本文選題：水難溶性藥物 + 納米乳給藥系統(tǒng)��； 參考：《廣東藥學院》2014年碩士論文

【摘要】：目的：以BCSⅡ類（Biopharmaceutics Classification System，BCS）難溶性藥物為模型藥物，設計納米乳給藥系統(tǒng)（(self)namoemulsion drug delivery system,(S)NEDDS），采用體外細胞模型，脂解模型及體內(nèi)藥動學模型研究脂解與非脂解條件下的納米乳口服吸收機理。 方法（：1）BCSII模型藥物NEDDS處方設計及質(zhì)量評價研究。通過測定4個BCSII類難溶性藥物在輔料中的溶解度選擇NEDDS處方成分，繪制偽三元相圖選擇最優(yōu)處方組成成分及比例。采用激光粒度測定儀測定粒徑及觀察載藥NEDDS24h內(nèi)穩(wěn)定性對載藥處方進行評價。 （2）BCSII模型藥物體外細胞膜滲透研究。構建MDCK細胞模型，比較4個BCSII類難溶性藥物NEDDS與其飽和水溶液的累積滲透百分率（CP%）及表觀滲透系數(shù)(Papp)，考察NEDDS對難溶性藥物細胞轉運滲透性的影響。 （3）桂利嗪中鏈油自納米乳（CIN-MCT-SNEDDS）處方設計及質(zhì)量評價研究。通過考察各輔料的混合均一性，優(yōu)選處方輔料，繪制偽三元相圖并結合藥物在輔料中的溶解度，確定優(yōu)選處方。通過測定自乳化速率、透光率和粒徑、以及考察不同載藥量SNEDDS的穩(wěn)定性對優(yōu)選處方進行評價。 （4）體外脂解模型的建立與優(yōu)化研究。通過參考文獻，建立體外脂解模型，并以MCT-SNEDDS脂解的速度與程度為指標，對胰脂酶濃度、膽鹽/磷脂膠束濃度、滴定用NaOH濃度、Trizma maleate濃度以及Ca2+加入方式等條件作進行優(yōu)化考察。 （5）CIN-MCT-SNEDDS脂解過程中CIN在各相中的動態(tài)分布及溶解度變化研究。采用已優(yōu)化的體外脂解模型進行CIN-MCT-SNEDDS脂解試驗，于不同時間點取樣，以臺式離心和超速離心的方式分離脂解液各相，HPLC測定不同時間點各相中藥物含量；對比CIN-MCT-SNEDDS脂解與非脂解條件下，水相中藥物的溶解度變化。 （6）CIN-MCT-SNEDDS大鼠體內(nèi)藥物動力學研究。比較CIN-MCT-SNEDDS與其混懸液（CIN-SUSP）藥物動力學。采用SD大鼠口服給藥，于給藥前、給藥后不同時間點取血、分離血漿，乙腈沉淀蛋白，HPLC測定血藥濃度。繪制各給藥組的平均血藥濃度-時間曲線，，線性梯形法計算藥時曲線下面積（AUC），并比較各主要藥動學參數(shù)。 結果：（1）BCSII模型藥物NEDDS處方設計及體外評價。NEDDS最優(yōu)處方比例組成為MCT oil: Tween80/Span80(HLB=11):水相=8:10:82(W/W)。在最優(yōu)處方比例下，制備4個難溶性藥物載藥NEDDS均能形成略帶藍色乳光的半透明納米乳液，粒徑在80nm以下，放置24h后均無藥物析出，穩(wěn)定性較好。 （2）BCSII模型藥物體外細胞膜滲透研究。NEDDS均可顯著性的提高GRI、IND、KET、PHE的溶解度，但GRI、IND、KET、PHE的NEDDS在MDCK細胞模型的轉運累積滲透百分率（CP%）和滲透系數(shù)（Papp）均明顯低于難溶性藥物的飽和水溶液（P 0.05）。 （3）CIN-SNEDDS處方設計及質(zhì)量評價。CIN-MCT-SNEDDS的最優(yōu)處方為（MCToil：辛酸=5:5）: Cremophor RH40: Ethanol=3:5:2。體外評價結果顯示MCT-SNEDDS在水、pH6.8消化緩沖液及膽鹽/磷脂膠束溶液中均能于3min內(nèi)形成均一、透明的納米乳液，粒徑29nm，載藥量為25mg的CIN-MCT-SNEDDS分散于上述介質(zhì)中放置24h均無藥物析出，體系均一穩(wěn)定。 （4）體外脂解模型的建立與優(yōu)化。確定體外脂解模型各條件為NaCl:50Mm；Trizma maleate:50mM；Ca2+:5mM（一次加入）；NaTDC/PC:5mM/1.25mM；胰脂酶:800TBU/mL；NaOH:1M。 （5）CIN在各溶液中的溶解度大小順序為MCT-SNEDDS脂解液可分離出水相和沉淀相，水相中CIN含量隨脂解的進行逐漸下降，沉淀相中藥物沉淀增加量與水相藥物含量下降趨勢相一致；CIN-MCT-SNEDDS在脂解狀態(tài)下藥物逐漸析出，在非脂解狀態(tài)下無藥物析出，但CIN-MCT-SNEDDS脂解60min后水相中的藥物濃度仍比其在水相中的飽和溶解度約高3倍。CIN溶解度大小為：pH1.2HCl脂解液水相NATDC/PC膠束溶液消化緩沖液≈水。還有在納米乳中的溶解度 （6）CIN-MCT-SNEDDS大鼠體內(nèi)藥物動力學研究。CIN口服后體內(nèi)吸收過程出現(xiàn)雙峰現(xiàn)象，CIN-MCT-SNEDDS與CIN-SUSP主要的藥動學參數(shù)C1max、C2max、T1max、T2max、 AUC0~24分別為0.44μg/mL、0.63μg/mL、2h、8h和6.27μg.h/mL與。。。。。。。。。。；與CIN-SUSP相比，CIN-SNEDDS主要藥動學參數(shù)C1max、C2max和AUC0~24顯著性增加，F(xiàn)r為179.66%，T2max明顯延長。 結論：NEDDS可提高4個模型藥物的的溶解度，但在MDCK細胞模型的跨膜轉運反而下降，因為與胃腸道的生理環(huán)境相差較大，此經(jīng)典體外細胞模型用于評價納米乳給藥系統(tǒng)口服吸收的準確性具有一定的局限性；CIN-MCT-SNEDDS體外脂解過程中藥物逐漸釋放，并被增溶于水相的混合膠束中；體內(nèi)藥動學研究結果表明CIN-MCT-SNEDDS可顯著提高藥物生物利用度，延緩藥物吸收；體外脂解后藥物膠束相溶解度的增加與體內(nèi)增加吸收具有一定的相關性。體外脂解模型用于評價和預測藥物的口服吸收具有一定的可信度。
[Abstract]:Objective: to design nanoscale drug delivery system (self) namoemulsion drug delivery system, (S) NEDDS) with BCS class II (Biopharmaceutics Classification System, BCS) refractory drugs, and to study the oral absorption mechanism of nanoscale milk under lipo and non lipo conditions by using in vitro cell model, lipo model and pharmacokinetic model in vivo.
Method (:1) BCSII model drug NEDDS prescription design and quality evaluation study. By determining the composition of NEDDS prescription components of 4 BCSII refractory drugs in the excipients, draw the optimal prescription composition and proportion of the pseudo three element phase diagram, determine the particle size by laser particle size analyzer and observe the stability of drug loading in the drug carrying drug. The prescription is evaluated.
(2) the membrane permeability of BCSII model drugs in vitro was studied. The MDCK cell model was constructed to compare the cumulative penetration percentage (CP%) and apparent osmotic coefficient (Papp) of the 4 BCSII refractory drugs, NEDDS and saturated aqueous solution, and to investigate the effect of NEDDS on the transport permeability of insoluble drugs.
(3) the study on the prescription design and quality evaluation of the chain oil self nanoscale (CIN-MCT-SNEDDS). By investigating the mixing homogeneity of the ingredients, selecting the prescription accessories, drawing the pseudo three element phase diagram and combining the solubility of the drugs in the excipients, the optimum prescription is determined. By measuring the rate of self emulsification, the transmittance and the particle size, and the investigation of the different drug loading amount, SNE The stability of DDS evaluates the preferred prescription.
(4) establish and optimize the model of lipolysis in vitro. By reference, the model of lipolysis in vitro was established, and the concentration of lipase, the concentration of bile salt / phospholipid micelle, the concentration of NaOH, the concentration of Trizma maleate, and the addition of Ca2+ were optimized by the speed and degree of MCT-SNEDDS lipase.
(5) study on the dynamic distribution and solubility changes of CIN in each phase during CIN-MCT-SNEDDS lipolysis. Using the optimized model of in vitro lipid solution for CIN-MCT-SNEDDS lipolysis test, sampling at different time points, separating all phases of lipolysis by table centrifugation and overspeed centrifugation, HPLC determination of drug content in each phase at different time points, and comparing CI The solubility of drugs in aqueous phase under N-MCT-SNEDDS lipolysis and non lipolytic conditions.
(6) pharmacokinetics study in CIN-MCT-SNEDDS rats. Compare the pharmacokinetics of CIN-MCT-SNEDDS and its suspension (CIN-SUSP). Take the oral administration of SD rats by oral administration. Before given, the blood was taken at different time points, plasma, acetonitrile precipitin and HPLC were used to determine the concentration of blood drug. The average concentration time curve of the drug group was drawn, and the linearity of the blood concentration time curve was drawn. Trapezoidal method was used to calculate the area under the time curve (AUC) and the main pharmacokinetic parameters were compared.
Results: (1) the formulation of BCSII model drug NEDDS prescription design and in vitro evaluation of.NEDDS optimal prescription proportion consists of MCT oil: Tween80/Span80 (HLB=11): aqueous =8:10:82 (W/W). Under the optimal prescription proportion, the preparation of 4 refractory drug carrying drugs NEDDS can form a translucent nanoscale emulsion with blue milk light with a particle size below 80nm. No drug precipitation, good stability.
(2) the study of cell membrane permeability in BCSII model drugs in vitro.NEDDS can significantly increase the solubility of GRI, IND, KET, PHE, but the percentage of GRI, IND, KET, PHE NEDDS in the MDCK cell model is significantly lower than the saturated solution of soluble drugs (0.05).
(3) the optimal prescription of CIN-SNEDDS prescription design and quality evaluation.CIN-MCT-SNEDDS is (MCToil: octane =5:5): Cremophor RH40: Ethanol=3:5:2. in vitro evaluation results show that MCT-SNEDDS can form all one in 3min in water, pH6.8 digestion buffer and bile salt / phospholipid micelle solution, transparent nanoscale emulsion, 29nm particle size, and drug loading amount of 25mg CIN-MCT-SNEDDS was dispersed in the above medium without 24h, and the system was stable.
(4) establishment and optimization of the model of lipolysis in vitro. The conditions for determining in vitro lipid model were NaCl:50Mm; Trizma maleate:50mM; Ca2+: 5mM (a addition); NaTDC/PC:5mM/1.25mM; pancreatic lipase: 800TBU/mL; NaOH:1M.
(5) the solubility of CIN in each solution is the MCT-SNEDDS lipolytic solution which can separate the effluent and the precipitate phase. The content of CIN in the aqueous phase decreases gradually with the lipid solution. The increase of the drug precipitation in the precipitate phase is consistent with the trend of the decrease of the water phase drug content; the drug gradually precipitates in the lipoid state and is in the non lipolysis state. There is no drug precipitation, but the concentration of the drug in the water phase after CIN-MCT-SNEDDS Liping 60min is still 3 times higher than that in the aqueous phase. The solubility of the.CIN solubility in the aqueous NATDC/PC micelle solution of the pH1.2HCl lipolysis and the solubility in the nano milk.
(6) pharmacokinetic study in CIN-MCT-SNEDDS rats, the absorption process of.CIN after oral administration appeared in Shuangfeng. The major pharmacokinetic parameters of CIN-MCT-SNEDDS and CIN-SUSP were C1max, C2max, T1max, T2max, and AUC0~24 were 0.44 mu g/mL, 0.63 mu g/mL, 2h, 6.27 Mu and... Max, C2max and AUC0~24 increased significantly, Fr was 179.66%, T2max significantly prolonged.
Conclusion: NEDDS can improve the solubility of the 4 model drugs, but the transmembrane transport of the MDCK cell model decreases because it is quite different from the physiological environment of the gastrointestinal tract. This classic extracorporeal cell model is used to evaluate the accuracy of the oral absorption of the nano emulsion system; CIN-MCT-SNEDDS in the process of in vitro lipid solution. The drug was released gradually and was solubilized in the mixed micelles of water phase. In vivo pharmacokinetics study showed that CIN-MCT-SNEDDS could significantly improve the bioavailability of drugs and delay the absorption of drugs; the increase of micelle solubility in vitro was related to the increase of absorption in the body. In vitro lipolysis model was used for evaluation and prediction. The oral absorption of drugs has certain credibility.
【學位授予單位】：廣東藥學院
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R943

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相關期刊論文 前4條

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本文編號：2003146