胰島素給藥途徑研究進(jìn)展外文翻譯

1、<p>　　畢業(yè)設(shè)計(jì)報(bào)告（論文） —課題英文文獻(xiàn)翻譯</p><p>　?。?2013 屆）</p><p>　　系 別：生物與制藥工程學(xué)院 </p><p>　　課題名稱：胰島素新劑型的研究與進(jìn)展 </p><p>　　指導(dǎo)教師：劉建芳

2、 </p><p>　　班 級：藥劑091 </p><p>　　學(xué)生姓名：章力 </p><p>　　胰島素給藥途徑研究進(jìn)展</p><p>　　摘要:胰島素治療糖尿病多年來一直采用皮下注射方法給藥,為提高病人用藥依從性,國內(nèi)外學(xué)者一直致力

3、于胰島素非注射途徑給藥的研究,探索理想的給藥途徑,進(jìn)一步提高療效。</p><p>　　關(guān)鍵詞:胰島素；劑型；給藥途徑</p><p>　　胰島素(insulin, INS)是治療糖尿病的一種多肽類藥物,自從1921年Banting和Best發(fā)現(xiàn)并首次在臨床應(yīng)用INS以來,一直采用皮下注射。幾十年來,人們?yōu)榱颂岣逫NS的療效,不斷改進(jìn)INS的劑型,不斷更新INS的注射裝置,但這些方法終究離

4、不開注射途徑。因此,非注射途徑應(yīng)用INS一直是人們探索的理想途徑。非注射途徑INS制劑包括肺吸入劑、口服制劑、黏膜給藥制劑以及經(jīng)皮給藥系統(tǒng)等[1]。由于諸多新技術(shù)的應(yīng)用,給INS非注射途徑的應(yīng)用帶來很好的發(fā)展。現(xiàn)就目前INS給藥途徑研究進(jìn)展進(jìn)行綜述。</p><p><b>　　1　INS注射給藥</b></p><p>　　1.1　皮下注射　不同部位INS皮下注射吸

5、收有快有慢,腹部注射吸收最快,其次分別為上臂、大腿、臀部。INS吸收還與劑量濃度和運(yùn)動(dòng)有關(guān),劑量越大、濃度越高,吸收越慢,并且運(yùn)動(dòng)也會(huì)使吸收率增加。腹部面積大,有皮下注射的優(yōu)點(diǎn),一般成人的腹部可供旋轉(zhuǎn)或排列式皮下注射,如兩點(diǎn)相距2 cm,可有180個(gè)注射點(diǎn)[2],按每天3次計(jì)算,能連續(xù)注射2個(gè)月,以后可循環(huán)往復(fù)。</p><p>　　1.2　靜脈輸注　主要適用糖尿病酮癥酸中毒、糖尿病非酮癥高滲性昏迷、嚴(yán)重外傷、感

6、染、外科治療圍術(shù)期者,選用小劑量速效INS靜脈輸注。</p><p>　　1.3　INS泵　INS泵治療糖尿病,可有效地模擬INS的持續(xù)基礎(chǔ)分泌和進(jìn)餐時(shí)的脈沖式釋放,把INS輸注到病人的體內(nèi),維持血液中INS水平,縮短控制高血糖的時(shí)間,減少低血糖發(fā)生,減輕病人多次皮下注射INS的痛苦,INS泵是強(qiáng)化治療的最佳手段。</p><p>　　1.4　肌肉注射　肌肉注射INS吸收快,適用于皮下注射

7、吸收不良者、INS用量已很大、血糖仍不能控制者、輕度酮癥酸中毒而又無條件靜脈輸注INS的病人。</p><p>　　2　INS非注射途徑給藥</p><p>　　2.1　局部給藥　對于糖尿病合并足潰瘍或糖尿病合并壓瘡[3]的病人,在處理患處時(shí)用INS聯(lián)合甲硝唑、山莨菪堿等敷于創(chuàng)面,次日將敷料揭開,可見分泌物明顯減少,淺層破潰創(chuàng)面小的部位3 d或4 d結(jié)痂愈合;深達(dá)肌層的創(chuàng)面也可逐漸見肉芽生

8、長,經(jīng)12周換藥后,創(chuàng)面結(jié)痂愈合。</p><p>　　2.2　吸入給藥　相對于蛋白多肽藥物的吸收而言,肺部具有較多的優(yōu)點(diǎn),如巨大的肺泡表面積(50 m2~140 m2)、極薄的肺泡細(xì)胞膜、豐富的毛細(xì)血管網(wǎng)、通透性高且無首過效應(yīng)、狹小的氣血通路、低酶活性、肺深處較慢的清除速率等,這些良好的生理環(huán)境為蛋白多肽的吸收提供了有利條件[4]。近年來,通過肺的給藥途徑逐漸受到關(guān)注。INS的吸入需要特別的技術(shù)和設(shè)施,常用的技

9、術(shù)有“Techno sphere和AIR[5]”。多數(shù)臨床試驗(yàn)表明,在1型和2型糖尿病病人中,吸入INS和皮下注射INS相比具有同樣的安全性和有效性,且病人更易接受[6-8]。INS肺部給藥制劑目前很引人注目,這對糖尿病人來說將是一個(gè)很大的福音。</p><p>　　2.3　口服給藥　口服給藥是所有給藥途徑中最為方便的一種,病人使用依從性最好。但由于INS作為一種蛋白質(zhì),在胃腸道內(nèi)的吸收難以克服酸催化分解、蛋白酶

10、降解以及黏膜穿透性差等屏障,具有生物利用度低下的缺點(diǎn),因而提高該藥物的生物利用度是藥劑學(xué)家多年來一直研究的難題。</p><p>　　2.4　腹腔內(nèi)給藥　腹腔內(nèi)給藥是國外研制出的一種裝置叫皮下腹膜入口裝置,將它移植在臍上,埋在皮下,內(nèi)部開口在腹腔,開關(guān)每日向腹腔內(nèi)注射所需INS[11]。</p><p>　　2.5　眼部給藥　INS滴眼劑滴眼劑是一種簡便易行的劑型,病人通過INS滴入眼結(jié)膜

11、加以吸收[12]。INS主要通過眼結(jié)膜和鼻淚管黏膜吸收進(jìn)入體循環(huán)而達(dá)到降糖效果。一般眼內(nèi)容量少,INS作用時(shí)間短,生物利用度低,因此人們致力于研究能延長INS作用時(shí)間的滴眼劑,并選擇刺激性小的滴眼劑。Yung-chi等[13]選用生物相容性好、理化性質(zhì)穩(wěn)定且可生物降解的明膠海綿作骨架制成INS眼內(nèi)給藥裝置,該裝置含吸收促進(jìn)劑,經(jīng)眼給藥后,2 h血糖下降50%~62%,且維持時(shí)間達(dá)4 h~6 h,是普通INS滴眼劑的10倍。</p&

12、gt;<p>　　2.6　鼻腔給藥　鼻黏膜內(nèi)血管豐富,黏膜上蛋白酶含量也比胃腸道中少,減少了INS被酶破壞失活,提高了藥物的生物利用度。許多藥物動(dòng)力學(xué)研究表明,鼻黏膜吸收INS的機(jī)制與體內(nèi)內(nèi)源性的INS釋放極為相似,為鼻腔INS給藥提供了理論依據(jù)。鼻腔給藥需要加入吸收促進(jìn)劑,如膽酸鹽、月桂醇酯等才能增加吸收效果。加入吸收促進(jìn)劑可提高藥物的生物利用度,但25%的病人出現(xiàn)鼻部刺激,而且可能潛在損害鼻黏膜和纖毛運(yùn)動(dòng)功能的危險(xiǎn)[1

13、4]。</p><p>　　2.7　口腔黏膜給藥　頰黏膜的吸收表面積為100 cm2~200cm2,通透良好,蛋白酶活性較低,血管豐富。因此,頰黏膜給藥也不失為肽類藥物較適合的一種給藥途徑。頰黏膜給藥制劑Oral-lyn由重組人INS和吸收促進(jìn)劑組成,配合Rapid MistTM裝置,可將藥物以高速、細(xì)小的霧狀形式噴入口腔,給藥后40min~60 min達(dá)到峰濃度,240 min降至最低濃度[15]。</p

14、><p>　　2.8　直腸給藥　INS直腸栓劑是代替注射給藥的重要途徑之一。為了增加吸收,需要向其中加入吸收促進(jìn)劑。直腸給藥方法具有兩大優(yōu)點(diǎn):①直腸內(nèi)pH接近中性或微堿性,且水解酶活性低,藥物極少被破壞;②可基本避免肝臟的首過效應(yīng)。因此,直腸給藥是一條頗為理想的給藥途徑。由于INS是大分子藥物,直腸內(nèi)吸收相對困難,因而要加入促吸收劑,以提高生物利用度[16]。</p><p>　　2.9　經(jīng)皮

15、給藥　皮膚中的水解酶活性很低,可利于INS透皮給藥,但這種大分子蛋白質(zhì)一般難于穿透皮膚,離子導(dǎo)入技術(shù)可使其在電場作用下透過皮膚角質(zhì)層而被吸收入血。角質(zhì)層對大分子肽類藥物的透皮吸收能力差,但只要措施得當(dāng),仍可透過皮膚發(fā)揮全身治療作用。Ryszka等[17]將INS制成軟膏,INS可從軟膏基質(zhì)中釋放出來,透過皮膚進(jìn)入大循環(huán),且體內(nèi)外釋藥量有一定相關(guān)性。超聲促滲技術(shù)可以顯著提高藥物經(jīng)皮吸收,提高藥物局部濃度,是經(jīng)皮給藥一種極具潛力的替代方式。

16、但超聲促滲技術(shù)還有很多局限性,需要系統(tǒng)研究皮膚對超聲波的耐受性和經(jīng)皮滲透性,以及超聲促滲技術(shù)與化學(xué)促進(jìn)劑、離子導(dǎo)入、電穿孔技術(shù)的協(xié)同作用[18]。</p><p><b>　　3　小結(jié)</b></p><p>　　隨著INS給藥系統(tǒng)新技術(shù)、新方法的不斷發(fā)展,醫(yī)護(hù)人員將有更多選擇,各醫(yī)院應(yīng)加強(qiáng)繼續(xù)教育,針對病人病情和需要,選擇最適合的給藥方式,滿足個(gè)體化的治療需要[19

17、]。</p><p><b>　　參考文獻(xiàn):</b></p><p>　　[1]Shaikh IM,Jadhav KR,Ganga S,et al.Advanced approaches in in-sulin delivery[J].Curr Pharm Biotechnol,2005,6(5):387-395.</p><p>　　[2]陳

18、艷.糖尿病的胰島素治療[M].北京:金盾出版社,2002:156-159.</p><p>　　[3]鐘一萍.胰島素外敷治療褥瘡[J].護(hù)士進(jìn)修雜志,2002,17(1): 486.</p><p>　　[4]Cefalu WT.Evolving strategies for insulin delivery and therapy [J].Drugs,2004,64(11):1149-1

19、161.</p><p>　　[5]李昌臣.2型糖尿病胰島素治療的利與弊評價(jià)[J].實(shí)用糖尿病雜志,2002,10(2):10.</p><p>　　[6]Brain JD.Unlocking the opportunity of tight glycaemic control in-haled insulin:Safety[J].Diabetes Obes Metab,2005,7(Su

20、ppl 1): 14-18.</p><p>　　[7]Gonzalez C,Kanevsky D,DeMarco R,etal.Non-invasive routes forinsulin administration:Current state and perspectives[J].ExpertOpin Drug Deliv,2006,3(6):763-770.</p><p>　　

21、[8]Cefalu WT.Concept strategies and feasibility of noninvasive insulin delivery[J].Diabetes Care,2004,27(1):239-246.</p><p>　　[9]Ramdas M,Dileep KJ, Anitha Y,et al.Alginate encapsulated bioadhesive chitosan

22、microspheres for intestinal drug delivery[J].JBiomater Appl,1999,13(4):290-296.</p><p>　　[10]吳正紅,平其能,宋斌梅,等.殼聚糖和殼聚糖EDTA接合物雙層包覆胰島素口服納米脂質(zhì)體的研究[J].藥學(xué)學(xué)報(bào),2004,39(11): 933-938.</p><p>　　[11]安紅蓮,許春華.胰島素不

23、同注射途徑與護(hù)理[J].實(shí)用護(hù)理雜志, 2002,18(9):48.</p><p>　　[12]向丁紅.糖尿病300個(gè)怎么辦[M].北京:北京醫(yī)科大學(xué)、中國協(xié)和醫(yī)科大學(xué)出版社,1997:156.</p><p>　　[13]Yungchi L,Pahala S,Samnel H,etal.Effect of brij-78 on systemic delivery of insulin

24、from an oculardevice[J].J Pharm Sci,1997, 86(4):430.</p><p>　　[14]Owens DR,Zinman B,Bolli G.Alternative routes of insulin delivery[J].Diabet Med,2003,20(11):886-898.</p><p>　　[15]Cernea S,Raz I.

25、Noninjectable methods of insulin administration [J].Drugs Today (Barc),2006,42(6):405-424.</p><p>　　[16]王靜,尹世玉,龔曉玲.胰島素非注射給藥途徑研究進(jìn)展[J].護(hù)理研究,2007,21(4B):953.</p><p>　　[17]Ryszka F,Calich B,Dolinska

26、 B,etal.Noninsulin-injection adminstration of progress[J].Biol Chim Feim,1993,132(6):197.</p><p>　　[18]Barry BW. Novelmechanisms and devices to enable successful transdermal drug delivery[J].Eur J Pharm Sci,

27、2001,1(2):101.</p><p>　　[19]趙京,蔣莉玲.臨床護(hù)士對胰島素應(yīng)用知識(shí)掌握情況調(diào)查[J].家庭護(hù)士,2006,4(3B):12.</p><p>　　Research progress on insulin administration route for patients</p><p>　　(Affiliated Sixth Peopl

28、e’s Hospital of Shanghai Jiao tong University, Shanghai 200233 China)</p><p>　　Abstract　For many years, insulin is administrated by subcutaneous injections to treat patients with diabetes. In order to enhanc

29、e the medication compliance of diabetes patients, scholars of both abroad and at home go in for study on non injection way of administration and probe into an ideal administration route of insulin so as to enhance the th

30、erapeutic effect of insulin.</p><p>　　Key words　insulin; dosage form; administration route</p><p>　　Insulin (insulin, INS) is a peptide drugs to treat diabetes, since 1921, Banting and Best disc

31、overed for the first time in the clinical application of INS has been using subcutaneous injection. For decades, people in order to improve the efficacy of INS, INS formulations continuous improvement, constantly updated

32、 INS injection devices, but these methods are ultimately inseparable from the injection means. Therefore, application of non-injecting means INS has been an ideal way for people to explo</p><p>　　1 INS injec

33、tion</p><p>　　1.1Subcutaneous injection </p><p>　　Different parts of the INS be fast or slow absorption of subcutaneous abdominal injection absorbed the fastest, followed by upper arms, thighs,

34、buttocks. INS also absorbed dose levels and physical activity, the greater the dose, the higher the concentration, slower absorption and absorption rate of movement will increase. Abdominal area, there are advantages of

35、subcutaneous injection, usually the abdomen of adult-type arrangement for rotation or subcutaneous injection, as two distance 2 cm, can </p><p>　　1.2Intravenous infusion</p><p>　　Mainly applied

36、to diabetic ketoacidosis, hyperosmolar nonketotic diabetic coma, severe trauma, infection, surgical treatment of perioperative who use intravenous infusion of small doses of available INS.</p><p>　　1.3 INS p

37、ump</p><p>　　INS pump treatment of diabetes, can effectively simulate the continuing based on INS secretion and meal pulsed release, the INS infusion into the patient's body to maintain blood levels of I

38、NS, shorten time to control high blood sugar and reduce the occurrence of low blood sugar, reduce Patients suffering multiple subcutaneous INS, INS pump is the best means of intensive therapy.</p><p>　　1.4 i

39、ntramuscular</p><p>　　INS intramuscular absorption of fast, poor absorption by subcutaneous injection for, INS has a large amount of blood sugar can not control those who unconditionally infusion mild ketoac

40、idosis INS patients.</p><p>　　2 INS administration of non-injecting means</p><p>　　2.1 Local Administration</p><p>　　For diabetic patients with diabetic foot ulcers or pressure sore

41、s [3] patients in the affected area when dealing with the INS combined with metronidazole, such as Fuyu anisodamine wounds, dressings opened the next day, showing significantly reduced secretion of shallow the site of ru

42、pture of small wounds, or 4 d 3 d scab healing; deep muscle can gradually see the wound granulation, after 12 weeks of dressing, the wound healing scab.</p><p>　　2.2 inhalation</p><p>　　Relative

43、 to the absorption of peptide drugs, the lungs have more advantages, such as large alveolar surface area (50 m2 ~ 140 m2), very thin alveolar membrane, rich capillary network, and not the first high-permeability pass eff

44、ect, narrow blood path, low activity, deep slow lung clearance rate, etc., these good physical environment for the absorption of peptide provided favorable conditions [4].In recent years, progressive pulmonary route of a

45、dministration attention. INS inhalation require spec</p><p>　　2.3 Oral administration</p><p>　　Route of administration of oral administration is the most convenient of all kind, patient complian

46、ce is best. However, INS, as a protein, the absorption in the gastrointestinal tract is difficult to overcome the acid catalyzed decomposition, protein degradation, and poor mucosal barrier penetration, with the disadvan

47、tage of low bioavailability, thereby improving the bioavailability of the drug is a pharmaceutical scientist Research has been the problem.</p><p>　　2.4 Intraperitoneal administration </p><p>　　

48、Intraperitoneal administration is foreign-developed a device called a subcutaneous peritoneal entry device, it would be on the transplant at the umbilicus, buried in the skin, the internal opening in the abdominal cavity

49、, the switch needed daily to the intraperitoneal injection of INS [11].</p><p>　　2.5 ocular drug delivery</p><p>　　INS eye drops eye drops is a simple and convenient dosage form, the conjunctiva

50、 of patients to be instilled through the absorption of INS [12]. INS mainly through the conjunctiva and nasolacrimal duct mucosa absorption of glucose into the systemic circulation to achieve the effect. The general cont

51、ent of less eyes, INS short duration of action, bioavailability is low, so people working on the role of time can be extended INS eye drops, eye drops and select a small irritant. Yung-chi, etc. [13] W</p><p&g

52、t;　　2.6 intranasal administration</p><p>　　Rich in blood vessels in nasal mucosa on the protease content of less than the gastrointestinal tract, reducing the destruction of enzyme inactivation of INS is to

53、improve the bioavailability of the drug. Many pharmacokinetic studies show that the mechanism of nasal absorption of INS and INS in vivo release of endogenous very similar, for nasal administration to provide a theoretic

54、al basis for INS. Intranasal administration need to add absorption enhancers, such as bile salts, lauryl, etc. in or</p><p>　　2.7 Oral administration </p><p>　　The absorption surface area of buc

55、cal mucosa 100 cm2 ~ 200cm2, transparent sound, low protease activity, vascular rich. Therefore, the buccal mucosa administration of peptide drugs may well be a more suitable route of administration. Buccal delivery for

56、mulations Oral-lyn by the INS and the absorption of recombinant human promoter composition, with the Rapid MistTM device can be drugs to high-speed, small form mist sprayed into the mouth, 40min ~ 60 min after administra

57、tion to reach peak concent</p><p>　　2.8 rectal</p><p>　　INS rectal suppository is an important way to replace the one injection. To increase absorption, which need to add absorption enhancer. Re

58、ctal administration method has two advantages: ① rectum close to neutral or slightly alkaline pH, and low hydrolase activity, drug rarely been destroyed; ② can basically avoid the liver first-pass effect. Therefore, rect

59、al administration is a rather ideal route of administration. Since INS is a macromolecular drugs, the rectum is relatively difficult to absorb</p><p>　　2.9 Transdermal Drug Delivery</p><p>　　Hyd

60、rolase activity in the skin is very low, transdermal administration may be beneficial to INS, but the large proteins generally difficult to penetrate the skin, iontophoresis technology to the electric field has been abso

61、rbed into the bloodstream through the skin, the stratum corneum. Cuticle of the macromolecular peptide transdermal drug absorption is poor, but as long as appropriate measures and systemic treatment can play a role throu

62、gh the skin. Ryszka [17] made the ointment INS, INS relea</p><p><b>　　3 Summary</b></p><p>　　With the new technology INS drug delivery systems, the continuous development of new meth

63、ods, health care workers will have more options, all hospitals should strengthen continuing education for the patient's condition and needs, choose the most suitable mode of administration, to meet the needs of indiv

64、idual treatment [19].</p><p>　　References:</p><p>　　[1] Shaikh IM, Jadhav KR, Ganga S, et al.Advanced approaches in in-sulin delivery [J].Curr Pharm Biotechnol, 2005,6 (5) :387-395. </p>

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