羟基磷灰石/胶原/聚乳酸三维多孔储存式药物控释载体的制备及其表征

背景:在骨科病的临床治疗中传统的给药方式容易引起血药浓度的较大波动和副作用,而植入式药物载体材料羟基磷灰石的机械性能较差使之难以应用于人体的承重部位,聚乳酸又易降解成酸性产物。研究制备羟基磷灰石/聚乳酸药物载体能仅对病患部位直接持续释放药物同时减少对其他部位的副作用,另外可获得羟基磷灰石和聚乳酸相互补强的功能,并消除组织炎症反应,促进骨组织再生。目的:观察可吸收靶向式药物控释载体的制备及模拟药物的应用情况。设计:观察试验。单位:重庆工学院与武汉理工大学。材料:大白鼠鼠尾及聚乳酸(武汉理工大学生物中心提供),胃蛋白酶(1∶10000,Sigma公司),Ca(OH)2、浓磷酸、NaOH、冰醋酸、磷酸盐缓冲液(pH=7.4配制)、1,4-二氧六环、无水乙醇等均为市购分析纯。方法:实验于2004-05/2006-03在重庆工学院及武汉理工大学完成。①采取酸溶法和碱提纯法制备鼠尾Ⅰ型胶原蛋白,在体外模拟天然骨的生物矿化过程,利用材料的自组装机制合成纳米羟基磷灰石/胶原类骨仿生复合材料,并采用X射线衍射分析和透射电镜观察对材料进行了结构、形貌的表征。②采用热致分相技术将制得的羟基磷灰石/胶原复合材料进一步与聚乳酸复合制备了具备特殊几何形状的三维多孔生物可吸收储存式药物控释载体,同时采用扫描电镜、材料试验机和比重测试法对比下观察孔结构形貌及其力学性能等。③将制得的羟基磷灰石/胶原/聚乳酸药物载体装填模型化合物溴百里酚蓝,在模拟体液中进行体外释放实验研究了其控释特性。主要观察指标:①羟基磷灰石/胶原类骨仿生复合材料制备后结构、形貌的表征。②羟基磷灰石/胶原/聚乳酸药物载体制备后的性能及制备工艺评估。③模型化合物体外控释试验结果评估。结果:①薄针片状纳米羟基磷灰石在胶原基质上生成并以其晶格c轴择优取向排列。②羟基磷灰石/胶原/聚乳酸药物载体具有适合药物控释的孔结构和和物理性能。③模型药物的体外释放试验表明药物在达到85%释放率之前近似为零级缓慢释放。结论:羟基磷灰石/胶原复合材料与天然骨类似,羟基磷灰石/胶原/聚乳酸储存式载体能达到控制释放的目的。

Preparation and characterization of hydroxyapatite/collagen/poly-L-lactic acid three-dimensional porous reservoir type drug carrier for controlled release

BACKGROUND: In the clinical therapy for orthopedic diseases, the traditional administration easily induces the great fluctuation of drug concentration and side effect, and implanted drug carrier material hydroxyapatite (Hap) cannot be used in human's load bearing parts due to its poor mechanical performances, and poly-L-lactic acid (PLLA) is effortlessly degraded to acid byproducts. Drug carriers made from Hap/PLLA are supposed to not only persist releasing drug onto the lesion and reduce the side effect,but also obtain strength enhancement and eliminate tissue inflammatory reaction in favor of bone regeneration.OBJECTIVE: To observe the preparation of absorbable target control-release drug carrier and simulate the application of drugs.DESIGN: Observation trial.SETTING: Chongqing Institute of Technology and Wuhan University of Technology.MATERIALS: Tails of albino rats and PLLA (offered by Biological Center of Wuhan University of Technology), pepsin (1:10 000, Sigma company), Ca(OH)2, strong phosphoric, NaOH, glacial acetic acid, phosphate buffer (pH=7.4), 1,4-dioxane, absolute alcohol (Analytical reagent available on market).METHODS: The experiment was carried out in Chongqing Institute of Technology and Wuhan University of Technology. ①Type Ⅰ collagen (Col)was prepared by acid dissolution and alkali purification methods. Hap/Col bone-like biomimetic composite was synthesized through self-assembly mechanism of materials simulating in vitro biomineralization process of nature bone. X ray diffraction analysis and transmission electron microscope were applied to observe the characterization of composite's structure and morphology. ②The resultant product of HAP/Col composite was further synthesized with PLLA to prepare the three-dimensional porous reservoir type carrier for controlled release of drug employing thermal-induced phase separation technique. Scanning electron microscope, material test machine and specific gravity test method were used to investigate the pore structure and mechanical property of carrier material. ③The prepared Hap/Col/PLLA drug carrier was loaded with bromothymol blue to investigate in vitro control-release characteristic in simulated body fluid.MAIN OUTCOME MEASURES: ①Characterization of structure and morphology of Hap/Col bone-like biomimetic composite; ②Evaluation on the property and preparation technique of Hap/Col/PLLA drug carrier; ③Assessment on results of in vitro control-release trail of model composite.RESULTS: ①Hap nanocrystals formed as slender needles aligning with its crystalline c-axis preferentially oriented.②Hap/Col/PLLA drug carrier possessed apt pore configuration and physical properties for drug controlrelease.③In vitro release test by model compound revealed an approximate zero-orderslow release prior to its 80% release percentage.CONCLUSION: Hap/Col composite material is similar with natural bone, and Hap/Col/PLLA reservoir carrier can control drug release.