地塞米松眼用微乳凝胶的制备及评价

发布时间：2018-05-17 01:12

本文选题：地塞米松 + 温敏型凝胶　；参考：《广东药科大学》2017年硕士论文

【摘要】：眼后段疾病如增殖性糖尿病性视网膜病变(PDR)、脉络膜新生血管(CNV)和老年人糖尿病性视网膜黄斑病变(AMD)等是导致视觉障碍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给药方式都难以在眼后段组织达到有效的治疗浓度。采用两种或两种以上的制剂手段制备复合体系已然成为眼部疾病治疗研究的新趋势:胶体给药体系可与角膜糖蛋白结合形成药物储库,促进药物的高效传递以及眼后段的靶向输送;环境敏感型凝胶由于温度、离子强度、p H等外界因素的改变,发生溶胶-凝胶相转变,延缓药物在眼前部的消除。基于此,在本课题组地塞米松微乳研究基础上,制备温敏型原位凝胶及微乳凝胶,对比研究了地塞米松微乳、原位凝胶、微乳凝胶胶凝后理化性质、动态流变学等性质。采用无膜溶出模型以及半透膜体外释放模型考察不同制剂中地塞米松体外释放行为。对不同制剂刺激性及房水药动学进行初步考察。第一章以非生理条件下的流动性和模拟泪液稀释生理条件下的胶凝能力为评价指标,考察了P407和P188作为凝胶载体的温敏性质。泊洛沙姆P407溶液具有浓度依赖性,随着浓度的增加,胶凝温度降低;体温条件下,单独使用P407无法获得理想的胶凝温度,通过合并应用泊洛沙姆同系物P188,可获得具有适宜胶凝温度的凝胶处方。生物黏附性聚合物聚卡波菲只需低浓度即表现高黏附性,因此,本文通过加入聚卡波菲、泊洛沙姆P407和泊洛沙姆P188共同为基质制备适宜于眼部的温敏型原位凝胶。第二章冷溶法制备凝胶体系,微乳中位径为(156.47±5.77)nm,原位凝胶及微乳凝胶中位径分别为(274.90±11.17)nm和(219.83±6.97)nm,将微乳制备成微乳凝胶体系,体系粒径变大,但仍小于人眼可以耐受的最大粒度。DSC测试结果显示,地塞米松以非结晶状态包载于凝胶结构中;红外图谱上1706-1622 cm-1之间地塞米松三个特征吸收峰发生蓝移及消失,地塞米松可能与凝胶基质发生相互作用,而非简单的物理混合。动态流变学结果表明,原位凝胶及微乳凝胶具备适宜的相转变温度,体温下即可形成凝胶;34℃条件下,弹性模量G'和粘性模量G''及相角δ均具有频率依赖性,微乳凝胶相对原位凝胶具有更低相角,表现出更佳的凝胶蠕变性质。凝胶制剂较微乳具有更小的接触角,角膜润湿性强。第三章地塞米松溶解度、脂/水分配系数均具有pH依赖性,pH增大,溶解度增大;脂/水分配系数则相反;pH对地塞米松离体角膜透过性无显著性影响。离体角膜透过性评价中,微乳、原位凝胶6 h累积透过量分别是水溶液的1.41倍和2.21倍,表观渗透系数是水溶液的2.56和4.84倍,微乳凝胶表观渗透系数Papp是水溶液的5.22倍,呈现出显著性差异(P0.05)。地塞米松原位凝胶、微乳、微乳凝胶透角膜释药均符合Riger-Peppas动力学特征,且n均大于0.85,其透角膜药物释放机制主要为骨架溶蚀型。凝胶溶蚀是影响药物释放的决定性因素,体外释药结果与凝胶的溶蚀过程基本一致;微乳凝胶对药物释放产生更为明显的缓释效果。第四章多次给药刺激性及眼部组织切片结果显示,脂肪乳凝胶对家兔眼部无明显刺激性。微乳、原位凝胶、微乳凝胶在兔眼房水中药动学参数显示,原位凝胶、微乳凝胶峰浓度Cmax高于微乳,微乳凝胶与原位凝胶相比具有更高的AUC0→∞、MRT,表明微乳凝胶有利于克服角膜屏障,提高药物眼内通透性;微乳凝胶有助于在眼前形成药物储库,提高生物利用度。本文通过原位凝胶及微乳凝胶处方工艺筛选优化、制剂特征评价、药物释放机制以及家兔房水药物动力学的研究,表明微乳凝胶具备微乳有效提高地塞米松在体系中溶解度以及凝胶可延长角膜滞留时间的优势,提高药物生物利用度。
[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.
【学位授予单位】：广东药科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

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