地塞米松植入剂的制备与释药行为调控
发布时间:2018-05-25 20:03
本文选题:地塞米松 + PLGA ; 参考:《上海医药工业研究院》2017年硕士论文
【摘要】:以PLGA为基质的可生物降解植入剂存在释药行为不稳定的现象,因此本课题旨在以地塞米松为模型药物,利用热熔挤出技术制备眼用植入剂,探究植入剂释药机理,实现植入剂零级释药调控。首先,建立了地塞米松含量测定的HPLC方法,并利用差示扫描量热法(DifferentialScanningCalorimetry,DSC)考察Dexa和PLGA的相容性,采用热重分析法(ThermoGravimetricAnalysis,TGA)以及杂质测定法考察Dexa的热稳定性。结果表明该HPLC方法具有良好的专属性、线性、精密度、准确度。DSC结果表明Dexa与PLGA两者具有一定的相容性。TGA和杂质测定结果表明Dexa和PLGA热稳定性良好。然后,利用热熔挤出技术制备Dexa植入剂,考察载药量、温度、转速对植入剂挤出胀大现象和体外释放行为的影响,采用DSC、X-射线粉末衍射(X-rayPowderDiffiractometry,XPRD)和扫描电子显微镜(ScanningElectronMicroscope,SEM)对植入剂进行表征。结果表明,当挤出温度为115℃,螺杆转速为30r/min时,挤出胀大比约为1,并且不受载药量的影响。挤出温度和螺杆转速对释放行为基本无影响,而载药量则影响第一天释放累积量。DSC、XPRD、SEM结果表明,Dexa主要以晶体形式存在于植入剂中。再次,通过考察pH、温度、SDS对植入剂体外释放行为的影响,建立了以含1%SDS和0.02%叠氮化钠的0.9%氯化钠溶液作为释放介质,水浴温度45℃,振摇速率为90r/min的体外加速释放方法。该方法与37℃实时释放方法具有较好的相关性。最后,通过体外释放度,质量损失,分子量变化,DSC,SEM等方法探究添加物对地塞米松植入剂释放的影响。SEM结果提示,无添加物的植入剂早期的迟滞阶段可能与植入剂致密的骨架结构有关。体外释放测定结果表明,F68、山梨醇、乳糖对Dexa植入剂的释放行为调节作用并不理想,释放曲线均呈多相,而添加甘露醇,可使植入剂体外释放近似零级释放。DSC结果表明,处方中的甘露醇经热熔挤出后依然以晶体的形式存在于体系中,并且在释放过程中,甘露醇含量越高,其从体系中释放的速率越快。质量损失,分子量变化和扫描电镜的结果表明,添加甘露醇可制备得到具有多孔结构的植入剂,而在释放过程中甘露醇溶解进一步在植入剂中形成孔道,使得PLGA降解产生的酸性物质扩散到释放介质中,从而降低PLGA的自身催化诱导降解作用。综上,加入甘露醇,采用热熔挤出法可制备得到具有孔洞结构的植入剂,体外释放过程可降低自身催化诱导降解效应,实现平稳释放。
[Abstract]:The release behavior of biodegradable implants based on PLGA is unstable. Therefore, the purpose of this paper is to use dexamethasone as model drug to prepare ophthalmic implants by hot melt extrusion, and to explore the mechanism of drug release. The control of zero-order drug release was realized. Firstly, a HPLC method for the determination of dexamethasone was established. The compatibility of Dexa and PLGA was investigated by differential scanning calorimetry (DSC). The thermal stability of Dexa was investigated by thermogravimetric analysis (TGA) and impurity determination. The results show that the HPLC method has good specificity, linearity, precision, accuracy. DSC results show that Dexa and PLGA have a certain compatibility. TGA and impurity determination results show that Dexa and PLGA have good thermal stability. Then, Dexa implants were prepared by hot melt extrusion. The effects of drug loading, temperature and rotational speed on extrusion swell and in vitro release behavior of the implants were investigated. The implants were characterized by DSC-X-ray powder diffraction X-ray diffraction (XPRD) and scanning electron microscope (SEM). The results show that when the extrusion temperature is 115 鈩,
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