本文選題：超支化聚縮水甘油醚 + β-環(huán)糊精�。� 參考：《天津醫(yī)科大學》2017年碩士論文

【摘要】：目的胰島素頻繁皮下注射易引起局部炎癥、皮下脂肪萎縮以及脂肪性營養(yǎng)不良等,給患者帶來很大痛苦。因此,迫切需要開發(fā)胰島素的非注射給藥技術。透皮給藥途徑因其具有易于吸收、避免肝臟首過效應、實現(xiàn)藥物控制釋放以及提高患者依從性等優(yōu)點,已經(jīng)成為該領域中研究的熱點。本文旨在合成一種新型的納米促滲劑,增加胰島素的透皮給藥,實現(xiàn)血糖的良好控制。方法采取通過陰離子開環(huán)聚合的方法合成超支化聚縮水甘油醚(HPG),進一步引入β-環(huán)糊精(β-CD),得到HPG-g-CD共聚物。通過納米技術和自組裝方法,構筑出負載胰島素的納米粒子,并采用動態(tài)光散射對其粒徑和電勢進行分析;并評價其載藥量和包封率,對胰島素體外釋放行為進行研究;通過實驗大鼠行活體及離體透皮實驗,運用激光共聚焦顯微鏡來定性觀察胰島素的透皮效果,并通過高效液相色譜儀來定量分析胰島素透過皮膚的滲透量;采用蘇木精-伊紅染色法(HE)染色法從組織病理學角度方面測定實驗材料對大鼠皮膚的刺激性,從而全面評價HPG-g-CD納米粒子作為藥物透皮遞送胰島素的可行性。結果通過調節(jié)HPG-NH2和6-OTs-β-CD質量比,篩選出載藥性能較好的HPG-g-CD3聚合物,通過核磁和紅外光譜并證實。該聚合物可自組裝成納米粒子,粒徑約為200 nm,zeta電勢+28.3~+45.5 mV,而且納米粒子粒徑隨β-CD比例的增高而增大;該納米�？捎行У刎撦d胰島素,包封率可高達85%,且胰島素包封率隨著β-CD的增加逐漸增大,而載藥量的差異不顯著;胰島素的體外釋放實驗結果顯示,在pH 7.4條件,隨著β-CD的增加,胰島素釋放速率和累積釋放百分率均增加;動物透皮實驗結果顯示,隨著時間的延長,FITC標記的胰島素載藥組對活體大鼠皮膚滲透可達真皮層,但游離胰島素懸液組僅停留在皮膚表層,說明HPG-g-CD促進胰島素的吸收;體外大鼠透皮實驗結果亦顯示,負載胰島素的HPG-g-CD納米粒子組在相同時間內,胰島素滲透量顯著高于胰島素溶液組,進一步證實HPG-g-CD納米粒能夠增加胰島素的透皮吸收。而且該納米粒不會誘導組織炎癥,呈現(xiàn)出良好的生物相容性。結論本文中制備出生物相容性良好的HPG-g-CD共聚物,通過自組裝技術構筑出分布均一納米粒,可有效地負載胰島素,促進胰島素透皮吸收,且不誘導組織炎癥。該納米吸收促進劑為胰島素給藥提供新的思路和新的策略,為臨床胰島素安全、有效地治療糖尿病提新的理論依據(jù)。
[Abstract]:Objective the frequent subcutaneous injection of insulin may cause local inflammation, subcutaneous fat atrophy and fatty malnutrition, which bring great pain to the patients. Therefore, there is an urgent need to develop non-injection insulin delivery technology. Because of its advantages of easy absorption, avoiding liver first-pass effect, controlling drug release and improving patient compliance, transdermal drug delivery has become a hot topic in this field. This paper aims to synthesize a new nano osmotic enhancer, to increase the transdermal delivery of insulin, and to control blood sugar well. Methods Hyperbranched polyglycidyl ether (HPG) was synthesized by anion ring-opening polymerization, and 尾 -cyclodextrin (尾 -CD) was further introduced to obtain HPG-g-CD copolymer. The nanoparticles loaded with insulin were constructed by nanotechnology and self-assembly, and their particle size and potential were analyzed by dynamic light scattering (DLS), and the drug loading and encapsulation efficiency were evaluated to study the release behavior of insulin in vitro. The transdermal effect of insulin was qualitatively observed by laser confocal microscope in vivo and in vitro, and the permeation of insulin through the skin was quantitatively analyzed by high performance liquid chromatography (HPLC). In order to evaluate the feasibility of HPG-g-CD nanoparticles as a drug for transdermal delivery of insulin, the irritation of experimental materials to rat skin was determined by hematoxylin-eosin staining (HE) from histopathological point of view. Results by adjusting the mass ratio of HPG-NH2 and 6-OTs- 尾 -CD, HPG-g-CD3 polymers with better drug loading properties were selected. The results were confirmed by NMR and IR spectra. The polymer can self-assemble into nanocrystalline particles, the particle size is about 28.3 ~ 45.5 MV, and the particle size increases with the increase of 尾 -CD ratio. The encapsulation efficiency of insulin increased gradually with the increase of 尾 -CD, but there was no significant difference in drug loading. The results of insulin release in vitro showed that, at pH 7.4, the entrapment rate of insulin increased with 尾 -CD. Both the rate of insulin release and the percentage of cumulative release were increased, and the results of transdermal experiments showed that the FITC labeled insulin loaded group could penetrate into the dermis of living rat skin with the prolongation of time. However, the free insulin suspension group only stayed on the skin surface, indicating that HPG-g-CD promoted the absorption of insulin. The results of rat transdermal experiments in vitro also showed that the HPG-g-CD nanoparticles loaded with insulin at the same time, The amount of insulin permeation was significantly higher than that in insulin solution group, which further confirmed that HPG-g-CD nanoparticles could increase the transdermal absorption of insulin. Moreover, the nanoparticles do not induce tissue inflammation and present good biocompatibility. Conclusion the HPG-g-CD copolymers with good biocompatibility were prepared in this paper. The homogenous nanoparticles were constructed by self-assembly technique, which can effectively load insulin, promote the transdermal absorption of insulin, and do not induce tissue inflammation. The nano-absorption accelerator provides new ideas and strategies for insulin administration and provides a new theoretical basis for clinical insulin safety and effective treatment of diabetes.
【學位授予單位】：天津醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R587.1

【參考文獻】

相關期刊論文 前1條

1 Subhashini Yaturu;;Insulin therapies: Current and future trends at dawn[J];World Journal of Diabetes;2013年01期

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本文編號：2106638