【摘要】：當(dāng)人體皮膚損傷至真皮層,組織修復(fù)過程中往往會(huì)形成增生性瘢痕。增生性瘢痕顏色暗紅,高于正常皮膚表面,易造成疼痛和瘙癢,有時(shí)還會(huì)造成關(guān)節(jié)部位移動(dòng)受限。瘢痕的發(fā)病機(jī)制復(fù)雜,導(dǎo)致臨床上治療難度大,復(fù)發(fā)率高。5-FU作為一種抗腫瘤藥,已證明對(duì)增生性瘢痕有確切療效。5-FU常采用病灶內(nèi)注射的給藥方式,此種給藥方式一次性劑量大,常引起紅斑、色素沉著等副作用,而且重復(fù)注射導(dǎo)致患者順應(yīng)性差。因此改變5-FU的給藥方式對(duì)增生性瘢痕的治療具有重要意義。經(jīng)皮給藥系統(tǒng)具有給藥方便,無(wú)侵入性,藥物釋放可控等優(yōu)點(diǎn),在針對(duì)某些疾病的治療時(shí),此種給藥方式要優(yōu)于口服和局部注射。本文擬將物理促滲因子駐極體和化學(xué)促滲劑相結(jié)合,將5-FU制備成經(jīng)皮給藥貼劑作用于大鼠創(chuàng)面,以期達(dá)到良好的抑制瘢痕生長(zhǎng)的效果。本文主要內(nèi)容包括:(一)含化學(xué)促滲劑5-FU貼劑處方篩選及駐極體對(duì)貼劑性質(zhì)的影響本文以尤特奇E100為基質(zhì),檸檬酸丁三酯為增塑劑,水溶性氮酮為化學(xué)促滲劑,將5-FU制備成壓敏膠貼劑。通過單因素考察發(fā)現(xiàn)E100、增塑劑和化學(xué)促滲劑對(duì)貼劑黏性均有顯著影響,之后以初黏力、持黏力和體外釋藥量為指標(biāo),進(jìn)行正交設(shè)計(jì)試驗(yàn),最終確定0.25gE100,55%m(增塑劑)/m(E100)和3%濃度的氮酮為最優(yōu)處方。最優(yōu)處方制備的貼劑皮膚刺激性,處方穩(wěn)定性和皮膚追隨性均符合藥典要求。本文還考察了駐極體對(duì)貼劑黏性及體外釋藥量的影響,結(jié)果發(fā)現(xiàn)較高電位的駐極體通過降低貼劑持黏力,并與5-FU產(chǎn)生靜電作用力而促進(jìn)了貼劑中藥物的體外釋放。(二)含化學(xué)促滲劑駐極體5-FU貼劑體外經(jīng)大鼠背部皮膚和體外經(jīng)大鼠瘢痕皮膚轉(zhuǎn)運(yùn)規(guī)律研究將不同電位不同極性含化學(xué)促滲劑駐極體5-FU貼劑(以下簡(jiǎn)稱駐極體貼劑),分別作用于離體大鼠背部皮膚和瘢痕皮膚,利用改良的Franz擴(kuò)散池和高效液相色譜儀檢測(cè)駐極體貼劑體外經(jīng)正常皮膚和經(jīng)瘢痕皮膚的轉(zhuǎn)運(yùn)規(guī)律。結(jié)果顯示:(1)駐極體貼劑經(jīng)兩類皮膚的累積釋藥規(guī)律和皮膚中藥物滯留規(guī)律相似。(2)較高電位駐極體貼劑的累積透皮量和皮膚中的藥物滯留量也較高,且相同電位負(fù)極性駐極體貼劑的累積透皮量和皮膚中藥物滯留量均高于正極性駐極體貼劑。(3)正常皮膚的累積透皮量高于瘢痕皮膚,而皮膚組織中的藥物含量卻低于瘢痕皮膚。(4)較高表面電位的駐極體貼劑增加了皮膚組織中的藥量含量,為后期駐極體貼劑的在體動(dòng)物實(shí)驗(yàn)奠定了基礎(chǔ)。(三)含化學(xué)促滲劑駐極體5-FU貼劑的動(dòng)物實(shí)驗(yàn)研究首先制造深及筋膜層的大鼠創(chuàng)面,于急性炎癥期過后,分別貼敷駐極體空白貼劑和駐極體藥物貼劑,將皮膚樣品于術(shù)后4周取樣,分別做HE和Masson染色,研究駐極體和駐極體貼劑對(duì)瘢痕的治療效果。結(jié)果顯示:(1)自然愈合組的表皮和真皮層明顯增生,膠原纖維沉積顯著,排列紊亂,符合增生性瘢痕的特征。(2)駐極體空白貼劑治療組形態(tài)學(xué)結(jié)構(gòu)與自然愈合組相似,未表現(xiàn)出顯著抑制瘢痕生長(zhǎng)的效果。(3)含化學(xué)促滲劑5-FU貼劑治療組一定程度上抑制了瘢痕的生長(zhǎng)。相較化學(xué)促滲組,駐極體貼劑治療組更大程度的抑制了瘢痕的增生。(四)含化學(xué)促滲劑駐極體5-FU貼劑抑制增生性瘢痕生長(zhǎng)的機(jī)制研究本文利用免疫組織化學(xué)方法,以平均光密度值評(píng)估增生性瘢痕組織中Ⅰ、Ⅲ型膠原、TGF-β1和HSP47的陽(yáng)性表達(dá)結(jié)果,進(jìn)一步探討駐極體貼劑抑制增生性瘢痕生長(zhǎng)的機(jī)制。結(jié)果發(fā)現(xiàn):(1)Ⅰ、Ⅲ型膠原、TGF-β1和HSP47在正常皮膚中均低表達(dá),而增生性瘢痕組織中Ⅰ、Ⅲ型膠原、TGF-β1和HSP47陽(yáng)性表達(dá)顯著上升。進(jìn)一步證明我們成功構(gòu)建了大鼠瘢痕模型。(2)與自然愈合組相比,駐極體治療組降低了Ⅲ型膠原的平均光密度值,對(duì)其它指標(biāo)無(wú)顯著影響。(3)含化學(xué)促滲劑5-FU貼劑治療組、駐極體貼劑治療組均降低了Ⅰ、Ⅲ型膠原、TGF-β1和HSP47的平均光密度值,而駐極體貼劑治療組對(duì)各指標(biāo)表達(dá)的抑制程度更顯著。綜上所述,駐極體貼劑在體外透皮試驗(yàn)中顯著增加了皮膚中的藥物含量,在動(dòng)物實(shí)驗(yàn)研究中駐極體貼劑通過抑制Ⅰ、Ⅲ型膠原、TGF-β1和HSP47的表達(dá)顯著抑制了大鼠瘢痕的生長(zhǎng),因此含化學(xué)促滲劑駐極體5-FU貼劑可以為臨床增生性瘢痕的治療提供一種新的思路和方法。
[Abstract]:Hypertrophic scars often form in the process of tissue repair when human skin is damaged to the dermis. Hypertrophic scars are dark red in color, higher than the normal skin surface, which can easily cause pain and itching, and sometimes restrict the movement of the joint. The pathogenesis of scars is complex, leading to difficult clinical treatment and high recurrence rate. 5-FU as an anti-inflammatory agent. Tumor drugs have been proved to have a definite therapeutic effect on hypertrophic scars. 5-FU is often administered by intralesional injection. This method of administration has a large dose at one time, which often causes side effects such as erythema and pigmentation, and the patient's compliance is poor after repeated injection. Therefore, it is important to change the administration of 5-FU in the treatment of hypertrophic scars. The transdermal delivery system has the advantages of convenient administration, non-invasiveness and controlled drug release. It is superior to oral and local injection in the treatment of some diseases. In this paper, the electret of physical osmotic enhancer and chemical osmotic enhancer are combined to prepare 5-FU transdermal patch to act on the wound of rats in order to achieve good results. The main contents of this paper are as follows: (1) Formula selection of 5-FU patch containing chemical penetration enhancer and the effect of electret on the properties of patch. In this paper, the pressure-sensitive patch was prepared from 5-FU patch based on EUTEC E100, butyl triester citrate and water-soluble azone. Plasticizers and chemical penetration enhancers had significant effects on the adhesive properties of patches. Then orthogonal design tests were carried out to determine the optimal formulation of 0.25 g E100, 55% m (plasticizer) / m (E100) and 3% azone with the indexes of initial adhesive strength, adhesive strength and drug release in vitro. The results showed that electrets with higher potential promoted the release of patches in vitro by reducing the adhesion of patches and producing electrostatic force with 5-FU. In vitro transport of electret 5-FU patches containing different potentials and different polarities of chemical penetration enhancers (hereinafter referred to as electret patches) on rat back skin and scar skin were studied. The electret patches were tested by modified Franz diffusion cell and high performance liquid chromatography (HPLC). The results showed that: (1) The cumulative release of electret patches through the two types of skin was similar to the retention of skin medicines. (2) The cumulative transdermal amount of electret patches with higher potential and the drug retention in the skin were also higher, and the cumulative transdermal amount of electret patches with the same potential and negative polarity and the retention of skin medicines were also higher. (3) The cumulative transdermal volume of normal skin was higher than that of scar skin, but the drug content in skin was lower than that of scar skin. (4) Electret patches with higher surface potential increased the drug content in skin tissue, which laid a foundation for the in vivo animal experiment of electret patches. (3) Inclusion In order to study the therapeutic effect of electret and electret patches on scars, the skin samples were collected 4 weeks after operation and stained with HE and Mason respectively. The results showed that: (1) The epidermis and dermis of the natural healing group were markedly hyperplasia, collagen fibers were deposited and arranged disorderly, which accorded with the characteristics of hypertrophic scars. (2) The morphological structure of the electret blank patch group was similar to that of the natural healing group, but the effect of inhibiting scar growth was not obvious. (3) The treatment group with 5-FU patch containing chemical osmotic enhancer had certain effect. Compared with the chemical osmosis group, the electret patch group inhibited the growth of hypertrophic scar to a greater extent. (4) The mechanism of the inhibitory effect of electret 5-FU patch containing chemical osmosis enhancer on the growth of hypertrophic scar. The results of positive expression of type I collagen, TGF-beta 1 and HSP47 showed that: (1) Collagen I, type III, TGF-beta 1 and HSP47 were low expressed in normal skin, while the positive expression of type I, type III collagen, TGF-beta 1 and HSP47 in hypertrophic scar tissue was significantly increased. (2) Compared with the natural healing group, the electret group decreased the average optical density of collagen type III, but had no significant effect on other indexes. (3) The electret patch group decreased the average optical density of collagen type I, III, TGF-beta 1 and HSP47, while the electret group decreased the average optical density of collagen type III, TGF-beta 1 and HSP47. In conclusion, electret patch significantly increased the drug content in the skin in vitro transdermal test. In animal experiments, electret patch significantly inhibited the growth of rat scar by inhibiting the expression of collagen I, III, TGF-beta 1 and HSP47, thus containing chemical stimulation. Infiltration electret 5-FU patch can provide a new idea and method for the treatment of hypertrophic scars.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R622

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