Nanotechnology in Insulin Delivery for Management of Diabetes

Author(s): Fatemah Bahman, Khaled Greish*, Sebastien Taurin*.

Journal Name: Pharmaceutical Nanotechnology

Volume 7 , Issue 2 , 2019

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Graphical Abstract:


Diabetes is a group of diseases characterized by hyperglycemia and originating from the deficiency or resistance to insulin, or both. Ultimately, the most effective treatment for patients with diabetes involves subcutaneous injections of insulin. However, this route of administration is often painful and inconvenient, as most patients will have to selfadminister it at least twice a day for the rest of their lives. Also, infection, insulin precipitation, and either lipoatrophy or lipohypertrophy are frequently observed at the site of injection. To date, several alternative routes of insulin administration have been explored, including nasal, pulmonary and oral. Although the delivery of insulin is an ideal route for diabetic patients, several limitations have to be overcome such as the rapid degradation of insulin in gastric fluid and low oral bioavailability. Numerous strategies have been carried out to improve these limited parameters such as the use of enzyme inhibitors, absorption enhancers, mucoadhesive polymers and chemical modification for receptor-mediated absorption. Also, insulin-loaded nanocarriers bypass several physiological barriers. This current review focuses on the various barriers existing in the delivery of insulin through the oral route and the strategies undertaken so far to overcome those obstacles using nanocarriers as a potential vehicle of insulin.

Keywords: Diabetes mellitus, insulin analog, insulin, nanoparticles, nasal delivery, oral delivery, pulmonary delivery.

American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014; 37(Suppl. 1): 81-90.
Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet 2001; 358(9283): 739-46.
Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet 2014; 383(9911): 69-82.
Nair M. Diabetes mellitus, part 1: physiology and complications. Br J Nurs 2007; 16(3): 184-8.
Kumar D, Mukherjee K. Economic impact of type-2 diabetes mellitus on households in Hisar district of Haryana state, India. Health Agenda 2014; 2(4): 125-9.
Barrett T. Type 2 diabetes mellitus: incidence, management and prognosis. Paediatr Child Health 2013; 23(4): 163-7.
Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018; 138: 271-81.
Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 2017; 128: 40-50.
Kaiser AB, Zhang N, Der Pluijm WV. Global prevalence of type 2 diabetes over the next ten years (2018-2028). Diabetes 2018; 67(Supplement . 1): 202. LB.
Katsarou A, Gudbjornsdottir S, Rawshani A, et al. Type 1 diabetes mellitus. Nat Rev Dis Primers 2017; 3: 17016.
International diabetes federation IDF Diabetes Atlas. 7th ed. Brussels: Inter-national Diabetes Federation 2015.
Werfalli M, Musekiwa A, Engel ME, Ross I, Kengne AP, Levitt NS. The prevalence of type 2 diabetes mellitus among older people in Africa: a systematic review study protocol. BMJ Open 2014; 4(6): 004747.
World Health Organization. Global report on diabetes.World Health Organization: Geneva 2018.
Zhang P, Gregg E. Global economic burden of diabetes and its implications. Lancet Diabetes Endocrinol 2017; 5(6): 404-5.
Bommer C, Sagalova V, Heesemann E, et al. Global economic burden of diabetes in adults: projections from 2015 to 2030. Diabetes Care 2018; 41(5): 963-70.
Rosenfeld L. Insulin: discovery and controversy. Clin Chem 2002; 48(12): 2270-88.
Al Rubeaan K, Rafiullah M, Jayavanth S. Oral insulin delivery systems using chitosan-based formulation: a review. Expert Opin Drug Deliv 2016; 13(2): 223-37.
Weiss M, Steiner DF, Philipson LH. Insulin biosynthesis, secretion, structure, and structure activity relationships. South Dartmouth: MDTextcom, Inc 2014.
Fu Z, Gilbert ER, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev 2013; 9(1): 25-53.
Sener A, Malaisse WJ. L-leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase. Nature 1980; 288(5787): 187-9.
McClements DJ. Encapsulation, protection, and delivery of bioactive proteins and peptides using nanoparticle and microparticle systems: a review. Adv Colloid Interface Sci 2018; 253: 1-22.
Tang-Christensen M, Larsen PJ, Thulesen J, Nielsen JR, Vrang N. Glucagon-like peptide 2, a neurotransmitter with a newly discovered role in the regulation of food ingestion. Ugeskr Laeger 2001; 163(3): 287-91.
Chance RE, Frank BH. Research, development, production, and safety of biosynthetic human insulin. Diabetes Care 1993; 16(Supplement. 3): 133-42.
Sanchez-Garcia L, Martín L, Mangues R, Ferrer-Miralles N, Vázquez E, Villaverde A. Recombinant pharmaceuticals from microbial cells: a 2015 update. Microb Cell Fact 2016; 15(1): 33.
Holleman F, Hoekstra JB. Insulin lispro. N Engl J Med 1997; 337(3): 176-83.
Raskin P, Guthrie RA, Leiter L, Riis A, Jovanovic L. Use of insulin aspart, a fast-acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. Diabetes Care 2000; 23(5): 583-8.
Becker RH, Frick AD. Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet 2008; 47(1): 7-20.
Ahmad K. Insulin sources and types: a review of insulin in terms of its mode on diabetes mellitus. J Tradit Chin Med 2014; 34(2): 234-7.
Li J, Kuang Y. Pharmacokinetical models of subcutaneous injection of insulin analogues for type 1 diabetes. Discrete Continuous Dyn Syst Ser B 2008; 12(2): 401-14.
Deckert T. Intermediate-acting insulin preparations: NPH and lente. Diabetes Care 1980; 3(5): 623-6.
Havelund S, Ribel U, Plum A, et al. The mechanism of protraction of insulin detemir, a long-acting, acylated analogue of human insulin. Diabetes 2004; 53: 109.
Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414(6865): 799.
Varewijck AJ, Janssen JA. Insulin and its analogues and their affinities for the IGF1 receptor. Endocr Relat Cancer 2012; 19(5): 63-75.
Shah RB, Patel M, Maahs DM, Shah VN. Insulin delivery methods: past, present and future. Int J Pharm Investig 2016; 6(1): 1-9.
Al-Tabakha MM, Arida AI. Recent challenges in insulin delivery systems: a review. Indian J Pharm Sci 2008; 70(3): 278-86.
Alai MS, Lin WJ, Pingale SS. Application of polymeric nanoparticles and micelles in insulin oral delivery. J Food Drug Anal 2015; 23(3): 351-8.
Kalra S, Gupta Y. Clinical applications of intramuscular insulin. Int J Endocrinol Metab Disord 2014; 4(3): 40-3.
Vaag A, Pedersen KD, Lauritzen M, Hildebrandt P, Beck-Nielsen H. Intramuscular versus subcutaneous injection of unmodified insulin: consequences for blood glucose control in patients with type 1 diabetes mellitus. Diabet Med 1990; 7(4): 335-42.
Kim H, Park H, Lee SJ. Effective method for drug injection into subcutaneous tissue. Sci Rep 2017; 7(1): 9613.
McAdams BH, Rizvi AA. An overview of insulin pumps and glucose sensors for the generalist. J Clin Med Res 2016; 5(1): 5.
Heinemann L, Fleming GA, Petrie JR, Holl RW, Bergenstal RM, Peters AL. Insulin pump risks and benefits: a clinical appraisal of pump safety standards, adverse event reporting and research needs. A joint statement of the European Association for the Study of Diabetes and the American Diabetes Association Diabetes Technology Working Group. Diabetologia 2015; 58(5): 862-70.
Hinchcliffe M, Illum L. Intranasal insulin delivery and therapy. Adv Drug Deliv Rev 1999; 35(2-3): 199-234.
Costantino HR, Illum L, Brandt G, Johnson PH, Quay SC. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm 2007; 337(1-2): 1-24.
Maitani Y, Takayama K, Nagai T. The effect of soybean-derived sterol and its glucoside as an enhancer of nasal absorption of insulin in rabbits in vitro and in vivo. Int J Pharm 1995; 117(2): 129-37.
Muramatsu K, Maitani Y, Takayama K, Nagai T. The relationship between the rigidity of the liposomal membrane and the absorption of insulin after nasal administration of liposomes modified with an enhancer containing insulin in rabbits. Drug Dev Ind Pharm 1999; 25(10): 1099-105.
Wan F, Møller EH, Yang M, Jørgensen L. Formulation technologies to overcome unfavorable properties of peptides and proteins for pulmonary delivery. Drug Discov Today Technol 2012; 9(2): 141-6.
Mohanty RR, Das S. Inhaled insulin-current direction of insulin research. J Clin Diagn Res 2017; 11(4): OE01.
Liu FY, Shao Z, Kildsig DO, Mitra AK. Pulmonary delivery of free and liposomal insulin. Pharm Res 1993; 10(2): 228-32.
Malathi S, Nandhakumar P, Pandiyan V, Webster TJ, Balasubramanian S. Novel PLGA-based nanoparticles for the oral delivery of insulin. Int J Nanomedicine 2015; 10: 2207-18.
Patton JS, Bukar JG, Eldon MA. Clinical pharmacokinetics and pharmacodynamics of inhaled insulin. Clin Pharmacokinet 2004; 43(12): 781-801.
Alabraba V, Farnsworth A, Leigh R, Dodson P, Gough SC, Smyth T. Exubera inhaled insulin in patients with type 1 and type 2 diabetes: the first 12 months. Diabetes Technol Ther 2009; 11(7): 427-30.
Kwok PCL, Chan H-K. Pulmonary delivery of peptides and proteins. In: Der-Walle CV, Ed Peptide and Protein Delivery. Amsterdam: Elsevier 2011; pp. 23-46.
Richardson PC, Boss AH. Technosphere® insulin technology. Diabetes Technol Ther 2007; 9(S1): 65-72.
Neumiller JJ, Campbell RK, Wood LD. A review of inhaled technosphere insulin. Ann Pharmacother 2010; 44(7-8): 1231-9.
Klonoff DavidC. Afrezza inhaled insulin. J Diabetes Sci Technol 2014; Nov 8(6): 1071-3.
Peppas NA, Kavimandan NJ. Nanoscale analysis of protein and peptide absorption: insulin absorption using complexation and pH-sensitive hydrogels as delivery vehicles. Eur J Pharm Sci 2006; 29(3-4): 183-97.
Ansari M. Oral delivery of insulin for treatment of diabetes: classical challenges and current opportunities. J Med Sci 2015; 15(5): 209-20.
Chellappan DK, Yenese Y, Wei CC, Chellian J, Gupta G. Oral insulin: current status, challenges, and future perspectives. J Environ Pathol Toxicol Oncol 2017; 36(4): 283-91.
Ahmad N, Mohd Amin MCI, Ismail I, Buang F. Enhancement of oral insulin bioavailability: in vitro and in vivo assessment of nanoporous stimuli-responsive hydrogel microparticles. Expert Opin Drug Deliv 2016; 13(5): 621-32.
Muheem A, Shakeel F, Jahangir MA, et al. A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives. Saudi Pharm J 2016; 24(4): 413-28.
Zhao X, Shan C, Zu Y, et al. Preparation, characterization, and evaluation in vivo of Ins-SiO2-HP55 (insulin-loaded silica coating HP55) for oral delivery of insulin. Int J Pharm 2013; 454(1): 278-84.
Najafzadeh H, Kooshapur H, Kianidehkordi F. Evaluation of an oral insulin formulation in normal and diabetic rats. Indian J Pharmacol 2012; 44(1): 103.
Wong CY, Martinez J, Dass CR. Oral delivery of insulin for treatment of diabetes: status quo, challenges and opportunities. J Pharm Pharmacol 2016; 68(9): 1093-108.
Yamamoto T. Effects of various protease inhibitors on the intestinal absorption and degradation of insulin in rats. Int J Pharm 1995; 117: 129-37.
Tozaki H. EMI Y, Horisaka E, Fujita T, Yamamoto A, Muranishi S. Degradation of insulin and calcitonin and their protection by various protease inhibitors in rat caecal contents: implications in peptide delivery to the colon. J Pharm Pharmacol 1997; 49(2): 164-8.
Werle M, Loretz B, Entstrasser D, Föger F. Design and evaluation of a chitosan-aprotinin conjugate for the peroral delivery of therapeutic peptides and proteins susceptible to enzymatic degradation. J Drug Target 2007; 15(5): 327-33.
Agarwal V, Khan MA. Current status of the oral delivery of insulin. Pharm Technol 2001; 10: 76-90.
Park K, Kwon IC, Park K. Oral protein delivery: current status and future prospect. React Funct Polym 2011; 71(3): 280-7.
Egelund R, Rodenburg KW, Andreasen PA, Rasmussen MS, Guldberg RE, Petersen TE. An ester bond linking a fragment of a serine proteinase to its serpin inhibitor. Biochemistry 1998; 37(18): 6375-9.
Nellans HN. (B) Mechanisms of peptide and protein absorption: (1) paracellular intestinal transport: modulation of absorption. Adv Drug Deliv Rev 1991; 7(3): 339-64.
Fonte P, Araujo F, Silva C, et al. Polymer-based nanoparticles for oral insulin delivery: revisited approaches. Biotechnol Adv 2015; 33(6 Pt 3): 1342-54.
Ahmad A, Othman I, Zaini A, Chowdhury E. Oral nano-insulin therapy: current progress on nanoparticle-based devices for intestinal epithelium-targeted insulin delivery. J Nanomedic Nanotechnol S 2014; 4: 1-10.
Kaklotar D, Agrawal P, Abdulla A, et al. Transition from passive to active targeting of oral insulin nanomedicines: enhancement in bioavailability and glycemic control in diabetes. Nanomedicine 2016; 11(11): 1465-86.
Mukhopadhyay P, Mishra R, Rana D, Kundu PP. Strategies for effective oral insulin delivery with modified chitosan nanoparticles: a review. Prog Polym Sci 2012; 37(11): 1457-75.
Zhao L, Su C, Zhu B, Jia Y. Development and optimization of insulin-chitosan nanoparticles. Trop J Pharm Res 2014; 13(1): 3-8.
Song L, Zhi Z-l, Pickup JC. Nanolayer encapsulation of insulin-chitosan complexes improves efficiency of oral insulin delivery. Int J Nanomedicine 2014; 9: 2127.
Pan Y, Li Y-J, Zhao H-Y, et al. Bioadhesive polysaccharide in protein delivery system: chitosan nanoparticles improve the intestinal absorption of insulin in vivo. Int J Pharm 2002; 249(1-2): 139-47.
Lin Y-H, Chen C-T, Liang H-F, et al. Novel nanoparticles for oral insulin delivery via the paracellular pathway. Nanotechnology 2007; 18(10): 105102.
Cui F, Qian F, Zhao Z, Yin L, Tang C, Yin C. Preparation, characterization, and oral delivery of insulin loaded carboxylated chitosan grafted poly (methyl methacrylate) nanoparticles. Biomacromolecules 2009; 10(5): 1253-8.
Elsayed A, Al Remawi M, Qinna N, Farouk A, Badwan A. Formulation and characterization of an oily-based system for oral delivery of insulin. Eur J Pharm Biopharm 2009; 73(2): 269-79.
Sarmento B, Martins S, Ribeiro A, Veiga F, Neufeld R, Ferreira D. Development and comparison of different nanoparticulate polyelectrolyte complexes as insulin carriers. Int J Pept Res Ther 2006; 12(2): 131-8.
Sarmento B, Martins S, Ferreira D, Souto EB. Oral insulin delivery by means of solid lipid nanoparticles. Int J Nanomedicine 2007; 2(4): 743-9.
Zhang N, Li J, Jiang W, Ren C, et al. Effective protection and controlled release of insulin by cationic β-cyclodextrin polymers from alginate/chitosan nanoparticles. Int J Pharm 2010; 393(1-2): 213-9.
Ma Z, Lim TM, Lim L. Pharmacological activity of peroral chitosan-insulin nanoparticles in diabetic rats. Int J Pharm 2005; 293(1-2): 271-80.
Li X, Qi J, Xie Y, et al. Nanoemulsions coated with alginate/chitosan as oral insulin delivery systems: preparation, characterization, and hypoglycemic effect in rats. Int J Nanomedicine 2013; 8: 23.
Sharma G, Sharma AR, Nam JS, Doss GP, Lee SS, Chakraborty C. Nanoparticle based insulin delivery system: the next generation efficient therapy for type 1 diabetes. J Nanobiotechnol 2015; 13: 74.
Chalasani KB, Russell-Jones G, Yandrapu SK, Diwan PV, Jain SK. A novel vitamin B12-nanosphere conjugate carrier system for peroral delivery of insulin. J Control Release 2007; 117(3): 421-9.
Reis CP, Veiga FJ, Ribeiro AJ, Neufeld RJ, Damgé C. Nanoparticulate biopolymers deliver insulin orally eliciting pharmacological response. J Pharm Sci 2008; 97(12): 5290-305.
Woitiski CB, Neufeld RJ, Veiga F, Carvalho RA, Figueiredo IV. Pharmacological effect of orally delivered insulin facilitated by multilayered stable nanoparticles. Eur J Pharm Sci 2010; 41(3-4): 556-63.
Yang J, Sun H, Song C. Preparation, characterization and in vivo evaluation of pH‐sensitive oral insulin‐loaded poly (lactic‐co‐glycolicacid) nanoparticles. Diabetes Obes Metab 2012; 14(4): 358-64.
Wu J-Z, Williams GR, Li H-Y, Wang D-X, Li S-D, Zhu L-M. Insulin-loaded PLGA microspheres for glucose-responsive release. Drug Deliv 2017; 24(1): 1513-25.
Peng Q, Sun X, Gong T, et al. Injectable and biodegradable thermosensitive hydrogels loaded with PHBHHx nanoparticles for the sustained and controlled release of insulin. Acta Biomater 2013; 9(2): 5063-9.
Hosseininasab S, Pashaei-Asl R, Khandaghi AA, et al. Synthesis, characterization, and in vitro studies of PLGA-PEG nanoparticles for oral insulin delivery. Chem Biol Drug Des 2014; 84(3): 307-15.
Cui F, Shi K, Zhang L, Tao A, Kawashima Y. Biodegradable nanoparticles loaded with insulin-phospholipid complex for oral delivery: preparation, in vitro characterization and in vivo evaluation. J Control Release 2006; 114(2): 242-50.
Tao A-j, Zhang L-q, Shi K, Cun D-m. Cui F-d. Preparation and characterization of insulin loaded PLGAHP55 nanoparticles. J Pharm Sci Pharmacol 2007; 1: 001.
Wang X-Q, Zhang Q. pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs. Eur J Pharm Biopharm 2012; 82(2): 219-29.
Wu ZM, Zhou L, Guo XD, et al. HP55-coated capsule containing PLGA/RS nanoparticles for oral delivery of insulin. Int J Pharm 2012; 425(1-2): 1-8.
Sun S, Liang N, Piao H, Yamamoto H, Kawashima Y, Cui F. Insulin-SO (sodium oleate) complex-loaded PLGA nanoparticles: formulation, characterization and in vivo evaluation. J Microencapsul 2010; 27(6): 471-8.
Jain S, Rathi VV, Jain AK, Das M, Godugu C. Folate-decorated PLGA nanoparticles as a rationally designed vehicle for the oral delivery of insulin. Nanomedicine 2012; 7(9): 1311-37.
Bock N, Dargaville TR, Woodruff MA. Electrospraying of polymers with therapeutic molecules: state of the art. Prog Polym Sci 2012; 37(11): 1510-51.
Damgé C, Maincent P, Ubrich N. Oral delivery of insulin associated to polymeric nanoparticles in diabetic rats. J Control Release 2007; 117(2): 163-70.
Damgé C, Vranckx H, Balschmidt P, Couvreur P. Poly (alkyl cyanoacrylate) nanospheres for oral administration of insulin. J Pharm Sci 1997; 86(12): 1403-9.
Hou Z, Zhang Z, Xu Z, Zhang H, Tong Z, Leng Y. The stability of insulin-loaded polybutylcyanoacrylate nanoparticles in an oily medium and the hypoglycemic effect in diabetic rats. Yao xue xue bao=. Acta pharmaceutica Sinica 2005; 40(1): 57-64.
Graf A, Rades T, Hook SM. Oral insulin delivery using nanoparticles based on microemulsions with different structure-types: optimisation and in vivo evaluation. Eur J Pharm Sci 2009; 37(1): 53-61.
Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery-a review of the state of the art. Eur J Pharm Biopharm 2000; 50(1): 161-77.
Mehnert W, Mäder K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev 2012; 64: 83-101.
Zhang N, Ping Q, Huang G, Xu W, Cheng Y, Han X. Lectin-modified solid lipid nanoparticles as carriers for oral administration of insulin. Int J Pharm 2006; 327(1-2): 153-9.
Fonte P, Nogueira T, Gehm C, Ferreira D, Sarmento B. Chitosan-coated solid lipid nanoparticles enhance the oral absorption of insulin. Drug Deliv Transl Res 2011; 1(4): 299-308.
Yang R, Gao R, Li F, He H, Tang X. The influence of lipid characteristics on the formation, in vitro release, and in vivo absorption of protein-loaded SLN prepared by the double emulsion process. Drug Dev Ind Pharm 2011; 37(2): 139-48.
Xu Y, Zheng Y, Wu L, Zhu X, Zhang Z, Huang Y. Novel solid lipid nanoparticle with endosomal escape function for oral delivery of insulin. ACS Appl Mater Interfaces 2018; 10(11): 9315-24.
Jin Y, Song Y, Zhu X, et al. Goblet cell-targeting nanoparticles for oral insulin delivery and the influence of mucus on insulin transport. Biomaterials 2012; 33(5): 1573-82.
Pridgen EM, Alexis F, Kuo TT, et al. Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery. Sci Transl Med 2013; 5(213): 167.
Hirlekar RS. Oral insulin delivery: novel strategies. Asian J Pharm 2017; 11(Supplementary 03): S434-43.
Arbit E, Kidron M. Oral insulin delivery in a physiologic J Diabetes Sci Technol 2017; 11(4): 825-32.
Easa N, Alany RG, Carew M, Vangala A. A review of non-invasive insulin delivery systems for diabetes therapy in clinical trials over the past decade. Drug Discov Today 2019; 24(2): 440-51.
Heinemann L, Jacques Y. Oral insulin and buccal insulin: a critical reappraisal. J Diabetes Sci Technol 2009; 3(3): 568-84.
Chen J, Liu R, Liu C, et al. Progress of oral insulin and related drug delivery systems and their pharmacokinetics. Curr Drug Metab 2018; 19(10): 863-70.
Li J, Wang Y, Han L, Sun X, Yu H, Yu Y. Time-action profile of an oral enteric insulin formulation in healthy chinese volunteers. Clin Ther 2012; 34(12): 2333-8.
Čilek A, Čelebi N, Tirnaksiz F. Lecithin-based microemulsion of a peptide for oral administration: preparation, characterization, and physical stability of the formulation. Drug Deliv 2006; 13(1): 19-24.
Elsayed A, Al-Remawi M, Farouk A, Badwan A. Insulin-chitosan polyelectrolyte-anocomplexes: preparation, characterization and stabilization of insulin. Sudan J Med Sci 2010; 5(2): 99-109.
Badwan A, Remawi M, Qinna N, et al. Enhancement of oral bioavailability of insulin in humans. Neuro Endocrinol Lett 2009; 30(1): 74-8.
Walsh EG, Adamczyk BE, Chalasani KB, et al. Oral delivery of macromolecules: rationale underpinning gastrointestinal permeation enhancement technology (GIPET®). Therap Deliv 2011; 2(12): 1595-610.
Zijlstra E, Heinemann L, Plum-Morschel L. Oral insulin reloaded: a structured approach. J Diabetes Sci Technol 2014; 8(3): 458-65.
Yu J, Qian C, Zhang Y, et al. Hypoxia and H2O2 dual-sensitive vesicles for enhanced glucose-responsive insulin delivery. Nano Lett 2017; 17(2): 733-9.
Wang C, Ye Y, Sun W, et al. Red blood cells for glucose‐responsive insulin delivery. Adv Mater 2017; 29(18): 1606617.

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Year: 2019
Page: [113 - 128]
Pages: 16
DOI: 10.2174/2211738507666190321110721

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