Recent technologies in insulin delivery systems

İnsülinin farklı yollardan uygulanması ile ilgili çalışmalar insülinin ilk keşfi ile birlikte başlamıştır. Ancak parenteral yol dışındaki uygulamalarda istenilen biyolojik etki sağlanamamıştır. Ne yazık ki insülinin mukozal peptidazlarla enzimatik yıkıma uğraması, mukozal bariyer nedeni ile yeterli absorbsiyonun olmaması ve intestinal mukoza boyunca absorbsiyonun yetersiz olması kullanımını parenteral yol ile kısıtlamıştır. İnsülinin parenteral kullanımı intramusküler, subkutan, intravenöz ve intraperitoneal olmak üzere farklı şekillerde mümkün olmakatadır. Ancak parenteral uygulamanın injeksiyon yerinde ağrı, injeksiyon bölgesinde kanama, lipohipertrofi gibi lokal rahatsızlık verici yan etkileri ve glisemik dalgalanma gibi dezavantajları bulunmaktadır. İnsülin, oral, nazal, bukkal, oftalmik, rektal, vaginal ve transdermal yollardan uygulanmış, ancak bu bariyerler nedeni ile başarılı sonuçlara ulaşılamamıştır. Ek olarak, parenteral uygulama dışında onaylanmış bir diğer insülin uygulama yolu pulmoner yoldur. Ancak bu yeni pulmoner teknoloji yüksek doz ve sık uygulama gerektirmektedir. İlave olarak sigara kullanımında, pulmoner hastalık ve enfeksiyon varlığında kullanılamamaktadır. Bugün, insülinin non-invaziv yollardan kullanımıyla ilgili istenilen klinik etkinlik ve güvenilirlik elde edilememiştir; bu nedenle çalışmalar yeni geliştirilen teknolojiler ile devam etmektedir.

Yeni teknolojilerle insülin uygulama yolları

Studies for different ways of insulin delivery have started since the first discovery of insulin. However, desired biological effect of non-parenteral routes has not been achieved, yet. Unfortunately the use of insulin has been limited to parenteral routes due to enzymatic degradation process by mucosal peptidase, mucosal barrier resulting in insufficient absorption and poor permeability throughout the intestinal mucosa. The parenteral route of insulin has been used in different ways including intramuscular, subcutaneous, intravenous and intraperitoneal ways. However, the parenteral route has side effects involving patient's incompliance due to fear of injection, local discomfort including bleeding at injection site, injection pain, lipohypertrophy as well as some disadvantages such as glycemic fluctuation. Alternative routes of non-invasive insulin delivery including oral, nasal, buccal, ophtalmic, rectal, vaginal and transdermal systems have been performed eventhough successful results have not been achived due to the abovementioned barriers. Additionally, recently approved tecnology of insulin delivery through pulmoner route has also been one of the methods aimed at replacing parenteral route. However, recent pulmonary technology of insulin delivery requires higher doses and frequent applications. Furthermore, inhaler insulin is not applicable to smokers and is not used in patients with pulmonary diseases or infections. Today, desired clinical efficacy and safety on the use of non-invasive routes of insulin have not yet been achieved and studies are continuing with newly developed technologies.

PDF

___

Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus: preliminary report. Can Med Assoc J 1962;17;87(20):1062-7.
Frederick Grant Banting (1891-1941), codiscoverer of insulin. Jama 1966;7;198(6):660-1.
Moore EW, Mitchell ML, Chalmers TC. Variability in absorption of insulin-I 131 in normal and diabetic subjects after subcutaneous and intramuscular injection. J Clin Invest 1959;38(7):1222-7.
Pearson TL. Practical aspects of insulin pen devices. J Diabetes Sci Technol 2010;1;4(3):522-31.
Brunton S. Insulin delivery systems: reducing barriers to insulin therapy and advancing diabetes mellitus treatment. Am J Med 2008;121(6):S35-41.
Pisano M. Overview of insulin and non-insulin delivery devices in the treatment of diabetes. P T. 2014;39(12):866-76.
Scheiner G, Sobel RJ, Smith DE, Pick AJ, Kruger D, King J. Insulin pump therapy: guidelines for successful outcomes. Diabetes Educ 2009;35(2):42-3.
Valeritas. V-Go. https://www.go-vgo.com access date 2013.
Zisser HC. The omnipod insulin management system: the latest innovation in insulin pump therapy. Diabetes Ther 2010;1(1):10-24.
A Review of the Omnipod Insulin Pump. http://www.livestrong.com/article/161601-a-review-of- the-omnipod-insulin-pump/ access date 12.03.2014.
Saudek CD. Implantable insulin infusion pumps: a case presentation. Diabetes Educ 1989;15(1):44-9.
Udelsman R, Chen H, Loman K, Pitt HA, Saudek CD. Implanted programmable insulin pumps: one hundred fifty-three patient years of surgical experience. Surgery 1997;122(6):1005-11.
Van Dijk PR, Logtenberg SJ, Gans RO, Bilo HJ,Kleefstra N. Intraperitoneal insulin infusion: treatment option for type 1 diabetes resulting in beneficial endocrine effects beyond glycaemia. Clin Endocrinol (Oxf) 2014;81(4):488- 97.
Von Heubner W, de Jongh, S. E. & Laquer, E. Uber inhalation von insulin. Klin. Wochenschrift 1924;51:2342-3.
Wigley FW, Londono JH, Wood SH, Shipp JC, Waldman RH. Insulin across respiratory mucosae by aerosol delivery. Diabetes 1971;20(8)552-6.
FDA Approves First Ever Inhaled Insulin Combination Product for Treatment of Diabetes. http://www.fda.gov/NewsEvents/Newsroom/PressAnno uncements/2006/ucm108585.htm access date 27.01.2006.
Heinemann L. The failure of exubera: are we beating a dead horse? J Diabetes Sci Technol 2008;2(3):518-29.
Keegan A. Exit Exubera. Inhalable insulin is withdrawn due to weak sales. Diabetes Forecast 2007;60(13):19.
Patton JS, Bukar J, Nagarajan S. Inhaled insulin. Adv Drug Deliv Rev 1999;1;35(2-3):235-47.
NCT00734591. Follow-Up Study for Exubera (FUSE). Clinical Trials. gov. A service of the U.S. National Institutes of Health. September, 2012.
Steiner S, Pfutzner A, Wilson BR, Harzer O, Heinemann L, Rave K. Technosphere/Insulin--proof of concept study with a new insulin formulation for pulmonary delivery. Exp Clin Endocrinol Diabetes 2002;110(1):17-21.
Rosenstock J, Bergenstal R, Defronzo RA, Hirsch IB, Klonoff D, Boss AH. Efficacy and safety of Technosphere inhaled insulin compared with Technosphere powder placebo in insulin-naive type 2 diabetes suboptimally controlled with oral agents. Diabetes Care 2008;31(11):2177-82.
Cassidy JP, Amin N, Marino M, Gotfried M, Meyer T, Sommerer K. Insulin lung deposition and clearance following Technosphere(R) insulin inhalation powder administration. Pharm Res 2011;28(9):2157-64.
Rave K, Heise T, Heinemann L, Boss AH. Inhaled technosphere insulin in comparison to subcutaneous regular human insulin: time action profile and variability in subjects with type 2 diabetes. J Diabetes Sci Technol 2008;2(2):205-12.
Rave K, Heise T, Pfutzner A, Boss AH. Coverage of postprandial blood glucose excursions with inhaled technosphere insulin in comparison to subcutaneously injected regular human insulin in subjects with type 2 diabetes. Diabetes care 2007;30(9):2307-8.
Follow-up Study for Exubera (FUSE). https://clinicaltrials.gov/ct2/show/results/NCT00734591 access date (erişim tarihi) 24.09.2012. ed.^eds.), p.^pp.
Choonara BF, Choonara YE, Kumar P, Bijukumar D, du Toit LC, Pillay V. A review of advanced oral drug delivery technologies facilitating the protection and absorption of protein and peptide molecules. Biotechnol Adv 2014;15;32(7):1269-82.
Wajcberg E, Miyazaki Y, Triplitt C, Cersosimo E, DeFronzo RA. Dose-response effect of a single administration of oral hexyl-insulin monoconjugate 2 in healthy nondiabetic subjects. Diabetes Care 2004;27(12):2868-73.
Kipnes M, Dandona P, Tripathy D, Still JG, Kosutic G. Control of postprandial plasma glucose by an oral insulin product (HIM2) in patients with type 2 diabetes. Diabetes Care 2003;26(2):421-6.
Luzio SD, Dunseath G, Lockett A, Broke-Smith TP, New RR, Owens DR. The glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes. Diabetes Obes Metab 2010;12(1): 82-7.
Geho WB, Geho HC, Lau JR, Gana TJ. Hepatic-directed vesicle insulin: a review of formulation development and preclinical evaluation. J Diabetes Sci Technol 2009;1;3(6):1451-9.
Pozzilli P, Raskin P, Parkin CG. Review of clinical trials: update on oral insulin spray formulation. Diabetes Obes Metab 2010;12(2):91-6.
Xu HB, Huang KX, Zhu YS, Gao QH, Wu QZ, Tian WQ. Hypoglycaemic effect of a novel insulin buccal formulation on rabbits. Pharmacol Res 2002;46(5):459- 67.
Sen A, Zhao YL, Hui SW. Saturated anionic phospholipids enhance transdermal transport by electroporation. Biophys J 2002;83(4):2064-73.
Prausnitz MR, Bose VG, Langer R, Weaver JC. Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery. Proc Natl Acad Sci U S A 1993;15;90(22):10504-8.
Liedtke RK, Sorger M, Merk F, Vetter H. [Transdermal administration of insulin in type II diabetics. Results of a clinical pilot study]. Arzneimittelforschung 1990;40(8):884-6.