本文選題：駐極體 + 胰島素�。� 參考：《第二軍醫(yī)大學》2015年碩士論文

【摘要】：糖尿病是以慢性高血糖為癥狀的自身代謝紊亂性疾病,已成為繼心腦血管疾病和腫瘤之后危害人類健康的“第三殺手”。目前針對糖尿病患者的治療藥物主要有胰島素和非胰島素類藥物,胰島素是當前糖尿病病人控制血糖最常用的藥物,臨床上通常采用皮下注射的方式給藥以獲得有效的降糖效果。但是,皮下注射不僅因疼痛不適等缺點給患者帶來不便和痛苦,導致患者的依從性差,而且長期頻繁注射還可引起患者皮下脂肪萎縮和低血糖等不良反應。為此,非侵入性給藥方式,如胰島素經(jīng)皮給藥制劑成為研究的熱點,它可有效避免藥物經(jīng)胃腸道及肝臟的首過效應,提高患者用藥的順應性,減輕患者的痛苦。因此,研究胰島素經(jīng)皮給藥具有非常重要的意義。由于皮膚最外層角質(zhì)層的屏障作用,大多數(shù)藥物的經(jīng)皮轉(zhuǎn)運速度或程度都很小或有限,需要各種促滲方法的推動。課題組前期的研究結(jié)果表明,駐極體對水楊酸甲酯、利多卡因、美洛昔康和環(huán)孢菌素A等藥物具有顯著的經(jīng)皮促滲作用。因此,課題組在前期研究的基礎(chǔ)上,采用駐極體、化學促滲劑和駐極體與化學法促滲劑聯(lián)合等方法對胰島素的經(jīng)皮給藥開展研究,探討駐極體促進胰島素經(jīng)皮吸收的可行性及其相關(guān)機制,為探索駐極體促進多肽類藥物的經(jīng)皮吸收研究提供-種新方法和新思路。本課題從以下幾個方面開展了研究。(一)駐極體對胰島素的極化及其規(guī)律的研究應用常溫柵控恒壓電暈充電系統(tǒng)制備了不同極性、不同表面電位的駐極體,作用于胰島素溶液和貼劑,測量施加在胰島素溶液和胰島素貼劑兩側(cè)的電場強度和壓電系數(shù)d33隨時間的變化規(guī)律,考察駐極體對胰島素的極化及其規(guī)律。結(jié)果表明：(1)駐極體能夠為胰島素溶液及胰島素貼劑提供穩(wěn)定的靜電場。(2)駐極體能夠引起胰島素的極化,經(jīng)不同極性和不同表面電位駐極體作用12小時,胰島素的極化趨于飽和(即d33值趨于穩(wěn)定)。(3)駐極體的表面電位越大,引起胰島素的極化越明顯。同時應用核磁共振、傅里葉紅外吸收光譜和非變性凝膠電泳技術(shù),進一步研究了駐極體對胰島素分子結(jié)構(gòu)的影響。結(jié)果顯示胰島素經(jīng)駐極體作用后,其分子的空間結(jié)構(gòu)沒有發(fā)生明顯改變,但分子的部分微結(jié)構(gòu)發(fā)生細微變化,是駐極體電場引起胰島素分子極化的結(jié)果。(二)駐極體、化學促滲劑及駐極體和化學促滲劑聯(lián)用對胰島素體外透皮規(guī)律的影響借助Franz擴散池和高效液相實驗技術(shù),系統(tǒng)考察了3%氮酮、7.5%丙二醇化學促滲劑,±500V、±1000V、±1500V駐極體,±1500V駐極體聯(lián)用3%氮酮對胰島素的經(jīng)皮促滲作用,以及胰島素在角質(zhì)層和去角質(zhì)層皮膚中的滯留量。結(jié)果顯示,(1)氮酮和丙二醇對胰島素具有較好的促滲作用,且3%氮酮的促滲效果明顯優(yōu)于7.5%丙二醇。化學促滲劑作用胰島素體外透皮36h后,3%氮酮組的胰島素在角質(zhì)層和去角質(zhì)層皮膚中的分布量最大。(2)負極性駐極體對胰島素具有良好的體外促滲效果,且駐極體表面電位絕對值越高,對胰島素的促滲效果越好。駐極體作用后,胰島素在角質(zhì)層中的分布與對照組相比無明顯區(qū)別,但是在去角質(zhì)層皮膚中的分布明顯增加。(3)-1500V駐極體聯(lián)合3%氮酮,36小時后胰島素的累積透皮量分別是3%氮酮組、+1500V駐極體聯(lián)合3%氮酮組和對照組的1.4倍、2.12倍和2.93倍。-1500V駐極體與3%氮酮聯(lián)合對胰島素具有很好的協(xié)同促滲作用。(三)駐極體對胰島素經(jīng)糖尿病大鼠皮膚的體外透皮規(guī)律研究本文通過注射鏈脲佐菌素成功構(gòu)建了糖尿病大鼠模型,考察了胰島素溶液、經(jīng)-1500V、-1000V、-500V駐極體作用后的胰島素溶液對糖尿病大鼠皮膚的體外透皮規(guī)律。結(jié)果顯示,胰島素溶液經(jīng)糖尿病大鼠皮膚的透過量顯著高于正常皮膚的透過量,36小時的累積透過量是經(jīng)正常皮膚透過量的3.2倍。36小時后,經(jīng)-1500V、-1000V、-500V駐極體作用后的胰島素溶液對糖尿病大鼠皮膚的累積透過量是經(jīng)正常皮膚透過量的4.00、3.86、3.54倍,表面電位絕對值越高,提高量越多。(四)駐極體對正常大鼠和糖尿病皮膚顯微結(jié)構(gòu)的影響研究利用免疫熒光技術(shù)和顯微結(jié)構(gòu)分析技術(shù),研究了不同極性、不同表面電位駐極體作用正常和糖尿病大鼠的顯微結(jié)構(gòu)。結(jié)果顯示1)駐極體可使正常大鼠皮膚的角質(zhì)層變薄,細胞間隙增大,毛囊口擴大。2)駐極體作用糖尿病大鼠皮膚后,皮膚的角質(zhì)層及真皮層略微變厚,對其有修復作用。3)駐極體作用后的胰島素其主要經(jīng)皮途徑是皮膚的毛囊結(jié)構(gòu)。(五)駐極體對胰島素降糖作用的影響經(jīng)駐極體作用的胰島素溶液與未經(jīng)駐極體作用的胰島素溶液具有相似的降糖規(guī)律,經(jīng)+1000V駐極體和-1000V駐極體作用胰島素的降糖效果更佳。駐極體胰島素經(jīng)皮給藥系統(tǒng)具有穩(wěn)定性好,使用方便,生物安全性好和不需外置儀器設(shè)備等特點。駐極體胰島素透皮給藥系統(tǒng)有望糖尿病患者提供新型的治療方法和手段。
[Abstract]:Diabetes is a metabolic disorder characterized by chronic hyperglycemia, which has become the "third killer" of human health after cardiovascular disease and tumor. At present, the main treatment drugs for diabetic patients are insulin and non insulin, and insulin is the most commonly used diabetic patients to control blood sugar. Medications are usually administered by subcutaneous injection to obtain effective hypoglycemic effect. However, subcutaneous injection is not only inconvenient and painful to patients because of pain discomfort, which leads to poor compliance of the patient, and long-term frequent injections can also cause adverse reactions such as hypodermic atrophy and hypoglycemia. The way of sex administration, such as insulin transdermal drug delivery, has become a hot spot of research. It can effectively avoid the first effect of the drugs through the stomach and the intestines and the liver, improve the compliance of the patients and alleviate the sufferings of the patients. Therefore, it is of great significance to study the transdermal delivery of insulin. The speed or degree of transdermal delivery of drugs is very small or limited, which requires the promotion of various methods of stimulation. The results of the previous research group showed that the electret had significant transdermal enhancers to Methylis salicylas, lidocaine, meloxicam and cyclosporin A. In order to explore the feasibility and related mechanism of electret promoting insulin absorption by the combination of chemical stimulating agent and electret and chemical permeating agent, the feasibility and mechanism of electret to promote the absorption of insulin by the electret are explored. Study. (1) study on polarization and regularity of insulin by electret application of constant temperature gate controlled constant pressure corona charging system to prepare electret with different polarity, different surface potential, acting on insulin solution and patch, measuring the electric field intensity and pressure coefficient d33 applied on both sides of insulin solution and insulin patch with time The polarization of the electret to insulin and its regularity were investigated. The results showed that: (1) the electret could provide stable electrostatic field for insulin solution and insulin patch. (2) the electret could cause insulin polarization, and the polarization of insulin was saturated by different polarity and different surface potential electret (d33). The higher the surface potential of the electret is (3) the greater the surface potential of the electret, the more obvious the polarization of insulin. At the same time, the effect of the electret on the molecular structure of insulin is further studied by NMR, Fourier infrared absorption spectroscopy and non denatured gel electrophoresis. The results show that the structure of the molecules is not in the space of the insulin after the action of the electret. There was obvious change, but the partial microstructure of the molecule changed slightly, which was the result of insulin molecular polarization induced by electret electric field. (two) the influence of electret, chemical permeation agent, electret and chemical permeation agent on the transdermal regulation of insulin in vitro was systematically investigated by Franz diffusion pool and high performance liquid phase experiment. 3% azone was systematically investigated. 7.5% propanediol chemical enhancer, + 500V, + 1000V, + 1500V electret, 3% azone combined with Azone on the skin of insulin, and the retention of insulin in the cuticle and the skin of the cuticle. The results showed that (1) azone and propanediol had better infiltration effect on insulin, and the effect of Azone was obviously better than that of 3% azone. The distribution of insulin in the 3% azone group is the largest in the cuticle and the cuticle skin after the action of 7.5% propanediol. (2) the negative electret has a good exosperation effect on the insulin in vitro, and the higher the absolute value of the electret surface potential, the better the effect of the insulin to the insulin. The distribution of insulin in the cuticle was not significantly different from that of the control group, but the distribution of insulin in the skin of the stratum corneum increased significantly. (3) -1500V electret combined with 3% azone, after 36 hours, the cumulative transdermal volume of insulin was 3% azone group, 1.4 times as much as 3% azone group and the control group, 2.12 times and 2.93 times.-1500V in the group of electret. The combination of polar body and azone with 3% azone has a good synergistic effect on insulin. (three) in vitro transdermal regulation of insulin through the skin of diabetic rats, a diabetic rat model was successfully constructed by injecting streptozotocin, and the insulin solution was examined by the insulin solution after the action of -1500V, -1000V, and -500V electret. The skin transdermal rule of diabetic rats showed that the skin permeation of diabetic rats was significantly higher than that of normal skin. The cumulative transmission of 36 hours was 3.2 times.36 hours after normal skin transmission, the insulin solution after the action of -1500V, -1000V, -500V electret to diabetic rats The cumulative permeation of the skin was 4.00,3.86,3.54 times of the normal skin transmission, the higher the absolute value of the surface potential, the more the increase. (four) the effect of electret on the microstructure of normal rats and diabetic skin was studied by using immunofluorescence technology and microstructural analysis techniques, and the effects of different polarity and surface potential electret were studied. The microstructure of normal and diabetic rats showed that 1) electret could thinner the cuticle of the skin of normal rats, increase the gap of the cells, enlarge the mouth of the hair follicle, and expand.2). After the electret acted on the skin of the diabetic rats, the cuticle and the dermis of the skin thickened slightly, and the insulin which had the repair effect of.3) the main transdermal path of the insulin after the action of the electret. The diameter is the structure of the hair follicle of the skin. (five) the effect of the electret on insulin hypoglycemic effect is similar to that of the insulin solution without electret acting on the electret body. The effect of insulin in the +1000V electret and the -1000V electret is better. The system of the electret insulin transdermal delivery system is stable. It is characterized by good quality, convenient use, good biological safety and no need for external instrument and equipment. The electret insulin transdermal delivery system is expected to provide new methods and means for patients with diabetes.
【學位授予單位】：第二軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R587.1

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本文編號：2011194