鮮 靜，張 晨，鐘雪梅，傅超美，高 飛，章津銘

中藥活性成分口服結(jié)腸靶向納米系統(tǒng)治療潰瘍性結(jié)腸炎的研究進(jìn)展

鮮 靜，張 晨，鐘雪梅，傅超美，高 飛*，章津銘*

成都中醫(yī)藥大學(xué)藥學(xué)院，四川 成都 611137

潰瘍性結(jié)腸炎（ulcerative colitis，UC）為現(xiàn)代常見病、難治病。因其發(fā)病反復(fù)，臨床常需反復(fù)長(zhǎng)期使用柳氮磺胺吡啶、免疫抑制劑等藥物，但其療效有限且易產(chǎn)生不良反應(yīng)。現(xiàn)代研究發(fā)現(xiàn)中藥多酚類、生物堿類、醌類、萜類等活性成分通過多靶點(diǎn)機(jī)制，表現(xiàn)出較好緩解UC的作用，且不良反應(yīng)相對(duì)較低，但存在水溶性差、胃腸道不穩(wěn)定和結(jié)腸靶向性差等制劑學(xué)問題。針對(duì)以上制劑學(xué)問題，研究者構(gòu)建了多種中藥活性成分的口服結(jié)腸靶向納米系統(tǒng)，通過避免胃腸道破壞、延長(zhǎng)腸滯留、實(shí)現(xiàn)藥物在病灶部位控釋等方式顯著提升了對(duì)UC的治療效果。對(duì)具有UC防治作用的中藥活性成分及其作用機(jī)制，以及口服結(jié)腸靶向納米系統(tǒng)用于UC治療的研究進(jìn)展進(jìn)行綜述，以期為中藥活性成分口服靶向治療UC提供思路。

中藥活性成分；潰瘍性結(jié)腸炎；納米制劑；結(jié)腸靶向；遞藥體系

潰瘍性結(jié)腸炎（ulcerative colitis，UC）是一種病程長(zhǎng)且難以治愈的非特異性炎癥性腸病，病區(qū)可至直腸黏膜下層，累及直腸、乙狀結(jié)腸乃至整個(gè)結(jié)腸區(qū)域[1]。其臨床表現(xiàn)為腹痛、腹瀉、體質(zhì)量減輕及便血，可反復(fù)發(fā)作，已經(jīng)被世界衛(wèi)生組織列為現(xiàn)代難治病之一，其發(fā)病機(jī)制復(fù)雜，與黏膜通透性增加、微生物水平失調(diào)和腫瘤壞死因子-α（tumor necrosis factor-α，TNF-α）、白介素-6（interleukin-6，IL-6）、白介素-10（interleukin-10，IL-10）等炎癥因子水平失調(diào)等因素相關(guān)[2]。目前治療UC的常用藥物有5-氨基水楊酸類、皮質(zhì)醇類和免疫抑制類等，但是長(zhǎng)期服用這些藥物會(huì)引起嚴(yán)重的不良反應(yīng)。根據(jù)疾病癥狀，UC在中醫(yī)上屬于“休息痢”“久痢”“腸癖”等范疇[3]?；诒孀C論治理念，中醫(yī)藥防治UC歷史悠久，臨床療效顯著且不良反應(yīng)較小。中藥治療UC具有多成分、多靶點(diǎn)、改善機(jī)體內(nèi)環(huán)境等優(yōu)勢(shì)，然而，中藥活性成分經(jīng)口服治療時(shí)，存在水溶性差、胃腸穩(wěn)定性低、口服生物利用度差等不足。如何實(shí)現(xiàn)中藥活性成分在結(jié)腸病變部位的高效遞送，是亟待解決的一個(gè)問題。本文通過查閱近年來的中英文文獻(xiàn)，總結(jié)并綜述了具有UC防治作用的中藥代表活性成分及其作用機(jī)制，以及口服結(jié)腸靶向納米系統(tǒng)用于UC治療的研究進(jìn)展，以期為中藥活性成分高效治療UC提供參考思路。

1 具有UC防治作用的中藥活性成分及其作用

中醫(yī)藥治療UC歷史悠久且療效明顯，特別是中藥多酚類、生物堿類、醌類、萜類等活性成分顯示出對(duì)UC的治療潛力。

1.1 多酚類

多酚類化合物是一類具有多個(gè)酚羥基的化合物，存在于多種中藥中，其中白藜蘆醇、蘆丁、水飛薊素、姜黃素等化合物均被報(bào)道有治療UC的作用。白藜蘆醇常存在于決明、藜蘆、虎杖等常用中藥中，在治療和預(yù)防各種疾病中具有重要作用。Rauf等[4]、Marques等[5]研究發(fā)現(xiàn)白藜蘆醇可通過下調(diào)TNF-α、環(huán)氧合酶2、C反應(yīng)蛋白、干擾素等炎癥生物標(biāo)志物而治療炎癥。蘆丁，又名蕓香苷，存在于槐米、蕎麥葉、蒲公英等中藥中，主要用于抗炎、抗病毒、抗氧化[6]。Nones等[7]、Habtemariam等[8]研究發(fā)現(xiàn)蘆丁可通過抑制TNF-α和核因子κB（nuclear factor kappa-B，NF-κB）。從水飛薊中提取得到的黃酮木脂素類化合物水飛薊素具有抗癌、抗炎癥的作用，水飛薊素可清除自由基和活性氧物質(zhì)，減少組胺釋放和TNF-α、IL-6、IL-8的表達(dá)，進(jìn)而有效改善UC的炎癥癥狀[9-10]。姜黃素來源于姜科植物姜黃，常作為一種食品添加劑，具有抗炎、抗氧化、抗腫瘤、保肝、抗血管生成等多種功效。因而，姜黃素在治療UC上具有良好的作用[11]。

1.2 生物堿類

生物堿類成分是一類含氮的堿性有機(jī)化合物。近年來，一些中藥中的生物堿類成分顯示出良好的UC治療作用。從毛茛科植物黃連中提取出的一種異喹啉生物堿小檗堿，常用于治療細(xì)菌相關(guān)的腹瀉。臨床可用于抗炎、抗腫瘤、免疫調(diào)節(jié)。研究表明，小檗堿可通過抑制某些炎癥因子的表達(dá)來改善UC[12]。青藤堿是從防己科植物青藤的根中提取的一種生物堿類成分，常被用于治療風(fēng)濕性關(guān)節(jié)炎。近年來，研究者發(fā)現(xiàn)青藤堿在治療慢性炎癥方面也具有一定作用[13]。Tang等[14]、Zhou等[15]發(fā)現(xiàn)青藤堿能通過調(diào)節(jié)Nrf2/NQO-1信號(hào)通路減輕由硫酸葡聚糖鈉（dextran sulfate sodium，DSS）誘導(dǎo)的UC小鼠的炎癥情況。氧化苦參堿是從豆科植物苦參中分離得到的活性成分，已有研究證實(shí)，氧化苦參堿具有抗肝炎病毒、抗腫瘤等作用。熊永愛等[16]開展實(shí)驗(yàn)證明氧化苦參堿對(duì)三硝基苯磺酸（trinitrobenzene sulfonic acid，TNBS）誘導(dǎo)的SD大鼠UC的療效明確。從黑胡椒中提取出的胡椒堿和防己中提取的粉防己堿也被證實(shí)具有一定的抗UC作用[17-18]。

1.3 醌類

具有UC治療作用的醌類成分主要是大黃素和大黃酸。大黃素是大多數(shù)中藥中含有的一種蒽醌類衍生物，具有抗腫瘤、抗菌、利尿、舒張血管的作用。研究發(fā)現(xiàn)大黃素能通過降低血液中抗鞭毛蛋白抗體的水平和下調(diào)Toll樣受體5（toll like receptor 5，TLR5）、NF-κB p65通路的表達(dá)來治療UC[19-20]。大黃酸是一種常被用于治療胃腸道疾病的蒽醌類化合物，可以減輕巨噬細(xì)胞RAW264.7因脂多糖誘導(dǎo)后產(chǎn)生的促炎癥因子的水平[21]。也有研究發(fā)現(xiàn)從百花酸藤果中提取出的信筒子醌亦可減少誘導(dǎo)型一氧化氮合酶（inducible nitric oxide synthase，iNOS）、TNF-α、IL-1β、IL-6的表達(dá)來緩解炎癥[22]。

1.4 萜類

萜類是異戊二烯的聚合物及其衍生物的總稱，研究發(fā)現(xiàn)某些倍半萜類、二萜類、三萜類成分具有治療UC的作用。從雷公藤中提取出的一種五環(huán)三萜類成分雷公藤紅素，對(duì)炎癥、癌癥和關(guān)節(jié)炎等均有潛在的治療作用[23]。Jia等[24]研究發(fā)現(xiàn)雷公藤紅素可抑制壞死性凋亡和緩解DSS誘導(dǎo)的UC小鼠炎癥。小白菊內(nèi)酯是一種倍半萜烯內(nèi)酯化合物，是菊科植物的重要有效成分，具有抗氧化應(yīng)激、抗炎、抑制細(xì)胞凋亡等生物學(xué)活性。研究發(fā)現(xiàn)，小白菊內(nèi)酯可作為一種NF-κB通路的抑制劑，緩解由DSS誘導(dǎo)的小鼠UC[25]。二萜類成分酯穿心蓮內(nèi)酯是穿心蓮中的一種重要成分，可影響UC患者體內(nèi)Th1/Th2/Th17反應(yīng)[26]。此外，Zhu等[27]發(fā)現(xiàn)穿心蓮內(nèi)酯對(duì)TNBS誘導(dǎo)的UC小鼠模型有較好的治療效果。二萜類成分二氫丹參酮Ⅰ也被報(bào)道具有治療UC的作用[28]。

1.5 其他

中藥中含有的其他成分，如西紅花酸、莽草酸、牛蒡子苷元、鴉膽子苦素以及多糖類成分果膠、纖維素、殼聚糖、車前籽膠等均被報(bào)道具有治療UC的作用[29-34]。一些中藥提取物，如生姜提取物亦被證明有抗炎作用。研究發(fā)現(xiàn)生姜提取物中的成分6-姜烯酚、6-姜辣素能夠抑制炎癥相關(guān)基因的表達(dá)，從而改善炎癥病情[35-37]。

具有UC防治作用的代表性中藥活性成分見圖1，其作用及其機(jī)制見表1。

圖1 具有UC防治作用的代表性中藥活性成分

表1 具有UC防治作用的代表性中藥活性成分及其作用機(jī)制

續(xù)表1

MPO-髓過氧化物酶 PPARγ-過氧化物酶體增殖物激活受體γ STAT-信號(hào)傳導(dǎo)及轉(zhuǎn)錄激活蛋白 COX-2-環(huán)氧化酶2 IFN-γ-γ干擾素 TGF-β-轉(zhuǎn)化生長(zhǎng)因子β Nrf2-核因子E-2-相關(guān)因子2

MPO-myeloperoxidase PPARγ-peroxisome proliferator-activated receptor γ STAT-signal transducer and activator of transcription COX-2- cyclooxygenase 2 IFN-γ-interferon γ TGF-β-transforming growth factor β Nrf2-nuelear factor E2-related factor 2

2 口服結(jié)腸靶向納米系統(tǒng)用于UC的治療效果

雖然中藥活性成分治療UC具有多途徑、多靶點(diǎn)、不良反應(yīng)小、改善機(jī)體內(nèi)環(huán)境等優(yōu)勢(shì)，但由于其本身存在的疏水性強(qiáng)、滲透性差、口服穩(wěn)定性差等不足，限制了其在治療UC方面的應(yīng)用。為了使中藥活性成分更有效地治療UC，一些基于粒子尺寸依賴、pH依賴、酶響應(yīng)、主動(dòng)靶向等原理的中藥活性成分口服結(jié)腸靶向納米系統(tǒng)被開發(fā)出來。與傳統(tǒng)的口服制劑相比，口服結(jié)腸靶向納米制劑具有更多的優(yōu)勢(shì)。首先，其可以提高藥物水溶性和穩(wěn)定性，避免腸道環(huán)境和某些酶對(duì)藥物的破壞，減少物理或化學(xué)降解，延緩藥物釋放時(shí)間，達(dá)到緩釋的目的；其次，當(dāng)把藥物制備成口服結(jié)腸靶向納米制劑時(shí)，納米級(jí)別的粒子在結(jié)腸部位有更好的靶向性，能有效地減輕系統(tǒng)不良反應(yīng)[53-54]，當(dāng)使用pH敏感材料、結(jié)腸微生物易降解材料構(gòu)建納米體系時(shí)，還能進(jìn)一步增強(qiáng)藥物的結(jié)腸靶向性。最后，由于納米制劑所具有的微小粒徑，使得藥物更易在結(jié)腸炎癥部位聚集，且以較低的藥物濃度便可以達(dá)到很好的治療效果[55]。

2.1 粒子尺寸依賴型

研究表明，UC患病區(qū)域腸道黏膜層被破壞，巨噬細(xì)胞等炎癥相關(guān)細(xì)胞增多，原有的腸道環(huán)境被破壞。納米級(jí)別的粒子可被巨噬細(xì)胞優(yōu)先吸收，同時(shí)可以通過結(jié)腸上皮高通透性和滯留效應(yīng)（enhanced permeability and retention effect，EPR）效應(yīng)將活性藥物遞送到結(jié)腸炎癥組織內(nèi)[56]。Lamprecht等[57]分別制備帶有熒光色素的3種納米粒子（粒徑分別為0.1、1、10 μm），給TNBS誘導(dǎo)的UC大鼠ig 3 d后觀察各種粒子的分布，3種不同粒徑的納米粒子在結(jié)腸部位的分布指數(shù)分別為（5.2±3.8）%、（9.1±4.2）%、（14.5±6.3）%。因此，在UC患病區(qū)域，當(dāng)粒徑足夠小時(shí)，藥物粒子能夠滲透進(jìn)入細(xì)胞，從而促進(jìn)其快速地通過黏膜屏障，與免疫系統(tǒng)作用，提高藥物的攝取、吸收、分布以及代謝[58-59]。Ma等[60]利用乳化溶劑蒸發(fā)法分別制備裝載姜黃素的微粒（粒徑1.7 μm）和納米粒（粒徑270 nm），與微粒相比，納米粒具有更高的釋放率，動(dòng)物實(shí)驗(yàn)中，姜黃素納米粒更易緩解DSS誘導(dǎo)的小鼠UC炎癥情況。

2.2 pH依賴型

胃腸道的pH值從胃到結(jié)腸逐漸升高。根據(jù)結(jié)腸pH 7～8的特點(diǎn)可以設(shè)計(jì)出pH依賴的納米遞送體系，該納米系統(tǒng)可在結(jié)腸部位靶向釋放[54,61-62]。通過在藥物表面包裹pH敏感的生物降解高分子材料可以設(shè)計(jì)出pH依賴的藥物遞送系統(tǒng)。甲基丙烯酸聚合物Eudragit?是常見的pH敏感材料。通過改變其側(cè)鏈可使其在不同的pH中溶解。Raj等[63]制備出pH敏感的姜黃素納米制劑，先用粒子凝膠法制備出殼聚糖包載的納米核結(jié)構(gòu)，再使用乳化溶劑蒸發(fā)法制備Eudragit FS 30D殼，得到核-殼結(jié)構(gòu)的納米，該納米制劑具有控釋藥物、結(jié)腸靶向的能力，釋放實(shí)驗(yàn)中，包裹pH敏感材料的殼聚糖納米粒在模擬結(jié)腸液（pH 7.4）中的累積釋放率達(dá)84.7%，且在24 h內(nèi)持續(xù)有藥物釋放。Beloqui等[11]也將姜黃素、pH敏感劑Eudragit?S100、聚乳酸-羥基乙酸共聚物[poly(lactic-co-glycolic acid)，PLGA]溶解于有機(jī)相中后滴入含有聚乙烯醇的水溶液中攪拌制得pH敏感納米制劑，該納米制劑系統(tǒng)在pH 1.5胃模擬液中和pH 4.5小腸模擬液中幾乎不釋放姜黃素，在pH 7.2結(jié)腸模擬液中1 h后的姜黃素釋放率達(dá)90%。細(xì)胞攝取實(shí)驗(yàn)中，姜黃素納米粒子比姜黃素游離溶液更易穿過上皮屏障，增加結(jié)腸癌Caco-2細(xì)胞對(duì)姜黃素的吸收。體內(nèi)實(shí)驗(yàn)中，pH敏感的姜黃素納米粒制劑明顯減少DSS誘導(dǎo)小鼠中性粒細(xì)胞的浸潤(rùn)和TNF-α的分泌，降低MPO的水平，緩解DSS誘導(dǎo)的小鼠體質(zhì)量下降，抑制結(jié)腸縮短；HE染色中，pH敏感納米制劑組明顯緩解結(jié)腸部位炎癥情況。蘆丁[64]、鞣花酸[65]、青藤堿[66]等也被報(bào)道有pH敏感型納米制劑用于UC的治療。

2.3 酶響應(yīng)型

研究顯示結(jié)腸含有大量有益微生物，這些微生物可以產(chǎn)生高活性的蛋白酶和多肽酶，可利用該特點(diǎn)制成結(jié)腸酶敏感的納米制劑。制劑到達(dá)結(jié)腸后，酶敏感材料降解使藥物釋放，提升藥物的生物利用度[67-69]。Castangia等[70]利用超聲波反應(yīng)法制備酶敏感的槲皮素脂質(zhì)體治療UC。Nutriose是一種可溶性玉米糊精，利用Nutriose的酶降解性制得酶敏感的復(fù)合脂質(zhì)體。體內(nèi)分布實(shí)驗(yàn)顯示未包裹Nutriose的脂質(zhì)體ig 4 h后在回腸和盲腸有較強(qiáng)的熒光，而在結(jié)腸只有微弱熒光；包裹Nutriose的脂質(zhì)體ig 4 h后在結(jié)腸有明顯的熒光。此外，該納米遞送體系能延遲藥物釋放，釋放實(shí)驗(yàn)中，包裹Nutriose的脂質(zhì)體在pH 7.0的結(jié)腸模擬液中8 h的累積釋放率比未包裹的低15%。體內(nèi)藥效實(shí)驗(yàn)中，納米制劑組明顯減輕結(jié)腸區(qū)域的出血和潰瘍情況，降低結(jié)腸水腫組織（colonic edema tissue，CAS）指數(shù)，降低MPO活性。殼聚糖包被海藻酸鈣的微球裝載淫羊藿苷也可通過酶響應(yīng)將藥物靶向遞送至結(jié)腸[71]。

2.4 主動(dòng)靶向型

研究發(fā)現(xiàn)，結(jié)腸的炎癥部位具有大量的炎癥相關(guān)蛋白，當(dāng)在納米粒上連接能特異性與其結(jié)合的物質(zhì)后，可通過配體-受體作用達(dá)到結(jié)腸靶向的目的。硫酸軟骨素（chondroitin sulfate，CS）是一種糖胺聚糖物質(zhì)，可特異性地與CD44受體結(jié)合。CD44是活性巨噬細(xì)胞表面的一種跨膜轉(zhuǎn)運(yùn)糖蛋白。Gou等[72]利用絲素蛋白制備姜黃素納米粒后在其表面接上CS，達(dá)到靶向結(jié)腸巨噬細(xì)胞的目的。巨噬細(xì)胞攝取實(shí)驗(yàn)中，給藥處理4 h后硫酸軟骨素納米粒（chondroitin sulfate nanoparticles，CS-NPS）熒光明顯強(qiáng)于姜黃素納米粒。CS-NPS ig后，明顯抑制小鼠體質(zhì)量下降，下調(diào)TNF-α、IL-6的水平，上調(diào)IL-10的水平；HE染色實(shí)驗(yàn)中，免疫細(xì)胞的積累減少。CS-NPS ig后，15 d DSS處理后的小鼠存活率達(dá)50%。研究發(fā)現(xiàn)，結(jié)腸炎癥老鼠體內(nèi)結(jié)腸上皮細(xì)胞中的CD98上調(diào)，可通過干擾其合成來達(dá)到治療UC的目的[73]。Xiao等[74]制備含CD98合成干擾RNA（CD98 siRNA，siCD98）的姜黃素水凝膠用于靶向治療UC。利用PLGA包裹姜黃素和siCD98形成納米粒，然后外包殼聚糖后與透明質(zhì)酸連接，最后在殼聚糖和海藻酸鈉存在下交聯(lián)成水凝膠。細(xì)胞攝取實(shí)驗(yàn)中，透明質(zhì)酸納米粒組熒光強(qiáng)于姜黃素納米組，證明表面修飾透明質(zhì)酸（hyaluronic acid，HA）后能提升細(xì)胞對(duì)納米粒子的攝取。進(jìn)一步的細(xì)胞實(shí)驗(yàn)顯示，該納米制劑系統(tǒng)降低結(jié)腸癌Colon-26細(xì)胞中CD98的表達(dá)，下調(diào)MPO和糞便中載脂蛋白2（lipocalin-2，Lcn-2）的水平，減輕結(jié)腸潰瘍情況，促進(jìn)結(jié)腸組織恢復(fù)正常。也有研究者將具有靶向性的siRNA載入生姜來源的天然納米粒中用于靶向治療UC[75]。

2.5 其他

除了上述提到的靶向納米系統(tǒng)外，還有一些如多孔納米制劑、自組裝納米遞送系統(tǒng)用于中藥活性成分的結(jié)腸靶向遞送。Chen等[76]利用雙重乳化溶劑蒸發(fā)技術(shù)使用PLGA/PF127包載姜黃素，以碳酸氫銨（ammonium bicarbonate，ABC）作為致孔劑，產(chǎn)生多孔納米粒，巨噬細(xì)胞攝取實(shí)驗(yàn)中，多孔納米粒制劑熒光強(qiáng)于無孔納米粒制劑。體內(nèi)實(shí)驗(yàn)顯示多孔納米粒在結(jié)腸組織有更多的積累。Dou等[77]用自組裝納米乳化法構(gòu)建鴉膽子苦素納米粒，將鴉膽子苦素（bruceine D，BD）溶解在（聚乙二醇-15-羥基硬脂酸酯）-丙二醇-中鏈三酰甘油（4∶2∶1）溶液中，攪拌即得自組裝納米粒。與BD游離溶液相比，BD自組裝納米系統(tǒng)具有更好地抑制促炎癥因子的作用，且能明顯緩解UC組織的損傷。

口服結(jié)腸靶向納米系統(tǒng)的遞送原理見圖2，中藥活性成分治療UC的口服結(jié)腸靶向納米系統(tǒng)見表2。

圖2 口服結(jié)腸靶向納米系統(tǒng)的遞送原理

表2 中藥活性成分治療UC的口服結(jié)腸靶向納米系統(tǒng)

↑-上升 ↓-下降 PF127-泊洛沙姆127 SF-絲素蛋白 PG-丙二醇 DAI-疾病活動(dòng)指數(shù) SBO-大豆油 VCO-天然椰油 MyD88-髓樣分化因子；TRAF6-腫瘤壞死因子受體相關(guān)蛋白6 LPO-脂過氧化物 GSH-谷胱甘肽 LDH-乳酸脫氫酶

↑-increase ↓-decrease PF127-poloxamer F127 SF-silk fibroin PG-propylene glycol DAI-disease active index SBO-soya bean oil VCO-virgin coconut oil MyD88-myeloid differentiation factor 88 TRAF6-TNF receptor associated factor 6 LPO-lipid peroxidation GSH-glutathione LDH-lactate dehydrogenase

3 結(jié)語

傳統(tǒng)中藥具有多成分、多靶點(diǎn)的特點(diǎn)，在治療以UC為代表性的慢性、復(fù)雜性疾病方面優(yōu)勢(shì)顯著。隨著研究的深入，中藥干預(yù)UC的有效成分被發(fā)現(xiàn)且機(jī)制逐漸清楚，如姜黃素、雷公藤紅素、白藜蘆醇等。但是，在制劑開發(fā)過程中，其水不溶性、低生物利用度和結(jié)腸靶向性差等問題，局限了其使用。因此，如何通過口服有效遞送藥物到達(dá)結(jié)腸患病部位釋放藥物發(fā)揮治療效果是亟待解決的問題?？诜Y(jié)腸靶向遞藥系統(tǒng)的構(gòu)建可以解決這一問題，可根據(jù)粒子尺寸依賴、pH依賴、酶響應(yīng)和配體-受體特異性配對(duì)等原理設(shè)計(jì)治療UC的納米制劑，一方面使藥物溶解度增大，另一方面通過納米功能化設(shè)計(jì)，使藥物靶向結(jié)腸，富集于結(jié)腸部位從而提升對(duì)UC的療效。然而，結(jié)腸靶向納米制劑仍然存在一些問題：結(jié)腸靶向納米制劑雖然能增加藥物溶解度，但在某些體系中，藥物的累積釋放率不高且抗胃酸環(huán)境破壞力較弱；許多納米的胃腸穩(wěn)定性局限于體外的研究，其體內(nèi)的變化有待進(jìn)一步觀察，且其長(zhǎng)期穩(wěn)定性有待深入；某些納米制劑抵達(dá)結(jié)腸部位后其釋放規(guī)律的準(zhǔn)確性需要進(jìn)一步的探討；某些納米制劑通過結(jié)腸黏膜細(xì)胞時(shí)滲透性不高，存在炎癥或免疫相關(guān)細(xì)胞攝取率不高等問題，這些問題都會(huì)進(jìn)一步限制結(jié)腸靶向納米制劑運(yùn)用于臨床。但是，近年來，隨著新型材料的運(yùn)用、結(jié)腸特異性受體的發(fā)現(xiàn)和UC發(fā)病機(jī)制的研究，將會(huì)進(jìn)一步提升口服制劑的結(jié)腸靶向性和專屬性，為口服中藥結(jié)腸靶向納米制劑的設(shè)計(jì)提供思路。

利益沖突 所有作者均聲明不存在利益沖突

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Research progress on oral colon targeting nano system of Chinese medicine active ingredients in treatment of ulcerative colitis

XIAN Jing, ZHANG Chen, ZHONG Xue-mei, FU Chao-mei, GAO Fei, ZHANG Jin-ming

School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China

Ulcerative colitis (UC) is a common and refractory disease. Because of its repeated onset, it is often necessary to use sulfasalazine, immunosuppressor agents and other drugs for a long time, but its efficacy is limited and it is easy to produce side effects. Modern studies have found that polyphenols, alkaloids, quinones, terpenoids and other active components of traditional Chinese medicine can alleviate UC better through multi-target mechanism, and the side effects are relatively low, but there are pharmaceutical problems such as poor water solubility, gastrointestinal instability and poor colon targeting. In view of the above problems, the researchers have constructed a variety of oral colon targeted nano system of active ingredients of traditional Chinese medicine, which can significantly improve the therapeutic effect of UC by avoiding gastrointestinal tract damage, prolonging intestinal retention, and achieving controlled release of drugs in the focus. In this paper, active components of traditional Chinese medicine with prevention and treatment effect of UC and their mechanisms, and the research progress on oral colon targeting nano system of Chinese herbal active ingredients in treatment of ulcerative colitisare reviewed, in order to provide ideas for active components of traditional Chinese medicine in oral targeted treatment of UC.

active components of traditional Chinese medicine; ulcerative colitis; nano-preparations; colon targeting; drug delivery system

R283.6

A

0253 - 2670(2021)06 - 1816 - 11

10.7501/j.issn.0253-2670.2021.06.031

2020-07-06

國家自然科學(xué)基金青年基金資助項(xiàng)目（81903811）；2018—2020年度中華中醫(yī)藥學(xué)會(huì)青年人才托舉工程資助項(xiàng)目（QNRC1-01）

鮮 靜（1996—），女，碩士研究生，研究方向?yàn)橹兴幩巹W(xué)。Tel: 18728456014 E-mail: xianjing4320@126.com

章津銘，男，博士，教授，主要從事中藥新制劑與新劑型研究。Tel: (028)61800101 E-mail: zhangjinming1987@126.com

高 飛，男，博士，副研究員。Tel: (028)61800101 E-mail: feigao207@yeah.net

[責(zé)任編輯 崔艷麗]