化学制药技术毕业论文-胰岛素新剂型的研究与进展-中英文资料外文翻译.doc

毕业设计报论文 课题英文文献翻译 系 别： 制药与生物工程技术系 课题名称： 胰岛素新剂型的研究与进展 班 级： 化学制药技术 Research progress on insulin administration route for patientsAbstractFor many years, insulin is administrated by subcutaneous injections to treat patients with diabetes. In order to enhance 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 therapeutic effect of insulin.Key wordsinsulin; dosage form; administration routeInsulin (insulin, INS) is a peptide drugs to treat diabetes, since 1921, Banting and Best discovered 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 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 explore. INS agents, including non-injecting means of lung inhalation,oral preparations, mucosal delivery formulations and trandermal delivery systems 1. Due to many new technologies, to the INS, the application of non-injecting means a very good development. INS is now the present we reviewed the route of administration.1 INS injection1.1Subcutaneous injection Different parts of the INS be fast or slow absorption of subcutaneous abdominal injection absorbed the fastest, followed by upper arms, thighs, 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 subcutaneous injection, usually the abdomen of adult-type arrangement for rotation or subcutaneous injection, as two distance 2 cm, can be injected with 180 points 2, 3 times per day calculated for continuous injection 2 months later to the cycle.1.2Intravenous infusionMainly applied to diabetic ketoacidosis, hyperosmolar nonketotic diabetic coma, severe trauma, infection, surgical treatment of perioperative who use intravenous infusion of small doses of available INS.1.3 INS pumpINS pump treatment of diabetes, can effectively simulate the continuing based on INS secretion and meal pulsed release, the INS infusion into the patients body to maintain blood levels of INS, 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.1.4 intramuscularINS 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 ketoacidosis INS patients.2 INS administration of non-injecting means2.1 Local AdministrationFor diabetic patients with diabetic foot ulcers or pressure sores 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 rupture 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.2.2 inhalationRelative 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 effect, 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 administration attention. INS inhalation require special technologies and facilities, common technologies that are Techno sphere and AIR 5. Most clinical trials show that in type 1 and type 2 diabetes patients, the inhaled and subcutaneous INS INS compared with the same safety and effectiveness, and more receptive to the patient 6-8. INS agents present compelling pulmonary delivery, which people with diabetes will be a great blessing.2.3 Oral administrationRoute of administration of oral administration is the most convenient of all kind, patient compliance 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 disadvantage of low bioavailability, thereby improving the bioavailability of the drug is a pharmaceutical scientist Research has been the problem.2.4 Intraperitoneal administration 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, the switch needed daily to the intraperitoneal injection of INS 11.2.5 ocular drug deliveryINS eye drops eye drops is a simple and convenient dosage form, the conjunctiva 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 content 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 With good biocompatibility, physical and chemical properties of stable and biodegradable gelatin sponge as a skeleton made of INS intraocular drug delivery device, the device with absorption enhancers, by the eye after administration, 2 h blood glucose decreased by 50% to 62%, and the duration of 4 h 6 h, is 10 times the normal eye drops INS.2.6 intranasal administrationRich 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 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 theoretical basis for INS. Intranasal administration need to add absorption enhancers, such as bile salts, lauryl, etc. in order to increase absorption. Adding absorption enhancers can improve the bioavailability of drugs, but 25% of the patients had nasal stimulation, and could potentially damage the nasal mucosa and the risk of ciliary motility 14.2.7 Oral administration The absorption surface area of buccal 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 formulations 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 administration to reach peak concentration, 240 min to a minimum concentration 15.2.8 rectalINS rectal suppository is an important way to replace the one injection. To increase absorption, which need to add absorption enhancer. Rectal administration method has two advantages: rectum close to neutral or slightly alkaline pH, and low hydrolase activity, drug rarely been destroyed; can basically avoid the liver first-pass effect. Therefore, rectal administration is a rather ideal route of administration. Since INS is a macromolecular drugs, the rectum is relatively difficult to absorb, and thus promote the absorbent be added to improve the bioavailability 16.2.9 Transdermal Drug DeliveryHydrolase 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 absorbed 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 through the skin. Ryszka 17 made the ointment INS, INS released from the ointment out of the matrix, through the skin into the circle, and a certain amount of in vivo release correlation. Ultrasonic penetration technique can significantly improve the drug percutaneous absorption and improve the local concentration of drug, transdermal drug delivery is a promising alternative. However, there are many ultrasonic penetration technology limitations, you need the skin to ultrasound system tolerance and percutaneous penetration, and ultrasound technology and chemical penetration enhancers, iontophoresis, electroporation technology synergies 18.3 SummaryWith the new technology INS drug delivery systems, the continuous development of new methods, health care workers will have more options, all hospitals should strengthen continuing education for the patients condition and needs, choose the most suitable mode of administration, to meet the needs of individual treatment 19.References:1 Shaikh IM, Jadhav KR, Ganga S, et al.Advanced approaches in in-sulin delivery J.Curr Pharm Biotechnol, 2005,6 (5) :387-395. 2Chen Yan. Diabetes insulin Treatment of M. Beijing: Golden Shield Press ,2002:156-159. 3 Zhong Yiping. insulin topical treatment of pressure ulcers J. Nurses Training Magazine, 2002,17 (1): 486. 4Cefalu WT. Evolving strategies for insulin delivery and therapy J. Drugs, 2004,64 (11) :1149-1161.5 Li Changchen Type 2 diabetes, evaluated the pros and cons of insulin therapy J. Practical Diabetology, 2002,10 (2): 10.6Brain JD.Unlocking the opportunity of tight glycaemic control in-haled insulin:SafetyJ.Diabetes Obes Metab,2005,7(Suppl 1): 14-18.7Gonzalez C,Kanevsky D,DeMarco R,etal.Non-invasive routes forinsulin administration:Current state and perspectivesJ.ExpertOpin Drug Deliv,2006,3(6):763-770.8Cefalu WT.Concept strategies and feasibility of noninvasive insulin deliveryJ.Diabetes Care,2004,27(1):239-246.9Ramdas M,Dileep KJ, Anitha Y,et al.Alginate encapsulated bioadhesive chitosan microspheres for intestinal drug deliveryJ.JBiomater Appl,1999,13(4):290-296.10 Wu Hung, Ping their best, Songbin Mei, et al. Chitosan and chitosan EDTA conjugates double-coated oral insulin nano-liposomes J. Pharmaceutical University, 2004,39 (11): 933 -938. 11 An Honglian, Xu Chunhua. insulin injections in different ways and nursing J. Practical Nursing, 2002,18 (9): 48. 12 to the Ding. diabetes, how to do 300 M . Beijing: Beijing Medical University and Peking Union Medical College Press, 1997:156. 13 Yungchi L, Pahala S, Samnel H, etal.Effect of brij-78 on systemic delivery of insulin from an oculardevice J. J Pharm Sci, 1997, 86 (4): 430. 14 Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery J. Diabet Med, 2003,20 (11) :886-898. 15 Cernea S, Raz I. Noninjectable methods of insulin administration J. Drugs Today (Barc), 2006,42 (6) :405-424. 16 Wang Jing, Yin Shiyu, Gong Xiaoling. Non-insulin injection Research progress J. Nursing Research, 2007,21 (4B): 953. 17 Ryszka F, Calich B, Dolinska B, etal.Noninsulin-injection adminstration of progress J. Biol Chim Feim, 1993,132 (6): 197. 18 Barry BW. Novelmechanisms and devices to enable successful transdermal drug delivery J. Eur J Pharm Sci, 2001,1 (2): 101. 19 Zhao Jing, Jiang Liling. clinical nurse knowledge of master insulin Survey J. family nurse, 2006,4 (3B): 12.胰岛素给药途径研究进展摘要:胰岛素治疗糖尿病多年来一直采用皮下注射方法给药,为提高病人用药依从性,国内外学者一直致力于胰岛素非注射途径给药的研究,探索理想的给药途径,进一步提高疗效。关键词:胰岛素；剂型；给药途径胰岛素(insulin, INS)是治疗糖尿病的一种多肽类药物,自从1921年Banting和Best发现并首次在临床应用INS以来,一直采用皮下注射。几十年来,人们为了提高INS的疗效,不断改进INS的剂型,不断更新INS的注射装置,但这些方法终究离不开注射途径。因此,非注射途径应用INS一直是人们探索的理想途径。非注射途径INS制剂包括肺吸入剂、口服制剂、黏膜给药制剂以及经皮给药系统等1。由于诸多新技术的应用,给INS非注射途径的应用带来很好的发展。现就目前INS给药途径研究进展进行综述。1INS注射给药1.1皮下注射不同部位INS皮下注射吸收有快有慢,腹部注射吸收最快,其次分别为上臂、大腿、臀部。INS吸收还与剂量浓度和运动有关,剂量越大、浓度越高,吸收越慢,并且运动也会使吸收率增加。腹部面积大,有皮下注射的优点,一般成人的腹部可供旋转或排列式皮下注射,如两点相距2 cm,可有180个注射点2,按每天3次计算,能连续注射2个月,以后可循环往复。1.2静脉输注主要适用糖尿病酮症酸中毒、糖尿病非酮症高渗性昏迷、严重外伤、感染、外科治疗围术期者,选用小剂量速效INS静脉输注。1.3INS泵INS泵治疗糖尿病,可有效地模拟INS的持续基础分泌和进餐时的脉冲式释放,把INS输注到病人的体内,维持血液中INS水平,缩短控制高血糖的时间,减少低血糖发生,减轻病人多次皮下注射INS的痛苦,INS泵是强化治疗的最佳手段。1.4肌肉注射肌肉注射INS吸收快,适用于皮下注射吸收不良者、INS用量已很大、血糖仍不能控制者、轻度酮症酸中毒而又无条件静脉输注INS的病人。2INS非注射途径给药2.1局部给药对于糖尿病合并足溃疡或糖尿病合并压疮3的病人,在处理患处时用INS联合甲硝唑、山莨菪碱等敷于创面,次日将敷料揭开,可见分泌物明显减少,浅层破溃创面小的部位3 d或4 d结痂愈合;深达肌层的创面也可逐渐见肉芽生长,经12周换药后,创面结痂愈合。2.2吸入给药相对于蛋白多肽药物的吸收而言,肺部具有较多的优点,如巨大的肺泡表面积(50 m2140 m2)、极薄的肺泡细胞膜、丰富的毛细血管网、通透性高且无首过效应、狭小的气血通路、低酶活性、肺深处较慢的清除速率等,这些良好的生理环境为蛋白多肽的吸收提供了有利条件4。近年来,通过肺的给药途径逐渐受到关注。INS的吸入需要特别的技术和设施,常用的技术有“Techno sphere和AIR5”。多数临床试验表明,在1型和2型糖尿病病人中,吸入INS和皮下注射INS相比具有同样的安全性和有效性,且病人更易接受6-8。INS肺部给药制剂目前很引人注目,这对糖尿病人来说将是一个很大的福音。2.3口服给药口服给药是所有给药途径中最为方便的一种,病人使用依从性最好。但由于INS作为一种蛋白质,在胃肠道内的吸收难以克服酸催化分解、蛋白酶降解以及黏膜穿透性差等屏障,具有生物利用度低下的缺点,因而提高该药物的生物利用度是药剂学家多年来一直研究的难题。2.4腹腔内给药腹腔内给药是国外研制出的一种装置叫皮下腹膜入口装置,将它移植在脐上,埋在皮下,内部开口在腹腔,开关每日向腹腔内注射所需INS11。2.5眼部给药INS滴眼剂滴眼剂是一种简便易行的剂型,病人通过INS滴入眼结膜加以吸收12。INS主要通过眼结膜和鼻泪管黏膜吸收进入体循环而达到降糖效果。一般眼内容量少,INS作用时间短,生物利用度低,因此人们致力于研究能延长INS作用时间的滴眼剂,并选择刺激性小的滴眼剂。Yung-chi等13选用生物相容性好、理化性质稳定且可生物降解的明胶海绵作骨架制成INS眼内给药装置,该装置含吸收促进剂,经眼给药后,2 h血糖下降50%62%,且维持时间达4 h6 h,是普通INS滴眼剂的10倍。2.6鼻腔给药鼻黏膜内血管丰富,黏膜上蛋白酶含量也比胃肠道中少,减少了INS被酶破坏失活,提高了药物的生物利用度。许多药物动力学研究表明,鼻黏膜吸收INS的机制与体内内源性的INS释放极为相似,为鼻腔INS给药提供了理论依据。鼻腔给药需要加入吸收促进剂,如胆酸盐、月桂醇酯等才能增加吸收效果。加入吸收促进剂可提高药物的生物利用度,但25%的病人出现鼻部刺激,而且可能潜在损害鼻黏膜和纤毛运动功能的危险14。2.7口腔黏膜给药颊黏膜的吸收表面积为100 cm2200cm2,通透良好,蛋白酶活性较低,血管丰富。因此,颊黏膜给药也不失为肽类药物较适合的一种给药途径。颊黏膜给药制剂Oral-lyn由重组人INS和吸收促进剂组成,配合Rapid MistTM装置,可将药物以高速、细小的雾状形式喷入口腔,给药后40min60 min达到峰浓度,240 min降至最低浓度15。2.8直肠给药INS直肠栓剂是代替注射给药的重要途径之一。为了增加吸收,需要向其中加入吸收促进剂。直肠给药方法具有两大优点:直肠内pH接近中性或微碱性,且水解酶活性低,药物极少被破坏;可基本避免肝脏的首过效应。因此,直肠给药是一条颇为理想的给药途径。由于INS是大分子药物,直肠内吸收相对困难,因而要加入促吸收剂,以提高生物利用度16。2.9经皮给药皮肤中的水解酶活性很低,可利于INS透皮给药,但这种大分子蛋白质一般难于穿透皮肤,离子导入技术可使其在电场作用下透过皮肤角质层而被吸收入血。角质层对大分子肽类药物的透皮吸收能力差,但只要措施得当,仍可透过皮肤发挥全身治疗作用。Ryszka等17将INS制成软膏,INS可从软膏基质中释放出来,透过皮肤进入大循环,且体内外释药量有一定相关性。超声促渗技术可以显著提高药物经皮吸收,提高药物局部浓度,是经皮给药一种极具潜力的替代方式。但超声促渗技术还有很多局限性,需要系统研究皮肤对超声波的耐受性和经皮渗透性,以及超声促渗技术与化学促进剂、离子导入、电穿孔技术的协同作用18。3小结随着INS给药系统新技术、新方法的不断发展,医护人员将有更多选择,各医院应加强继续教育,针对病人病情和需要,选择最适合的给药方式,满足个体化的治疗需要19。参考文献:1Shaikh IM,Jadhav KR,Ganga S,et al.Advanced approaches in in-sulin deliveryJ.Curr Pharm Biotechnol,2005,6(5):387-395.2陈艳.糖尿病的胰岛素治疗M.北京:金盾出版社