本文選題：地塞米松 + 溫敏型凝膠　； 參考：《廣東藥科大學(xué)》2017年碩士論文

【摘要】：眼后段疾病如增殖性糖尿病性視網(wǎng)膜病變(PDR)、脈絡(luò)膜新生血管(CNV)和老年人糖尿病性視網(wǎng)膜黃斑病變(AMD)等是導(dǎo)致視覺(jué)障礙甚至失明的主要原因。由于血眼屏障、角膜屏障、血-房水屏障的存在使得各給藥方式都難以在眼后段組織達(dá)到有效的治療濃度。采用兩種或兩種以上的制劑手段制備復(fù)合體系已然成為眼部疾病治療研究的新趨勢(shì):膠體給藥體系可與角膜糖蛋白結(jié)合形成藥物儲(chǔ)庫(kù),促進(jìn)藥物的高效傳遞以及眼后段的靶向輸送;環(huán)境敏感型凝膠由于溫度、離子強(qiáng)度、p H等外界因素的改變,發(fā)生溶膠-凝膠相轉(zhuǎn)變,延緩藥物在眼前部的消除�；诖�,在本課題組地塞米松微乳研究基礎(chǔ)上,制備溫敏型原位凝膠及微乳凝膠,對(duì)比研究了地塞米松微乳、原位凝膠、微乳凝膠膠凝后理化性質(zhì)、動(dòng)態(tài)流變學(xué)等性質(zhì)。采用無(wú)膜溶出模型以及半透膜體外釋放模型考察不同制劑中地塞米松體外釋放行為。對(duì)不同制劑刺激性及房水藥動(dòng)學(xué)進(jìn)行初步考察。第一章以非生理?xiàng)l件下的流動(dòng)性和模擬淚液稀釋生理?xiàng)l件下的膠凝能力為評(píng)價(jià)指標(biāo),考察了P407和P188作為凝膠載體的溫敏性質(zhì)。泊洛沙姆P407溶液具有濃度依賴(lài)性,隨著濃度的增加,膠凝溫度降低;體溫條件下,單獨(dú)使用P407無(wú)法獲得理想的膠凝溫度,通過(guò)合并應(yīng)用泊洛沙姆同系物P188,可獲得具有適宜膠凝溫度的凝膠處方。生物黏附性聚合物聚卡波菲只需低濃度即表現(xiàn)高黏附性,因此,本文通過(guò)加入聚卡波菲、泊洛沙姆P407和泊洛沙姆P188共同為基質(zhì)制備適宜于眼部的溫敏型原位凝膠。第二章冷溶法制備凝膠體系,微乳中位徑為(156.47±5.77)nm,原位凝膠及微乳凝膠中位徑分別為(274.90±11.17)nm和(219.83±6.97)nm,將微乳制備成微乳凝膠體系,體系粒徑變大,但仍小于人眼可以耐受的最大粒度。DSC測(cè)試結(jié)果顯示,地塞米松以非結(jié)晶狀態(tài)包載于凝膠結(jié)構(gòu)中;紅外圖譜上1706-1622 cm-1之間地塞米松三個(gè)特征吸收峰發(fā)生藍(lán)移及消失,地塞米松可能與凝膠基質(zhì)發(fā)生相互作用,而非簡(jiǎn)單的物理混合。動(dòng)態(tài)流變學(xué)結(jié)果表明,原位凝膠及微乳凝膠具備適宜的相轉(zhuǎn)變溫度,體溫下即可形成凝膠;34℃條件下,彈性模量G'和粘性模量G''及相角δ均具有頻率依賴(lài)性,微乳凝膠相對(duì)原位凝膠具有更低相角,表現(xiàn)出更佳的凝膠蠕變性質(zhì)。凝膠制劑較微乳具有更小的接觸角,角膜潤(rùn)濕性強(qiáng)。第三章地塞米松溶解度、脂/水分配系數(shù)均具有pH依賴(lài)性,pH增大,溶解度增大;脂/水分配系數(shù)則相反;pH對(duì)地塞米松離體角膜透過(guò)性無(wú)顯著性影響。離體角膜透過(guò)性評(píng)價(jià)中,微乳、原位凝膠6 h累積透過(guò)量分別是水溶液的1.41倍和2.21倍,表觀(guān)滲透系數(shù)是水溶液的2.56和4.84倍,微乳凝膠表觀(guān)滲透系數(shù)Papp是水溶液的5.22倍,呈現(xiàn)出顯著性差異(P0.05)。地塞米松原位凝膠、微乳、微乳凝膠透角膜釋藥均符合Riger-Peppas動(dòng)力學(xué)特征,且n均大于0.85,其透角膜藥物釋放機(jī)制主要為骨架溶蝕型。凝膠溶蝕是影響藥物釋放的決定性因素,體外釋藥結(jié)果與凝膠的溶蝕過(guò)程基本一致;微乳凝膠對(duì)藥物釋放產(chǎn)生更為明顯的緩釋效果。第四章多次給藥刺激性及眼部組織切片結(jié)果顯示,脂肪乳凝膠對(duì)家兔眼部無(wú)明顯刺激性。微乳、原位凝膠、微乳凝膠在兔眼房水中藥動(dòng)學(xué)參數(shù)顯示,原位凝膠、微乳凝膠峰濃度Cmax高于微乳,微乳凝膠與原位凝膠相比具有更高的AUC0→∞、MRT,表明微乳凝膠有利于克服角膜屏障,提高藥物眼內(nèi)通透性;微乳凝膠有助于在眼前形成藥物儲(chǔ)庫(kù),提高生物利用度。本文通過(guò)原位凝膠及微乳凝膠處方工藝篩選優(yōu)化、制劑特征評(píng)價(jià)、藥物釋放機(jī)制以及家兔房水藥物動(dòng)力學(xué)的研究,表明微乳凝膠具備微乳有效提高地塞米松在體系中溶解度以及凝膠可延長(zhǎng)角膜滯留時(shí)間的優(yōu)勢(shì),提高藥物生物利用度。
[Abstract]:Posterior segment diseases such as proliferative diabetic retinopathy (PDR), choroidal neovascularization (CNV) and senile diabetic retinopathy of macular disease (AMD) are the main causes of visual impairment or blindness. The presence of blood barrier, corneal barrier, and blood water barrier makes it difficult to reach the posterior segment of the eye. The preparation of the compound system with two or more than two kinds of agents has become a new trend in the treatment of ocular diseases. The colloid administration system can combine with corneal glycoprotein to form a drug reservoir, promote the efficient delivery of the drug and target delivery in the posterior segment of the eye; the environmental sensitive gel is due to the temperature and ionic strength. On the basis of the study of dexamethasone microemulsion, the thermosensitive in situ gel and microemulsion gel were prepared on the basis of the study of dexamethasone microemulsion, and the properties of dexamethasone microemulsion, in situ gel and microemulsion gel after gelation were compared and the properties of dynamic rheology and other properties were studied. The release behavior of dexamethasone in different preparations was investigated by a membrane free dissolution model and a semi permeable membrane in vitro release model. The irritation of different preparations and the pharmacokinetics of aqueous humor were preliminarily investigated. In the first chapter, P407 and P18 were examined for the evaluation index of the fluidity under non physiological conditions and the gelation ability of the simulated tear diluting physiological conditions. 8 as the temperature sensitive property of the gel carrier, Poisson Losham P407 solution has a concentration dependence and the gelation temperature decreases with the increase of concentration. Under the condition of body temperature, P407 can not obtain the ideal gelation temperature. By combining the application of mooring Losham homologue P188, the gel prescription with suitable gelation temperature can be obtained. In this paper, a thermosensitive in situ gel suitable for the eye was prepared by adding polychatfei, mooring Losham P407 and moor Losham P188. The second chapter cold solution method was used to prepare the gel system. The microemulsion was (156.47 + 5.77) nm, in situ gel and microemulsion gel. The microemulsion was prepared into microemulsion gel system (274.90 + 11.17) nm and (219.83 + 6.97) nm respectively. The particle size of the system was larger, but it was still less than the maximum granularity.DSC test that the human eye could tolerate. The results showed that dexamethasone was loaded in the gel structure in non crystalline state, and three characteristic peaks of dexamethasone on the infrared spectrum were 1706-1622 cm-1. With blue shift and disappearance, dexamethasone may interact with the gel matrix rather than a simple physical mixture. The dynamic rheology results show that the in-situ gel and microemulsion gel have a suitable phase transition temperature, and the gel can be formed under temperature. At 34, the modulus of elasticity, modulus G'', and phase angle delta are frequency dependent, microemulsion, and microemulsion at 34. The gel has a lower phase angle than the in-situ gel, showing a better gel creep property. The gel has a smaller contact angle than the microemulsion, and the corneal wettability is strong. The solubility of dexamethasone in third chapters and the lipid / water distribution coefficient are pH dependent, pH increases, the solubility increases, and the lipid / water distribution coefficient is opposite; pH to dexamethasone in vitro cornea The permeability of microemulsion and in situ gel 6 h was 1.41 times and 2.21 times more than that in aqueous solution. The apparent osmotic coefficient was 2.56 and 4.84 times of water solution, and the apparent permeability coefficient Papp of microemulsion gel was 5.22 times of water solution, showing significant difference (P0.05). Dexamethasone orthotopic gel was found. Microemulsion and microemulsion gel permeation were all consistent with Riger-Peppas kinetics, and N was more than 0.85, and the mechanism of drug release was mainly skeleton dissolution. Gel dissolution was the decisive factor affecting the release of drugs. The release results in vitro were basically the same as the dissolution process of the gel; microemulsion gel was more obvious for the release of drugs. The results of sustained release in the fourth chapter showed that there was no obvious irritation to rabbit eye. Microemulsion, in situ gel, microemulsion gel in rabbit eye aqueous humor showed that in situ gel, microemulsion gel peak concentration Cmax was higher than microemulsion, microemulsion gel had a higher AU than in situ gel. C0 - infinity, MRT, indicates that microemulsion gel is beneficial to overcome corneal barrier and improve the intraocular permeability of drugs; microemulsion gel helps to form a drug reservoir in front of the eyes and improves bioavailability. In this paper, the optimization of the formulation process by the orthotopic gel and microemulsion gel, the evaluation of the preparation characteristics, the mechanism of drug release and the research of the pharmacokinetics of rabbit aqueous humor It shows that microemulsion can effectively improve the solubility of dexamethasone in the system and prolong the retention time of the cornea, and improve the bioavailability of the drug.
【學(xué)位授予單位】：廣東藥科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R943

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本文編號(hào)：1899234