the clinic requirement at a concentration of or below 0.2mL/g. The compressive strength also increased with increasing Xiangdan concentration. No difference in phase conversion degree was observed between hydrated CPCs with and without Xiangdan. SEM found that the morphology of crystals changed from particles to plates with the increase in Xiangdan concentration. In the first 4 h, the in vitro release of Xiangdan from CPCs with a Xiangdan concentration of 0.1-0.5ml/g could satisfy with the clinic requirement. It was concluded that both the setting time and in vitro Xiangdan release from CPC with Xiangdan concentrations of 0.1-0.2ml/g could meet the requirement of clinical applications in the initial stage. In addition, the effect of Xiangdan on the Zeta potential, pH and raw materials was studied to understand the mechanisms of the influence of Xiangdan on the properties of CPCs. The addition of Xiangdan was found to result in decreased Zeta potential, pH, and the ratio of calcium ions in the fragment ions. These findings suggested that the prolonged setting time was attributed to the coverage of reaction active center of CPC as well as the polar groups of Xiangdan, which resulted in increased CPC fluidity. The increased compressive strength was attributed to the change of microstructure of CPC and the bonding between calcium and Xiangdan.
The long-retention of antibiotics in CPCs may induce the development of drug resistance. Fast-releasing CPC containing antibiotics (FRCPC) was proposed as a solution to this problem and studied in this work. The FRCPC containing different proportions of soluble component were prepared and characterized. The setting time, compressive strength, degree of the conversion, in vitro antibiotic release, and fractography of FRCPC were studied. The results showed that the setting time increased, the compressive strength decreased, the in vitro antibiotic release accelerated with increasing fraction of soluble component in FRCPC. SEM showed that the porosity and pore size increased with increasing fraction of soluble component. The setting time and compressive strength of FRCPCs containing 20 wt% soluble component were close to the requirements of clinic applications, and the in vitro release was completed within 7 d. The FRCPCs containing 20 wt% may be useful in clinical applications after appropriate modifications. The mechanisms of in vitro antibiotic release from these FRCPCs were studied. X-ray diffraction and titration revealed a rapid dissolution of the soluble component during the in vitro release, and SEM showed a higher porosity and larger pore size compared with the control CPC at the same time points. These findings explained an accelerated drug release. The release kinetics followed the Higuchi's diffusion-controlled model. These FRCPCs may prevent the development of drug resistance and may find applications in clinics.
To address the different requirements of treatment at different clinical stages, gelatin /CPCs composite containing two drug components, paracetamol and chloromycetin, were prepared to realize the temporally-ordered release of two drugs. The drug intended to be released at the late stage was encapsulated in gelatin microspheres. The drug load in microspheres was enhanced by a modified emulsion crosslink method. The concentrations of released drugs were assayed by dual-wavelength spectrophotometry. The assay was confirmed to have a high recovery, ensuring an excellent accuracy. Gelatin/CPCs composite containing two drug components were prepared by mixing CPC, free chloromycetin, and paracetamol-containing microspheres. The optimum powder:liquid ratio for the formation of CPC was studied to prevent the disintegration of gelatin/CPCs composite. The result showed that the gelatin/CPCs composite design realized the temporally-ordered release of the two drugs. At the powder:liquid ratio of 0.85g/mL, gelatin/CPCs composite containing two drug components were readily formed and could resist disintegration in aqueous solution; the compressive strength obtained at this powder:liquid ratio was within the range of the clinic applications. The delayed release of drug was realized by encapsulation in microspheres, thus successfully achieving a temporally-ordered release of two drugs from gelatin/CPCs composite.
引文
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