Novel noninvasive techniques in management of diabetes

Nadaf Sameer


Since the discovery, insulin remains as effective means of curing the diabetes. During the last decades, diabetes has become
a life‑threatening disease, because of this people initially goes for insulin injections but the inconvenience leads to the
development of noninvasive techniques, which has recently replaced the insulin injection. These techniques overcome the
barrier for the insulin treatment and ultimately control the glucose level of patient effectively than invasive technique. In
these review, an attempt has been made to cover overall techniques available for diabetes treatment noninvasively. In an
attempt of this, data has been collected, which includes insulin delivery via oral, nasal, pulmonary, rectal, buccal and ocular
route. Along with these devices available in the market and under trials for diabetes treatment has also been covered. As this disease requires continuous treatment, it is advisable to go with noninvasive means of insulin delivery.
Key words: Diabetes, insulin, iontophoresis, sonophoresis, pulmonary

Full Text:



Alberti KG, Zimmet PZ. Definition, diagnosis and classification

of diabetes mellitus and its complications. Part 1: Diagnosis and

classification of diabetes mellitus provisional report of a WHO

consultation. Diabet Med 1998;15:539‑53.

Yadav N, Morris G, Harding SE, Ang S, Adams GG. Insulin delivery

through nasal route using thiolated microspheres. Endocr Metab

Immune Disord Drug Targets 2009;9:1‑13.

Giugliano D, Ceriello A, Esposito K. Glucose metabolism and

hyperglycemia. Am J Clin Nutr 2008;87:217S‑22.

Pickup JC, Keen H, Parsons JA, Alberti KG. Continuous subcutaneous

insulin infusion: An approach to achieving normoglycaemia. Br Med J


Gwinup G, Elias AN, Vaziri ND. A case for oral insulin therapy in the

prevention of diabetic micro‑ And macroangiopathy. Int J Artif Organs


Owens DR. New horizons – Alternative routes for insulin therapy. Nat

Rev Drug Discov 2002;1:529‑40.

Cefalu WT. Concept, strategies, and feasibility of noninvasive insulin

delivery. Diabetes Care 2004;27:239‑46.

Goldberg M, Gomez‑Orellana I. Challenges for the oral delivery of

macromolecules. Nat Rev Drug Discov 2003;2:289‑95.

Khan Ghilzai NM. New developments in insulin delivery. Drug Dev Ind

Pharm 2003;29:253‑65.

Khafagy el‑S, Morishita M, Onuki Y, Takayama K. Current challenges in

non‑invasive insulin delivery systems: A comparative review. Adv Drug

Deliv Rev 2007;59:1521‑46.

Guyton AC. Digestion and absorption in the gastrointestinal tract;

gastrointestinal disorders. In: Sunder WB, editor. Human Physiology and

Mechanisms of Disease. 5th ed. Philadelphia: Elsevier Health Sciences;

p. 500‑9.

Pauletti G, Gangwar S, Knipp GT, Nerurkar MM, Okuma FW, Tamura K.

Structural requirements for intestinal absorption of peptide drug.

J Control Release 1996;41:3‑17.

Mahato RI, Narang AS, Thoma L, Miller DD. Emerging trends in oral

delivery of peptide and protein drugs. Crit Rev Ther Drug Carrier Syst


Morishita M, Morishita I, Takayama K, Machida Y, Nagai T.

Site‑dependent effect of aprotinin, sodium caprate, Na2EDTA and

sodium glycocholate on intestinal absorption of insulin. Biol Pharm

Bull 1993;16:68‑72.

Wadher K, Kalsait R, Umekar M. Oral insulin delivery: Facts,

developments and challenges. Pharm Lett 2009;1:121‑9.

Lane ME, O’driscoll CM, Corrigan OI. Quantitative estimation of

the effects of bile salt surfactant systems on insulin stability and

permeability in the rat intestine using a mass balance model. J Pharm

Pharmacol 2005;57:169‑75.

Fasano A, Uzzau S. Modulation of intestinal tight junctions by zonula

occludens toxin permits enteral administration of insulin and other

macromolecules in an animal model. J Clin Invest 1997;99:1158‑64.

Hosny EA, Al‑Shora HI, Elmazar MM. Oral delivery of insulin from

enteric‑coated capsules containing sodium salicylate: Effect on relative

hypoglycemia of diabetic beagle dogs. Int J Pharm 2002;237:71‑6.

Morishita M, Aoki Y, Sakagami M, Nagai T, Takayama K. In situ ileal

absorption of insulin in rats: Effects of hyaluronidase pretreatment

diminishing the mucous/glycocalyx layers. Pharm Res 2004;21:309‑16.

Morishita M, Kajita M, Suzuki A, Takayama K, Chiba Y, Tokiwa S, et al. The

dose‑related hypoglycemic effects of insulin emulsions incorporating

highly purified EPA and DHA. Int J Pharm 2000;201:175‑85.

Nishihata T, Rytting JH, Kamada A, Higuchi T. Enhanced

intestinal absorption of insulin in rats in the presence of sodium

‑methoxysalicylate. Diabetes 1981;30:1065‑7.

Agarwal V, Nazzal S, Reddy IK, Khan MA. Transport studies of insulin

across rat jejunum in the presence of chicken and duck ovomucoids.

J Pharm Pharmacol 2001;53:1131‑8.

Agarwal V, Reddy IK, Khan MA. Oral delivery of proteins: Effect

of chicken and duck ovomucoid on the stability of insulin in the

presence of α‑chymotrypsin and trypsin. Pharm Pharmacol Commun


Agarwal V, Reddy IK, Khan MA. Polymethyacrylate based microparticulates

of insulin for oral delivery: Preparation and in vitro dissolution stability

in the presence of enzyme inhibitors. Int J Pharm 2001;225:31‑9.

Marschütz MK, Bernkop‑Schnürch A. Oral peptide drug delivery:

Polymer‑inhibitor conjugates protecting insulin from enzymatic

degradation in vitro. Biomaterials 2000;21:1499‑507.

Yamamoto A, Taniguchi T, Rikyuu K, Tsuji T, Fujita T, Murakami M, et al.

Effects of various protease inhibitors on the intestinal absorption and

degradation of insulin in rats. Pharm Res 1994;11:1496‑500.

Morishita M, Goto T, Peppas NA, Joseph JI, Torjman MC, Munsick C,

et al. Mucosal insulin delivery systems based on complexation polymer

hydrogels: Effect of particle size on insulin enteral absorption. J Control

Release 2004;97:115‑24.

Aoki Y, Morishita M, Asai K, Akikusa B, Hosoda S, Takayama K.

Region‑dependent role of the mucous/glycocalyx layers in insulin

permeation across rat small intestinal membrane. Pharm Res


Chowdary KP, Rao YS. Mucoadhesive microspheres for controlled drug

delivery. Biol Pharm Bull 2004;27:1717‑24.

Bernkop‑Schnürch A, Scerbe‑Saiko A. Synthesis and in vitro evaluation

of chitosan‑EDTA‑protease‑inhibitor conjugates which might be useful

in oral delivery of peptides and proteins. Pharm Res 1998;15:263‑9.

Dorkoosh FA, Stokkel MP, Blok D, Borchard G, Rafiee‑Tehrani M,

Verhoef JC, et al. Feasibility study on the retention of superporous

hydrogel composite polymer in the intestinal tract of man using

scintigraphy. J Control Release 2004;99:199‑206.

Bernkop‑Schnürch A, Kast CE, Richter MF. Improvement in the

mucoadhesive properties of alginate by the covalent attachment of

cysteine. J Control Release 2001;71:277‑85.

Bernkop‑Schnürch A. Thiomers: A new generation of mucoadhesive

polymers. Adv Drug Deliv Rev 2005 3;57:1569‑82.

Bernkop‑Schnürch A, Steininger S. Synthesis and characterisation of

mucoadhesive thiolated polymers. Int J Pharm 2000;194:239‑47.

Bernkop‑Schnürch A, Clausen AE, Hnatyszyn M. Thiolated polymers:

Synthesis and in vitro evaluation of polymer‑cysteamine conjugates. Int

J Pharm 2001;226:185‑94.

Bernkop‑Schnürch A, Scholler S, Biebel RG. Development of controlled

drug release systems based on thiolated polymers. J Control Release


Bernkop‑Schnürch A, Brandt UM, Clausen AE. Synthesis and

in vitro evaluation of chitosan – Cysteine conjugates. Sci Pharm


Bernkop‑Schnürch A, Hornof M, Zoidl T. Thiolated polymers – thiomers:

Synthesis and in vitro evaluation of chitosan‑2‑iminothiolane conjugates.

Int J Pharm 2003;260:229‑37.

Roldo M, Hornof M, Caliceti P, Bernkop‑Schnürch A. Mucoadhesive

thiolated chitosans as platforms for oral controlled drug delivery:

Synthesis and in vitro evaluation. Eur J Pharm Biopharm 2004;57:115‑21.

Bernkop‑Schnürch A, Hopf TE. Synthesis and in vitro evaluation of

chitosan – Thioglycolic acid conjugates. Sci Pharm 2001;69:109‑18.

Kast CE, Bernkop‑Schnürch A. Thiolated polymers – thiomers:

Development and in vitro evaluation of chitosan‑thioglycolic acid

conjugates. Biomaterials 2001;22:2345‑52.

Wagh MP, Joshi OU, Patel JS, Jain VR. Thiomers: A new generation of

mucoadhesive polymers. Res J Pharm Technol 2009;2:250‑5.

Nema T, Jain A, Jain A, Shilpi S, Gulbake A, Hurkat P, et al. Insulin

delivery through nasal route using thiolated microspheres. Endocr

Metab Immune Disord Drug Targets 2009;9:1‑13.

Takeuchi H, Yamamoto H, Niwa T, Hino T, Kawashima Y. Enteral

absorption of insulin in rats from mucoadhesive chitosan‑coated

liposomes. Pharm Res 1996;13:896‑901.

Bernkop‑Schnürch A, Krajicek ME. Mucoadhesive polymers as platforms

for peroral peptide delivery and absorption: Synthesis and evaluation of

different chitosan‑EDTA conjugates. J Control Release 1998;50:215‑23.

Lehr CM. Lectin‑mediated drug delivery: The second generation of

bioadhesives. J Control Release 2000;65:19‑29.

Lowman AM, Morishita M, Kajita M, Nagai T, Peppas NA. Oral delivery

of insulin using pH‑responsive complexation gels. J Pharm Sci


Nakamura K, Murray RJ, Joseph JI, Peppas NA, Morishita M, Lowman AM.

Oral insulin delivery using P (MAA‑g‑EG) hydrogels: Effects of network

morphology on insulin delivery characteristics. J Control Release


López JE, Peppas NA. Effect of poly (ethylene glycol) molecular weight

and microparticle size on oral insulin delivery from P (MAA‑g‑EG)

microparticles. Drug Dev Ind Pharm 2004;30:497‑504.

Onuki Y, Morishita M, Takayama K. Formulation optimization of

water‑in‑oil‑water multiple emulsion for intestinal insulin delivery.

J Control Release 2004;97:91‑9.

Yamagata T, Morishita M, Kavimandan NJ, Nakamura K, Fukuoka Y,

Takayama K, et al. Characterization of insulin protection properties

of complexation hydrogels in gastric and intestinal enzyme fluids.

J Control Release 2006;112:343‑9.

Morishita M, Goto T, Takayama K, Peppas NA. Oral insulin delivery

systems based on complexation polymer hydrogels. J Drug Deliv Sci

Technol 2006;16:19‑24.

Pan Y, Li YJ, Zhao HY, Zheng JM, Xu H, Wei G, et al. Bioadhesive

polysaccharide in protein delivery system: Chitosan nanoparticles

improve the intestinal absorption of insulin in vivo. Int J Pharm


Krauland AH, Guggi D, Bernkop‑Schnürch A. Oral insulin delivery: The

potential of thiolated chitosan‑insulin tablets on non‑diabetic rats.

J Control Release 2004;95:547‑55.

Lueben HL, de Leeuw BJ, Perard D, Lehr CM, de Boer AG, Verhoef JC, et al.

Mucoadhesive polymers in peroral peptide drug delivery: I, influence

of mucoadhesive excipients on the proteolytic activity of intestinal

enzymes. Eur J Pharm Sci 1996;4:117‑28.

He P, Tang Z, Lin L, Deng M, Pang X, Zhuang X, et al. Novel biodegradable

and pH‑sensitive poly (ester amide) microspheres for oral insulin

delivery. Macromol Biosci 2012;12:547‑56.

Brayden DJ, Jepson MA, Baird AW. Keynote review: Intestinal

Peyer’s patch M cells and oral vaccine targeting. Drug Discov Today


Desai MP, Labhasetwar V, Walter E, Levy RJ, Amidon GL. The mechanism

of uptake of biodegradable microparticles in Caco‑2 cells is size

dependent. Pharm Res 1997;14:1568‑73.

Pan Y, Zheng JM, Zhao HY, Li YJ, Xu H, Wei G. Relationship between drug

effects and particle size of insulin‑loaded bioadhesive microspheres.

Acta Pharmacol Sin 2002;23:1051‑6.

Deluca P, Jiang G, Woo B. (Poly (acryloyl‑hydroxyethyl starch)‑plga

composition microspheres. US20070122487 A1, 31 May 2007.

Wei W, Ma GH, Wang LY, Wu J, Su ZG. Hollow quaternized chitosan

microspheres increase the therapeutic effect of orally administered

insulin. Acta Biomater 2010;6:205‑9.

Zhang Y, Wei W, Lv P, Wang L, Ma G. Preparation and evaluation of

alginate‑chitosan microspheres for oral delivery of insulin. Eur J Pharm

Biopharm 2011;77:11‑9.

Marschütz MK, Caliceti P, Bernkop‑Schnürch A. Design and in vivo

evaluation of an oral delivery system for insulin. Pharm Res


Pai CM, Bae YH, Mack EJ, Wilson DE, Kim SW. Concanavalin A

microspheres for a self‑regulating insulin delivery system. J Pharm Sci


Ubaidulla U, Khar RK, Ahmed FJ, Panda AK. Development and in‑vivo

evaluation of insulin‑loaded chitosan phthalate microspheres for oral

delivery. J Pharm Pharmacol 2007;59:1345‑51.

Radwan MA. Enhancement of absorption of insulin‑loaded

polyisobutylcyanoacrylate nanospheres by sodium cholate after oral

and subcutaneous administration in diabetic rats. Drug Dev Ind Pharm


Kisel MA, Kulik LN, Tsybovsky IS, Vlasov AP, Vorob’yov MS, Kholodova EA,

et al. Liposomes with phosphatidylethanol as a carrier for oral delivery

of insulin: Studies in the rat. Int J Pharm 2001;216:105‑14.

Degim Z, Unal N, Essiz D, Abbasoglu U. The effect of various liposome

formulations on insulin penetration across Caco‑2 cell monolayer. Life

Sci 2004;75:2819‑27.

Goto T, Morishita M, Nishimura K, Nakanishi M, Kato A, Ehara J, et al.

Novel mucosal insulin delivery systems based on fusogenic liposomes.

Pharm Res 2006;23:384‑91.

Dwivedi N, Ma A, Sharma S, Bellare J. Silica coated liposomes for insulin

delivery. J Nanomater 2010;Article ID 652048:1‑8.

Niu M, Lu Y, Hovgaard L, Wu W. Liposomes containing glycocholate

as potential oral insulin delivery systems: Preparation, in vitro

characterization, and improved protection against enzymatic

degradation. Int J Nanomedicine 2011;6:1155‑66.

Nakashima K, Miyagi M, Goto K, Matsumoto Y, Ueoka R. Hybrid

liposomes as a drug carrier for the oral administration of insulin in

diabetic rats. Yakugaku Zasshi 2004;124:231‑5.

Jones M, Leroux J. Polymeric micelles‑A new generation of colloidal

drug carriers. Eur J Pharm Biopharm 1999;48:101‑11.

Toorisaka E, Hashida M, Kamiya N, Ono H, Kokazu Y, Goto M. An

enteric‑coated dry emulsion formulation for oral insulin delivery.

J Control Release 2005;107:91‑6.

Toorisaka E, Ono H, Arimori K, Kamiya N, Goto M. Hypoglycemic

effect of surfactant‑coated insulin solubilized in a novel

solid‑in‑oil‑in‑water (S/O/W) emulsion. Int J Pharm 2003 18;252:271‑4.

Sharma G, Wilson K, van der Walle CF, Sattar N, Petrie JR, Ravi

Kumar MN. Microemulsions for oral delivery of insulin: Design,

development and evaluation in streptozotocin induced diabetic rats.

Eur J Pharm Biopharm 2010;76:159‑69.

Cilek A, Celebi N, Tirnaksiz F, Tay A. A lecithin‑based microemulsion

of rh‑insulin with aprotinin for oral administration: Investigation of

hypoglycemic effects in non‑diabetic and STZ‑induced diabetic rats.

Int J Pharm 2005;298:176‑85.

Cilek A1, Celebi N, Tirnaksiz F. Lecithin‑based microemulsion of a

peptide for oral administration: Preparation, characterization, and

physical stability of the formulation. Drug Deliv 2006;13:19‑24.

Li X, Qi J, Xie Y, Zhang X, Hu S, Xu Y, Lu Y, Wu W. Nanoemulsions coated

with alginate/chitosan as oral insulin delivery systems: Preparation,

characterization, and hypoglycemic effect in rats. Int J Nanomedicine


Ye S, Wang C, Liu X, Tong Z, Ren B, Zeng F. New loading process

and release properties of insulin from polysaccharide microcapsules

fabricated through layer‑by‑layer assembly. J Control Release

Kim BS, Oh JM, Hyun H, Kim KS, Lee SH, Kim YH, Park K, Lee HB,

Kim MS. Insulin‑loaded microcapsules for in vivo delivery. Mol Pharm


Leung YF, O’Shea GM, Goosen MF, Sun AM. Microencapsulation of

crystalline insulin or islets of Langerhans: An insulin diffusion study.

Artif Organs 1983;7:208‑12.

Clayton HA, James RF, London NJ. Islet microencapsulation: A review.

Acta Diabetol 1993;30:181‑9.

Zhou W, Li B, Du W. Microencapsulation of insulin into biodegradable

microcapsules by the high voltage field method. Conf Proc IEEE Eng

Med Biol Soc 2005;2:1264‑7.

Watnasirichaikul S, Davies NM, Rades T, Tucker IG. Preparation

of biodegradable insulin nanocapsules from biocompatible

microemulsions. Pharm Res 2000;17:684‑9.

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;37:53‑61.

Wang J, Tabata Y, Morimoto K. Aminated gelatin microspheres as a

nasal delivery system for peptide drugs: Evaluation of in vitro release

and in vivo insulin absorption in rats. J Control Release 2006;113:31‑7.

Jain D, Panda AK, Majumdar DK. Eudragit S100 entrapped insulin

microspheres for oral delivery. AAPS PharmSciTech 2005;6:E100‑7.

Mundargi RC, Rangaswamy V, Aminabhavi TM. pH‑Sensitive oral insulin

delivery systems using Eudragit microspheres. Drug Dev Ind Pharm


Sajeesh S, Sharma CP. Novel pH responsive polymethacrylic

acid‑chitosan‑polyethylene glycol nanoparticles for oral peptide

delivery. J Biomed Mater Res B Appl Biomater 2006;76:298‑305.

He H, Ye J, Sheng J, Wang J, Huang Y, Chen G, et al. Overcoming oral

insulin delivery barriers: Application of cell penetrating peptide

and silica‑based nanoporous composites. Front Chem Sci Eng


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


Sarmento B, Martins S, Ferreira D, Souto EB. Oral insulin delivery by

means of solid lipid nanoparticles. Int J Nanomedicine 2007;2:743‑9.

Wu ZM, Ling L, Zhou LY, Guo XD, Jiang W, Qian Y, et al. Novel preparation

of PLGA/HP55 nanoparticles for oral insulin delivery. Nanoscale Res Lett


Pardakhty A, Moazeni E, Varshosaz J, Hajhashemi V, Rouholamini

Najafabadi A. Pharmacokinetic study of niosome‑loaded insulin in

diabetic rats. Daru 2011;19:404‑11.

Pettit DK, Gombotz WR. The development of site‑specific drug‑delivery

systems for protein and peptide biopharmaceuticals. Trends Biotechnol


Mrsny RJ. The colon as a site for drug delivery. J Control Release


Haupt S, Rubinstein A. The colon as a possible target for orally

administered peptide and protein drugs. Crit Rev Ther Drug Carrier

Syst 2002;19:499‑551.

Katsuma M, Watanabe S, Kawai H, Takemura S, Sako K. Effects of

absorption promoters on insulin absorption through colon‑targeted

delivery. Int J Pharm 2006;307:156‑62.

Tozaki H, Nishioka J, Komoike J, Okada N, Fujita T, Muranishi S, et al.

Enhanced absorption of insulin and (Asu (1,7)) eel‑calcitonin using novel

azopolymer‑coated pellets for colon‑specific drug delivery. J Pharm Sci


Shakweh M, Besnard M, Nicolas V, Fattal E. Poly (lactide‑co‑glycolide)

particles of different physicochemical properties and their uptake by

Peyer’s patches in mice. Eur J Pharm Biopharm 2005;61:1‑13.

Joseph JW, Kalitsky J, St‑Pierre S, Brubaker PL. Oral delivery of

glucagon‑like peptide‑1 in a modified polymer preparation normalizes

basal glycaemia in diabetic db/db mice. Diabetologia 2000;43:1319‑28.

Xia CQ, Wang J, Shen WC. Hypoglycemic effect of insulin‑transferrin

conjugate in streptozotocin‑induced diabetic rats. J Pharmacol Exp

Ther 2000;295:594‑600.

Xia CQ, Shen WC. Tyrphostin‑8 enhances transferrin receptor‑mediated

transcytosis in Caco‑2‑ cells and inreases hypoglycemic effect of orally

administered insulin‑transferrin conjugate in diabetic rats. Pharm Res


Al‑Achi A, Greenwood R. Erythrocytes as oral delivery systems for

human insulin. Drug Dev Ind Pharm 1998;24:67‑72.

al‑Achi A, Greenwood R. Buccal administration of human insulin in

streptozocin‑diabetic rats. Res Commun Chem Pathol Pharmacol


Agu RU, Ugwoke MI, Armand M, Kinget R, Verbeke N. The lung as a

route for systemic delivery of therapeutic proteins and peptides. Respir

Res 2001;2:198‑209.

Bellary S, Barnett AH. Inhaled insulin: New technology, new possibilities.

Int J Clin Pract 2006;60:728‑34.

Lim SH, Park HW, Shin CH, Kwon JH, Kim CW. Human insulin

microcrystals with lactose carriers for pulmonary delivery. Biosci

Biotechnol Biochem 2009;73:2576‑82.

Kwon JH, Kim CW, Choi SH. Controlled release preparation of insulin

and its method. US Patent 20030125237 A1, 3 July 2003.

Kwon JH, Kim CW. A novel insulin microcrystal preparation using a seed

zone method. J Cryst Growth 2004;263:536‑43.

Lin SH, Park HW, Shin CH, Kwon JH, Kim CW. Enhanced hypoglycemic

activity following intratracheal administration of insulin microcrystal

suspension with injection adjuvant. Biosci Biotechnol Biochem


Shen ZC, Cheng Y, Zhang Q, Wei SL, Li RC, Wang K. Lanthanides enhance

pulmonary absorption of insulin. Biol Trace Elem Res 2000;75:215‑25.

Korc M. Effect of lanthanum on pancreatic protein synthesis in

streptozotocin‑diabetic rats. Am J Physiol 1983;244:G321‑6.

Granado M, Martín AI, Priego T, Villanúa MA, López‑Calderón A.

Inactivation of Kupffer cells by gadolinium administration prevents

lipopolysaccharide‑induced decrease in liver insulin‑like growth

factor‑I and IGF‑binding protein‑3 gene expression. J Endocrinol


Zhao YZ, Xu YY, Li X, Lu CT, Zhang L, Dai DD, et al. An in vivo experiment

to improve pulmonary absorption of insulin using microbubbles.

Diabetes Technol Ther 2011;13:1013‑21.

Xu YY, Lu CT, Fu HX, Zhao YZ, Yang W, Li X, et al. Comparing the

enhancement efficiency between liposomes and microbubbles for

insulin pulmonary absorption. Diabetes Technol Ther 2011;13:759‑65.

Surendrakumar K, Martyn GP, Hodgers EC, Jansen M, Blair JA. Sustained

release of insulin from sodium hyaluronate based dry powder

formulations after pulmonary delivery to beagle dogs. J Control Release


Pezron I, Mitra R, Pal D, Mitra AK. Insulin aggregation and asymmetric

transport across human bronchial epithelial cell monolayers (Calu‑3).

J Pharm Sci 2002;91:1135‑46.

Bi R, Shao W, Wang Q, Zhang N. Spray‑freeze‑dried dry powder

inhalation of insulin‑loaded liposomes for enhanced pulmonary

delivery. J Drug Target 2008;16:639‑48.

Mitra R, Pezron I, Li Y, Mitra AK. Enhanced pulmonary delivery of insulin

by lung lavage fluid and phospholipids. Int J Pharm 2001;217:25‑31.

Todo H, Okamoto H, Iida K, Danjo K. Effect of additives on insulin

absorption from intratracheally administered dry powders in rats. Int

J Pharm 2001;220:101‑10.

Todo H, Okamoto H, Iida K, Danjo K. Improvement of stability and

absorbability of dry insulin powder for inhalation by powder‑combination

technique. Int J Pharm 2004;271:41‑52.

Hussain A, Yang T, Zaghloul AA, Ahsan F. Pulmonary absorption of insulin

mediated by tetradecyl‑beta‑maltoside and dimethyl‑beta‑cyclodextrin.

Pharm Res 2003;20:1551‑7.

Huang YY, Wang CH. Pulmonary delivery of insulin by liposomal carriers.

J Control Release 2006;113:9‑14.

Garcia‑Contreras L, Morçöl T, Bell SJ, Hickey AJ. Evaluation of novel

particles as pulmonary delivery systems for insulin in rats. AAPS

PharmSci 2003;5:E9.

Fiegel J, Ehrhardt C, Schaefer UF, Lehr CM, Hanes J. Large porous particle

impingement on lung epithelial cell monolayers – Toward improved

particle characterization in the lung. Pharm Res 2003;20:788‑96.

Kawashima Y, Yamamoto H, Takeuchi H, Fujioka S, Hino T. Pulmonary

delivery of insulin with nebulized DL‑lactide/glycolide copolymer (PLGA)

nanospheres to prolong hypoglycemic effect. J Control Release


Zhang Q, Shen Z, Nagai T. Prolonged hypoglycemic effect of

insulin‑loaded polybutylcyanoacrylate nanoparticles after pulmonary

administration to normal rats. Int J Pharm 2001;218:75‑80.

Grenha A, Seijo B, Remuñán‑López C. Microencapsulated chitosan

nanoparticles for lung protein delivery. Eur J Pharm Sci 2005;25:427‑37.

Al‑Qadi S, Grenha A, Carrión‑Recio D, Seijo B, Remuñán‑López C.

Microencapsulated chitosan nanoparticles for pulmonary protein

delivery: In vivo evaluation of insulin‑loaded formulations. J Control

Release 2012;157:383‑90.

Rosenstock J, Zinman B, Murphy LJ, Clement SC, Moore P, Bowering CK,

et al. Inhaled insulin improves glycemic control when substituted for or

added to oral combination therapy in type 2 diabetes: A randomized,

controlled trial. Ann Intern Med 2005;143:549‑58.

DeFronzo RA, Bergenstal RM, Cefalu WT, Pullman J, Lerman S, Bode BW,

et al. Efficacy of inhaled insulin in patients with type 2 diabetes not

controlled with diet and exercise: A 12‑week, randomized, comparative

trial. Diabetes Care 2005;28:1922‑8.

Stoever JA, Palmer JP. Inhaled insulin and insulin antibodies: A new

twist to an old debate. Diabetes Technol Ther 2002;4:157‑61.

Skyler JS, Weinstock RS, Raskin P, Yale JF, Barrett E, Gerich JE, et al. Use

of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic

subjects: A 6‑month, randomized, comparative trial. Diabetes Care


Barnett AH, Amiel SA, Hopkins D. Six month efficacy and 2‑years safety

of inhaled insulin as adjunctive therapy in combination with oral agent.

Diabet Med 2005;22:82.

Sudhakar Y, Kuotsu K, Bandyopadhyay AK. Buccal bioadhesive drug

delivery – A promising option for orally less efficient drugs. J Control

Release 2006;114:15‑40.

Veuillez F, Kalia YN, Jacques Y, Deshusses J, Buri P. Factors and strategies

for improving buccal absorption of peptides. Eur J Pharm Biopharm


Morishita M, Barichello JM, Takayama K, Chiba Y, Tokiwa S, Nagai T.

Pluronic F‑127 gels incorporating highly purified unsaturated fatty

acids for buccal delivery of insulin. Int J Pharm 2001;212:289‑93.

Starokadomskyy PL, Dubey IY. New absorption promoter for the buccal

delivery: Preparation and characterization of lysalbinic acid. Int J Pharm


Yang TZ, Wang XT, Yan XY, Zhang Q. Phospholipid deformable vesicles

for buccal delivery of insulin. Chem Pharm Bull (Tokyo) 2002;50:749‑53.

Venugopalan P, Sapre A, Venkatesan N, Vyas SP. Pelleted bioadhesive

polymeric nanoparticles for buccal delivery of insulin: Preparation and

characterization. Pharmazie 2001;56:217‑9.

Hosny EA, Elkheshen SA, Saleh SI. Buccoadhesive tablets for insulin

delivery: in‑vitro and in‑vivo studies. Boll Chim Farm 2002;141:210‑7.

Xu HB, Huang KX, Zhu YS, Gao QH, Wu QZ, Tian WQ, et al.

Hypoglycaemic effect of a novel insulin buccal formulation on rabbits.

Pharmacol Res 2002;46:459‑67.

Chien YW, Chang SF. Intranasal drug delivery for systemic medications.

Crit Rev Ther Drug Carrier Syst 1987;4:67‑194.

Chien YW, Su KS, Chang SF. Intranasal delivery of peptide/protein drugs,

intranasal delivery of nonpeptide molecules, intranasal delivery of

diagnostic drugs. In: Chien YW, Su KS, Chang SF, editors. Nasal Systemic

Drug Delivery. New York: Marcel Dekker Press; 1989. p. 89‑298.

Pontiroli AE, Calderara A, Pozza G. Intranasal drug delivery. Potential

advantages and limitations from a clinical pharmacokinetic perspective.

Clin Pharmacokinet 1989;17:299‑307.

Hinchcliffe M, Illum L. Intranasal insulin delivery and therapy. Adv Drug

Deliv Rev 1999;35:199‑234.

Kissel T, Werner U. Nasal delivery of peptides: An in vitro cell culture

model for the investigation of transport and metabolism in human

nasal epithelium. J Control Release 1998;53:195‑203.

Ridley D, Perkins AC, Washington N, Wilson CG, Wastie ML, Oflynn P,

et al. The effect of posture on nasal clearance of bioadhesive starch

microspheres. STP Pharm Sci 1995;5:442‑6.

Bonde NN, Khan SA, Pande SD, Tapar KK. Review: Nasal drug delivery.

IJPRD 2012;4:143‑54.

Gizurarson S, Bechgaard E. Intranasal administration of insulin to

humans. Diabetes Res Clin Pract 1991;12:71‑84.

Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery.

Diabet Med 2003;20:886‑98.

Türker S, Onur E, Ozer Y. Nasal route and drug delivery systems. Pharm

World Sci 2004;26:137‑42.

Pringels E, Callens C, Vervaet C, Dumont F, Slegers G, Foreman P, et al.

Influence of deposition and spray pattern of nasal powders on insulin

bioavailability. Int J Pharm 2006;310:1‑7.

Pillion DJ, Ahsan F, Arnold JJ, Balusubramanian BM, Piraner O,

Meezan E. Synthetic long‑chain alkyl maltosides and alkyl sucrose

esters as enhancers of nasal insulin absorption. J Pharm Sci


Fernández‑Urrusuno R, Calvo P, Remuñán‑López C, Vila‑Jato JL,

Alonso MJ. Enhancement of nasal absorption of insulin using chitosan

nanoparticles. Pharm Res 1999;16:1576‑81.

Mitra R, Pezron I, Chu WA, Mitra AK. Lipid emulsions as vehicles for

enhanced nasal delivery of insulin. Int J Pharm 2000;205:127‑34.

Schipper NG, Romeijn SG, Verhoef JC, Merkus FW. Nasal insulin

delivery with dimethyl‑beta‑cyclodextrin as an absorption enhancer

in rabbits: Powder more effective than liquid formulations. Pharm Res


Najafabadi AR, Moslemi P, Tajerzadeh H. Intranasal bioavailability

of insulin from carbopol‑based gel spray in rabbits. Drug Deliv


Varshosaz J, Sadrai H, Heidari A. Nasal delivery of insulin using

bioadhesive chitosan gels. Drug Deliv 2006;13:31‑8.

Varshosaz J, Sadrai H, Alinagari R. Nasal delivery of insulin using chitosan

microspheres. J Microencapsul 2004;21:761‑74.

Joshi HM, Bhumkar DR, Joshi K, Pokharkar V, Sastry M. Gold

nanoparticles as carriers for efficient transmucosal insulin delivery.

Langmuir 2006;22:300‑5.

Krauland AH, Guggi D, Bernkop‑Schnürch A. Thiolated chitosan

microparticles: A vehicle for nasal peptide drug delivery. Int J Pharm


Wang LY, Gu YH, Su ZG, Ma GH. Preparation and improvement of release

behavior of chitosan microspheres containing insulin. Int J Pharm


Jain SK, Jain NK, Gupta Y, Jain A, Jain D, Chaurasia M. Mucoadhesive

chitosan microspheres for non‑invasive and improved nasal delivery

of insulin. Indian J Pharm Sci 2007;69:498‑504.

Jain SK, Jain NK, Gupta Y, Jain A, Jain D, Chaurasia M. Muco‑adhesive

multivesicular liposomes as an effective carrier for transmucosal insulin

delivery. Inf Healthc 2007;15:417‑27.

Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol


Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev


Karande P, Jain A, Mitragotri S. Discovery of transdermal penetration

enhancers by high‑throughput screening. Nat Biotechnol 2004;22:192‑7.

Chen Y, Shen Y, Guo X, Zhang C, Yang W, Ma M, et al. Transdermal protein

delivery by a coadministered peptide identified via phage display. Nat

Biotechnol 2006;24:455‑60.

Guo J, Ping Q, Zhang L. Transdermal delivery of insulin in mice by using

lecithin vesicles as a carrier. Drug Deliv 2000;7:113‑6.

Higaki M, Kameyama M, Udagawa M, Ueno Y, Yamaguchi Y, Igarashi R,

et al. Transdermal delivery of CaCO3‑nanoparticles containing insulin.

Diabetes Technol Ther 2006;8:369‑74.

Cevc G, Gebauer D, Stieber J, Schätzlein A, Blume G. Ultraflexible

vesicles, Transfersomes, have an extremely low pore penetration

resistance and transport therapeutic amounts of insulin across the

intact mammalian skin. Biochim Biophys Acta 1998;1368:201‑15.

Panchagnula R, Pillai O, Nair VB, Ramarao P. Transdermal iontophoresis

revisited. Curr Opin Chem Biol 2000;4:468‑73.

Dixit N, Bali V, Baboota S, Ahuja A, Ali J. Iontophoresis‑An approach for

controlled drug delivery: A review. Curr Drug Deliv 2007;4:1‑10.

Batheja P, Thakur R, Michniak B. Transdermal iontophoresis. Expert

Opin Drug Deliv 2006;3:127‑38.

Mao XM, Liang BW, Fang SZ, Li Q, Yao YP, Zhou MW. Facilitated

transdermal delivery of insulin by pulse current iontophoresis. Yao

Xue Xue Bao 1995;30:302‑6.

Pillai O, Nair V, Panchagnula R. Transdermal iontophoresis of insulin:

IV. Influence of chemical enhancers. Int J Pharm 2004;269:109‑20.

Akram M, Naqvi SB, Khan A. Design and development of insulin emulgel

formulation for transdermal drug delivery and its evaluation. Pak J

Pharm Sci 2013;26:323‑32.

Kanikkannan N, Singh J, Ramarao P. Transdermal iontophoretic delivery

of bovine insulin and monomeric human insulin analogue. J Control

Release 1999;59:99‑105.

Pillai O, Borkute SD, Sivaprasad N, Panchagnula R. Transdermal

iontophoresis of insulin. II. Physicochemical considerations. Int J Pharm


Pillai O, Panchagnula R. Transdermal iontophoresis of insulin. VI.

Influence of pretreatment with fatty acids on permeation across rat

skin. Skin Pharmacol Physiol 2004;17:289‑97.

Murthy SN, Zhao YL, Marlan K, Hui SW, Kazim AL, Sen A. Lipid

and electroosmosis enhanced transdermal delivery of insulin by

electroporation. J Pharm Sci 2006;95:2041‑50.

Pillai O, Panchagnula R. Transdermal delivery of insulin from poloxamer

gel: Ex vivo and in vivo skin permeation studies in rat using iontophoresis

and chemical enhancers. J Control Release 2003;89:127‑40.

Pitt WG, Husseini GA, Staples BJ. Ultrasonic drug delivery – a general

review. Expert Opin Drug Deliv 2004;1:37‑56.

Mitragotri S, Edwards DA, Blankschtein D, Langer R. A mechanistic

study of ultrasonically‑enhanced transdermal drug delivery. J Pharm

Sci 1995;84:697‑706.

Bommannan D, Okuyama H, Stauffer P, Guy RH. Sonophoresis. I. The

use of high‑frequency ultrasound to enhance transdermal drug delivery.

Pharm Res 1992;9:559‑64.

Tezel A, Sens A, Tuchscherer J, Mitragotri S. Synergistic effect of

low‑frequency ultrasound and surfactants on skin permeability. J Pharm

Sci 2002;91:91‑100.

Tezel A, Mitragotri S. Interactions of inertial cavitation bubbles with

stratum corneum lipid bilayers during low‑frequency sonophoresis.

Biophys J 2003;85:3502‑12.

Lee S, Snyder B, Newnham RE, Smith NB. Noninvasive ultrasonic

transdermal insulin delivery in rabbits using the light‑weight cymbal

array. Diabetes Technol Ther 2004;6:808‑15.

Park EJ, Werner J, Smith NB. Ultrasound mediated transdermal

insulin delivery in pigs using a lightweight transducer. Pharm Res


Smith NB, Lee S, Maione E, Roy RB, McElligott S, Shung KK.

Ultrasound‑mediated transdermal transport of insulin in vitro through

human skin using novel transducer designs. Ultrasound Med Biol


Al‑Bataineh OM, Lweesyb K, Fraiwan L. Noninvasive transdermal insulin

delivery using piston‑shaped PZT transducers: In vivo rabbits evaluation.

Jordan J Mech Ind Eng 2012;6:11‑6.

McAllister DV, Wang PM, Davis SP, Park JH, Canatella PJ, Allen MG, et al.

Microfabricated needles for transdermal delivery of macromolecules

and nanoparticles: Fabrication methods and transport studies. Proc

Natl Acad Sci U S A 2003;100:13755‑60.

Griss P, Enoksson P, Tolvanen‑Laakso HK, Merilainen P, Ollmar S,

Stemme G. Micromachined electrodes for biopotential measurements.

J Microelectromech Syst 2001;10:10‑6.

Gill HS, Prausnitz MR. Coated microneedles for transdermal delivery.

J Control Release 2007 12;117:227‑37.

Davis SP, Martanto W, Allen MG, Prausnitz MR. Hollow metal

microneedles for insulin delivery to diabetic rats. IEEE Trans Biomed

Eng 2005;52:909‑15.

Chiou GC. Systemic delivery of polypeptide drugs through ocular route.

J Ocul Pharmacol 1994;10:93‑9.

Lee YC, Simamora P, Pinsuwan S, Yalkowsky SH. Review on the systemic

delivery of insulin via the ocular route. Int J Pharm 2002;233:1‑18.

Yamamoto A, Luo AM, Dodda‑Kashi S, Lee VH. The ocular route for

systemic insulin delivery in the albino rabbit. J Pharmacol Exp Ther


Chiou GC, Li BH. Chronic systemic delivery of insulin through the ocular

route. J Ocul Pharmacol 1993;9:85‑90.

Pillion DJ, Atchison JA, Wang RX, Meezan E. Alkylglycosides enhance

systemic absorption of insulin applied topically to the rat eye.

J Pharmacol Exp Ther 1994;271:1274‑80.

Morgan RV, Huntzicker MA. Delivery of systemic regular insulin via the

ocular route in dogs. J Ocul Pharmacol Ther 1996;12:515‑26.

Ahsan F, Arnold JJ, Meezan E, Pillion DJ. Sucrose cocoate, a component of

cosmetic preparations, enhances nasal and ocular peptide absorption.

Int J Pharm 2003;251:195‑203.

Srinivasan R, Jain SK. Insulin delivery through the ocular route. Drug

Deliv 1998;5:53‑5.

Lee Y, Yalkowsky SH. Systemic absorption of insulin from a Gelfoam

ocular device. Int J Pharm 1999;190:35‑40.

Lee YC, Simamora P, Yalkowsky SH. Effect of Brij‑78 on systemic delivery

of insulin from an ocular device. J Pharm Sci 1997;86:430‑3.

Lee YC, Simamora P, Yalkowsky SH. Systemic delivery of insulin via an

enhancer‑free ocular device. J Pharm Sci 1997;86:1361‑4.

Lee YC, Yalkowsky SH. Effect of formulation on the systemic

absorption of insulin from enhancer‑free ocular devices. Int J Pharm


Lee YC, Yalkowsky SH. Ocular devices for the controlled systemic

delivery of insulin: In vitro and in vivo dissolution. Int J Pharm


Ichikawa K, Ohata I, Mitomi M, Kawamura S, Maeno H, Kawata H.

Rectal absorption of insulin suppositories in rabbits. J Pharm Pharmacol


Watanabe Y, Matsumoto Y, Hori N, Funato H, Matsumoto M. Enhanced

rectal absorption of insulin in rabbits from hollow‑type suppositories

containing insulin and glyceryl‑1‑monooctanoate. Chem Pharm

Bull (Tokyo) 1991;39:3007‑12.

Hosny EA, Al‑Shora HI, Elmazar MM. Effect of different bile salts

on the relative hypoglycemia of Witepsol W35 suppositories

containing insulin in diabetic Beagle dogs. Drug Dev Ind Pharm


Hosny EA, Al‑Shora HI, Elmazar MM. Relative hypoglycemic effect of

insulin suppositories in diabetic beagle dogs: Optimization of various

concentrations of sodium salicylate and polyoxyethylene‑9‑lauryl ether.

Biol Pharm Bull 2001;24:1294‑7.

Yun M, Choi H, Jung J, Kim C. Development of a thermo‑reversible

insulin liquid suppository with bioavailability enhancement. Int J Pharm


Adikwu MU. Evaluation of snail mucin motifs as rectal absorption

enhancer for insulin in non‑diabetic rat models. Biol Pharm Bull


Available from: [Last retrieved on 2014 Jan 02].

Available from: [Last retrieved on 2013 Jul 11].

Available from: http://www.phx.corporate‑ [Last

retrieved on 2013 Jul 11].

Malkov D, Angelo R, Wang HZ, Flanders E, Tang H, Gomez‑Orellana I.

Oral delivery of insulin with the eligen technology: Mechanistic studies.

Curr Drug Deliv 2005;2:191‑7.

Kinesh VP, Neelam DP, Punit BP, Bhavesh BV, Pragna KS. Novel approaches for oral delivery of insulin and and current status of oral insulin

products. Int J Pharm Sci Nanotechnology 2010;3:1057‑64.

Sircar AR. Alternate routes of insulin delivery. Int J Diabet Dev Ctries


Available from: [Last retrieved on 2013 Sep 10].

Available from: [Last retrieved on

Sep 10].

Available from: [Last retrieved on

Sep 10].

Available from: [Last retrieved on

Sep 10].

CobalaminTM – Mediated Oral Drug Delivery. Available from: [Last retrieved on 2013 Aug 13].

Available from: [Last retrieved on 2013

Aug 14].

Available from:

[Last retrieved on 2013 Sep 20].

Available from: [Last retrieved

on 2013 Sep 20].

Available from: [Last retrieved on 2013 Sep 25].

Available from: [Last retrieved on 2013 Jul 09].

Available from: [Last retrieved on 2013 Jul 09].

Available from: [Last retrieved on 2013 Aug 10].

Available from: [Last retrieved on 2013 Aug 10].

Available from: [Last retrieved on 2013 Aug 12]

Olivia J, Phung P. Technosphere insulin: An inhaled mealtime insulin

for the treatment of type 1 and type 2 diabetes mellitus. Formul J


Richardson PC, Boss AH. Technosphere insulin technology. Diabetes

Technol Ther 2007;9 Suppl 1:S65‑72.

Hermansen K, Rönnemaa T, Petersen AH, Bellaire S, Adamson U.

Intensive therapy with inhaled insulin via the AERx insulin diabetes

management system: A 12‑week proof‑of‑concept trial in patients with

type 2 diabetes. Diabetes Care 2004;27:162‑7.

Moses RG, Bartley P, Lunt H, O’Brien RC, Donnelly T, Gall MA, et al.

Safety and efficacy of inhaled insulin (AERx iDMS) compared with

subcutaneous insulin therapy in patients with Type 1 diabetes: 1‑year

data from a randomized, parallel group trial. Diabet Med 2009;26:260‑7.

Available from: [Last retrieved on 2013 June 15].

Kim D, Mudaliar S, Chinnapongse S, Chu N, Boies SM, Davis T,

et al. Dose‑response relationships of inhaled insulin delivered via the

aerodose insulin inhaler and subcutaneously injected insulin in patients

with type 2 diabetes. Diabetes Care 2003;26:2842‑7.

Available from: [Last retrieved on 2013 Sep 23].

Phillips E, Witham C. In: Rathbone MJ, Hadgraft J, Roberts MS,

editors. Modified‑Release Drug Delivery Technology. New York: Informa

Healthcare; 2002. p. 913‑24.

Available from: [Last retrieved

on 2013 Sep 17].

Heise T, Brugger A, Cook C, Eckers U, Hutchcraft A, Nosek L, et al.

PROMAXX inhaled insulin: Safe and efficacious administration with

a commercially available dry powder inhaler. Diabetes Obes Metab


Stote R, Miller M, Marbury T, Shi L, Strange P. Enhanced absorption

of Nasulin™, an ultrarapid‑acting intranasal insulin formulation, using

single nostril administration in normal subjects. J Diabetes Sci Technol


Available from: [Last retrieved on 2013

Sep 20].

Available from: [Last retrieved on 2013 Sep 20].

Available from: [Last retrieved on 2013 Sep 20].

Matriano JA, Cormier M, Johnson J, Young WA, Buttery M, Nyam K,

et al. Macroflux microprojection array patch technology: A new

and efficient approach for intracutaneous immunization. Pharm Res


Available from: [Last retrieved on

June 22].

Available from:

Zhang J, Hodge W, Hutnick C, Wang X. Noninvasive diagnostic devices

for diabetes through measuring tear glucose. J Diabetes Sci Technol


Available from: [Last retrieved on

June 24]



  • There are currently no refbacks.