本文選題：地塞米松 + PLGA　； 參考：《上海醫(yī)藥工業(yè)研究院》2017年碩士論文

【摘要】：以PLGA為基質的可生物降解植入劑存在釋藥行為不穩(wěn)定的現(xiàn)象,因此本課題旨在以地塞米松為模型藥物,利用熱熔擠出技術制備眼用植入劑,探究植入劑釋藥機理,實現(xiàn)植入劑零級釋藥調控。首先,建立了地塞米松含量測定的HPLC方法,并利用差示掃描量熱法(DifferentialScanningCalorimetry,DSC)考察Dexa和PLGA的相容性,采用熱重分析法(ThermoGravimetricAnalysis,TGA)以及雜質測定法考察Dexa的熱穩(wěn)定性。結果表明該HPLC方法具有良好的專屬性、線性、精密度、準確度。DSC結果表明Dexa與PLGA兩者具有一定的相容性。TGA和雜質測定結果表明Dexa和PLGA熱穩(wěn)定性良好。然后,利用熱熔擠出技術制備Dexa植入劑,考察載藥量、溫度、轉速對植入劑擠出脹大現(xiàn)象和體外釋放行為的影響,采用DSC、X-射線粉末衍射(X-rayPowderDiffiractometry,XPRD)和掃描電子顯微鏡(ScanningElectronMicroscope,SEM)對植入劑進行表征。結果表明,當擠出溫度為115℃,螺桿轉速為30r/min時,擠出脹大比約為1,并且不受載藥量的影響。擠出溫度和螺桿轉速對釋放行為基本無影響,而載藥量則影響第一天釋放累積量。DSC、XPRD、SEM結果表明,Dexa主要以晶體形式存在于植入劑中。再次,通過考察pH、溫度、SDS對植入劑體外釋放行為的影響,建立了以含1%SDS和0.02%疊氮化鈉的0.9%氯化鈉溶液作為釋放介質,水浴溫度45℃,振搖速率為90r/min的體外加速釋放方法。該方法與37℃實時釋放方法具有較好的相關性。最后,通過體外釋放度,質量損失,分子量變化,DSC,SEM等方法探究添加物對地塞米松植入劑釋放的影響。SEM結果提示,無添加物的植入劑早期的遲滯階段可能與植入劑致密的骨架結構有關。體外釋放測定結果表明,F68、山梨醇、乳糖對Dexa植入劑的釋放行為調節(jié)作用并不理想,釋放曲線均呈多相,而添加甘露醇,可使植入劑體外釋放近似零級釋放。DSC結果表明,處方中的甘露醇經熱熔擠出后依然以晶體的形式存在于體系中,并且在釋放過程中,甘露醇含量越高,其從體系中釋放的速率越快。質量損失,分子量變化和掃描電鏡的結果表明,添加甘露醇可制備得到具有多孔結構的植入劑,而在釋放過程中甘露醇溶解進一步在植入劑中形成孔道,使得PLGA降解產生的酸性物質擴散到釋放介質中,從而降低PLGA的自身催化誘導降解作用。綜上,加入甘露醇,采用熱熔擠出法可制備得到具有孔洞結構的植入劑,體外釋放過程可降低自身催化誘導降解效應,實現(xiàn)平穩(wěn)釋放。
[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，

本文編號：1934500