Gels for constant and smart delivery of insulin

M Joan Taylor, Krishan P Chauhan, Tarsem S Sahota

Abstract


The focus of this review is the role of gelatinous materials for oral, transdermal and peritoneal insulin platforms as alternatives to the ubiquitous subcutaneous depot approach. Hydrogels that form hydrated, cohesive materials and the topologically complex micellar types can add ligand interaction, bond vulnerability and rheological characteristics to develop reliable programmed release, including closed loop (automated basal and bolus) activity in non-oral routes. In addition, the potential protection of the protein and likely increased paracellular uptake mean that orally active insulin is feasible. While unlikely to be suitable for closed loop delivery, the driver for gut absorption is not only to increase the convenience and decrease dosage trauma, but to target the mesentery-portal vasculature rather than peripheral tissue, thus improving hepatic glycogen equilibrium and reducing the obesogenic effect and hypoglycaemic episodes.

Keywords


insulin, drug delivery, polymer, gel, hydrogel, micelle, critical solution temperature, rheology, visco-elastic, closed loop, kinetic, enzyme protection, ligand, interactive, oral, subcutaneous, peritoneal

Full Text:

PDF HTML

References


Joslin EP. The treatment of diabetes mellitus. Can Med Assoc J 1916; 6(8):673–84.

Home PD. Impact of the UKPDS--an overview. Diabet Med 2008;25(Suppl 2):2–8.

Nathan DM. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care 2014;37(1):9–16. https://doi.org/10.2337/dc13-2112.

de Lusignan S, Hinton W, Konstantara E, et al. Intensification to injectable therapy in type 2 diabetes: Mixed methods study (protocol). BMC Health Serv Res 2019;19(1):284–94. https://doi.org/10.1186/s12913-019-4112-3.

Bloomgarden Z. Is insulin the preferred treatment for HbA1c >9%? J Diabetes 2017;9(9):814–6. https://doi.org/10.1111/1753-0407.12575 .

Sarbacker GB, Urteaga EM. Adherence to insulin therapy. Diabetes Spectrum 2016;29(3):166–70. https://doi.org/10.2337/diaspect.29.3.166 .

Weiss MA, Lawrence MC. A thing of beauty: structure and function of insulin's "aromatic triplet". Diabetes Obes Metab 2018;20(Suppl 2):51–63. https://doi.org/10.1111/dom.13402.

Nur M, Vasiljevic T. Can natural polymers assist in delivering insulin orally? Int J Biol Macromol 2017;103:889–901. https://doi.org/S0141-8130(17)30213-1 [pii].

Chaturvedi K, Ganguly K, Nadagouda MN, Aminabhavi TM. Polymeric hydrogels for oral insulin delivery. J Controlled Release 2013;165(2):129–38. https://doi.org/10.1016/j.jconrel.2012.11.005.

Zare Y, Rhee KY. Prediction of loss factor (tan δ) for polymer nanocomposites as a function of yield tress, relaxation time and the width of transition region between newtonian and power-law behaviors. J Mechanical Behavior Biomed Materials 2019;96:136–43. https://doi.org/10.1016/j.jmbbm.2019.04.045.

Jacob J, Haponiuk JT, Thomas S, Gopi S. Biopolymer based nanomaterials in drug delivery systems: a review. Materials Today Chemistry 2018;9:43–55. https://doi.org/10.1016/j.mtchem.2018.05.002.

Yang G, Wang Q, Gao Y, Yang C, Hu L. Combination of coating and injectable hydrogel depot to improve the sustained delivery of insulin. J Drug Delivery Sci Technol 2018;45:415–21. https://doi.org/10.1016/j.jddst.2018.03.028.

Bodratti AM, Alexandridis P. Amphiphilic block copolymers in drug delivery: advances in formulation structure and performance. Expert Opin Drug Deliv 2018;15(11):1085–104. https://doi.org/10.1080/17425247.2018.1529756.

Taylor MJ, Tomlins P, Sahota ST. Thermoresponsive gels. Gels 2017;3(1). https://doi.org/10.3390/gels3010004.

Choi S, Kim SW. Controlled release of insulin from injectable biodegradable triblock copolymer depot in ZDF rats. Pharm Res 2003;20(12):2008–10. https://doi.org/10.1023/b:pham.0000008050.99985.5c.

Chen Y, Li Y, Shen W, et al. Controlled release of liraglutide using thermogelling polymers in treatment of diabetes. Sci Rep 2016;6:31593. https://doi.org/10.1038/srep31593.

Sharma G, Sharma AR, Nam J, Doss GPC, Lee S, Chakraborty C. Nanoparticle based insulin delivery system: the next generation efficient therapy for type 1 diabetes. J Nanobiotechnology 2015;13:74. https://www.ncbi.nlm.nih.gov/pubmed/26498972; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619439/. https://doi.org/10.1186/s12951-015-0136-y.

Borzacchiello A, Russo L, Malle BM, Schwach-Abdellaoui K, Ambrosio L. Hyaluronic acid based hydrogels for regenerative medicine applications. Biomed Res Int 2015;2015:871218. https://doi.org/10.1155/2015/871218.

Caló E, Khutoryanskiy VV. Biomedical applications of hydrogels: a review of patents and commercial products. Eur Polymer J 2015;65:252–67. https://doi.org/10.1016/j.eurpolymj.2014.11.024.

Ionov L. Hydrogel-based actuators: possibilities and limitations. Materials Today 2014;17(10):494–503. https://doi.org/10.1016/j.mattod.2014.07.002.

Bae JW, Choi JH, Lee Y, Park KD. Horseradish peroxidase-catalysed in situ-forming hydrogels for tissue-engineering applications. J Tissue Eng Regen Med 2015;9(11):1225–32. https://doi.org/10.1002/term.1917.

Nguyen DT, Phan VHG, Lee DS, Thambi T, Huynh DP. Bioresorbable pH- and temperature-responsive injectable hydrogels-incorporating electrosprayed particles for the sustained release of insulin. Polym Degrad Stab 2019;162:36–46. https://doi.org/10.1016/j.polymdegradstab.2019.02.013.

Custodio CA, Reis RL, Mano JF. Photo-cross-linked laminarin-based hydrogels for biomedical applications. Biomacromolecules 2016;17(5):1602–09. https://doi.org/10.1021/acs.biomac.5b01736.

El-Sherbiny I, Yacoub MH. Hydrogel scaffolds for tissue engineering: Progress and challenges. Global Cardiol Sci Pract 2013;2013(3):316–42. https://doi.org/10.5339/gcsp.2013.38.

Bai X, Gao M, Syed S, Zhuang J, Xu X, Zhang X. Bioactive hydrogels for bone regeneration. Bioactive Materials 2018;3(4):401–17. https://doi.org/10.1016/j.bioactmat.2018.05.006.

Arciola C, Campoccia D, Montanaro L. Implant infections: Adhesion, biofilm formation and immune evasion. Volume 16, 2018. https://doi.org/10.1038/s41579-018-0019-y.

Mallawarachchi S, Mahadevan A, Gejji V, Fernando S. Mechanics of controlled release of insulin entrapped in polyacrylic acid gels via variable electrical stimuli. Drug Deliv Transl Res 2019;9(4):783–94. https://doi.org/10.1007/s13346-019-00620-7.

Zhou T, Ding L, Che G, Jiang W, Sang L. Recent advances and trends of molecularly imprinted polymers for specific recognition in aqueous matrix: Preparation and application in sample pretreatment. TrAC Trends in Analytical Chemistry 2019;114:11–28. https://doi.org/10.1016/j.trac.2019.02.028.

Arifuzzaman MD, Zhao W, Zhao Y. Surface ligands in the imprinting and binding of molecularly imprinted cross-linked micelles. Supramol Chem 2018;30(11):929–39. https://doi.org/10.1080/10610278.2018.1489540.

Yao Y, Wei Y, Chen S. Size effect of the surface energy density of nano- particles. Surface Sci 2015;636:19–24. https://doi.org/10.1016/j.susc.2015.01.016.

Han L, Zhao Y, Yin L, et al. Insulin-loaded pH-sensitive hyaluronic acid nanoparticles enhance transcellular delivery. AAPS PharmSciTech 2012;13(3):836–45. https://doi.org/10.1208/s12249-012-9807-2.

Arbit E, Kidron M. Oral insulin delivery in a physiologic context: review. J Diabetes Sci Technol 2017;11(4):825–32. https://doi.org/10.1177/1932296817691303.

Hu Q, Luo Y. Recent advances of polysaccharide-based nanoparticles for oral insulin delivery. Int J Biol Macromol 2018;120:775–82. https://doi.org/10.1016/j.ijbiomac.2018.08.152.

Mukhopadhyay P, Mishra R, Rana D, Kundu PP. Strategies for effective oral insulin delivery with modified chitosan nanoparticles: a review. Progress in Polymer Sci 2012;37(11):1457–75. https://doi.org/10.1016/j.progpolymsci.2012.04.004.

Fonte P, Araújo F, Silva C, et al. Polymer-based nanoparticles for oral insulin delivery: Revisited approaches. Biotechnol Adv 2015;33(6, Part 3):1342–54. https://doi.org/10.1016/j.biotechadv.2015.02.010.

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. https://doi.org/10.1016/j.jfda.2015.01.007.

Mumuni MA, Kenechukwu FC, Ofokansi KC, Attama AA, Díaz DD. Insulin-loaded mucoadhesive nanoparticles based on mucin-chitosan complexes for oral delivery and diabetes treatment. Carbohydr Polym 2020; 229:115506. https://doi.org/10.1016/j.carbpol.2019.115506.

Sharma D, Singh J. Long-term glycemic control and prevention of diabetes complications in vivo using oleic acid-grafted-chitosan zinc-insulin complexes incorporated in thermosensitive copolymer. J Controlled Release 2020;323:161–78. https://doi.org/10.1016/j.jconrel.2020.04.012.

Sudhakar S, Chandran SV, Selvamurugan N, Nazeer RA. Biodistribution and pharmacokinetics of thiolated chitosan nanoparticles for oral delivery of insulin in vivo. Int J Biol Macromol 2020;150:281–8. https://doi.org/10.1016/j.ijbiomac.2020.02.079.

Wong CY, Al-Salami H, Dass CR. Recent advancements in oral administration of insulin-loaded liposomal drug delivery systems for diabetes mellitus. Int J Pharm 2018;549(1):201–7. https://doi.org/10.1016/j.ijpharm.2018.07.041.

Mohsen AM. Nanotechnology advanced strategies for the management of diabetes mellitus. Curr Drug Targets 2019;20(10):995–1007 https://doi.org/10.2174/1389450120666190307101642.

Zhang T, Luo J, Peng Q, et al. Injectable and biodegradable phospholipid-based phase separation gel for sustained delivery of insulin. Colloids and Surfaces B: Biointerfaces 2019;176:194–201. https://doi.org/10.1016/j.colsurfb.2019.01.003.

Yang J, Cao Z. Glucose-responsive insulin release: analysis of mechanisms, formulations, and evaluation criteria. J Controlled Release 2017;263:231–9. https://doi.org/10.1016/j.jconrel.2017.01.043.

Wang J, Ye Y, Yu J, et al. Core-shell microneedle gel for self-regulated insulin delivery. ACS Nano 2018;12(3):2466–73. https://doi.org/10.1021/acsnano.7b08152.

Woo VC. New insulins and new aspects in insulin delivery. Can J Diabetes 2015;39(4):335–43. http://dx.doi.org/10.1016/j.jcjd.2015.04.006.

Priya James H, John R, Alex A, Anoop KR. Smart polymers for the controlled delivery of drugs - a concise overview. Acta Pharm Sin B 2014;4(2):120–7. https://doi.org/10.1016/j.apsb.2014.02.005 .

Su FY, Lin KJ, Sonaje K, et al. Protease inhibition and absorption enhancement by functional nanoparticles for effective oral insulin delivery. Biomaterials 2012;33(9):2801–11. https://doi.org/10.1016/j.biomaterials.2011.12.038.

Chuang EY, Lin KJ, Su FY, et al. Calcium depletion-mediated protease inhibition and apical-junctional-complex disassembly via an EGTA-conjugated carrier for oral insulin delivery. J Control Release 2013;169(3):296–305. https://doi.org/10.1016/j.jconrel.2012.11.011.

Mohammadpour F, Hadizadeh F, Tafaghodi M, et al. Preparation, in vitro and in vivo evaluation of PLGA/chitosan based nano-complex as a novel insulin delivery formulation. Int J Pharm 2019;572:118710. https://doi.org/10.1016/j.ijpharm.2019.118710.

Agrawal G, Wakte P, Shelke S. Formulation optimization of human insulin loaded microspheres for controlled oral delivery using response surface methodology. Endocr Metab Immune Disord Drug Targets 2017; 17(2):149–65. https://doi.org/10.2174/1871530317666170503120129.

Baykan O, Yaman A, Gerin F, Sirikci O, Haklar G. The effect of different protease inhibitors on stability of parathyroid hormone, insulin, and prolactin levels under different lag times and storage conditions until analysis. J Clin Lab Anal 2017;31(6). Epub 30 Jan 2017. https://doi.org/10.1002/jcla.22144.

Hu J, Chen Y, Li Y, Zhou Z, Cheng Y. A thermo-degradable hydrogel with light-tunable degradation and drug release. Biomaterials 2017;112:133–40. https://doi.org/10.1016/j.biomaterials.2016.10.015.

Sun DD, Lee PI. Crosslinked hydrogels-a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs. Acta Pharm Sin B 2014;4(1):26–36. https://doi.org/10.1016/j.apsb.2013.12.002.

Ferreira NN, Ferreira LMB, Cardoso VMO, Boni FI, Souza ALR, Gremião MPD. Recent advances in smart hydrogels for biomedical applications: from self-assembly to functional approaches. Eur Polymer J 2018;99:117–33. https://doi.org/10.1016/j.eurpolymj.2017.12.004.

Lin Y, Mi F, Lin P, et al. Strategies for improving diabetic therapy via alternative administration routes that involve stimuli-responsive insulin-delivering systems. Adv Drug Deliv Rev 2019;139:71–82. https://doi.org/10.1016/j.addr.2018.12.001.

Lim H, Ooi C, Tey B, Chan E. Controlled delivery of oral insulin aspart using pH-responsive alginate/κ-carrageenan composite hydrogel beads. React Funct Polym 2017;120:20–9. https://doi.org/10.1016/j.reactfunctpolym.2017.08.015.

Li X, Fu M, Wu J, et al. pH-sensitive peptide hydrogel for glucose-responsive insulin delivery. Acta Biomaterialia 2017;51:294–303. https://doi.org/10.1016/j.actbio.2017.01.016.

Nguyen DT, Phan VHG, Lee DS, Thambi T, Huynh DP. Bioresorbable pH- and temperature-responsive injectable hydrogels-incorporating electrosprayed particles for the sustained release of insulin. Polym Degrad Stab 2019;162:36–46. https://doi.org/10.1016/j.polymdegradstab.2019.02.013.

Shen D, Yu H, Wang L, et al. Recent progress in design and preparation of glucose-responsive insulin delivery systems. J Controlled Release 2020;321:236–58. https://doi.org/10.1016/j.jconrel.2020.02.014.

Zhao L, Wang L, Zhang Y, et al. Glucose oxidase-based glucose-sensitive drug delivery for diabetes treatment. Polymers (Basel) 2017;9(7):255–76. https://doi.org/10.3390/polym9070255.

Fischel-Ghodsian F, Newton JM. Simulation and optimisation of a self- regulating insulin delivery system. J Drug Target 1993;1(1):67–80. https://doi.org/10.3109/10611869308998766.

Peppas N, Bures,Christie. Glucose-responsive hydrogels. Volume 112, 2008. https://doi.org/10.1201/b18990-114.

Yu J, Zhang Y, Ye Y, et al. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proc Natl Acad Sci USA 2015;112(27):8260–5. https://doi.org/10.1073/pnas.1505405112.

Jana BA, Shinde U, Wadhwani A. Preparation of enzyme based polymeric biomimetic nanoparticle for the controlled release of insulin. Sensing and Bio-Sensing Res 2020;28:100342. https://doi.org/10.1016/j.sbsr.2020.100342.

Scheja S, Domanskyi S, Gamella M, et al. Glucose-triggered insulin release from Fe3+-cross-linked alginate hydrogel: experimental study and theoretical modeling. ChemPhysChem 2017;18(12):1541–51. https://doi.org/10.1002/cphc.201700195.

Zhang Y, Yu J, Kahkoska AR, Wang J, Buse JB, Gu Z. Advances in transdermal insulin delivery. Adv Drug Deliv Rev 2019;139:51–70. https://doi.org/10.1016/j.addr.2018.12.006.

Luo J, Cao S, Chen X, et al. Super long-term glycemic control in diabetic rats by glucose-sensitive LbL films constructed of supramolecular insulin assembly. Biomaterials 2012;33(33):8733–42. https://doi.org/10.1016/j.biomaterials.2012.08.041.

Wu J, Bremner DH, Li H, Sun X, Zhu L. Synthesis and evaluation of temperature- and glucose-sensitive nanoparticles based on phenylboronic acid and N-vinylcaprolactam for insulin delivery. Materials Science and Engineering: C 2016;69:1026–35. https://doi.org/10.1016/j.msec.2016.07.078.

Wu J, Bremner DH, Li H, Niu S, Li S, Zhu L. Phenylboronic acid-diol crosslinked 6-O-vinylazeloyl-d-galactose nanocarriers for insulin delivery. Materials Science and Engineering: C 2017;76:845–55. https://doi.org/10.1016/j.msec.2017.03.139.

Joseph VS, Hong J. Phenylboronic acid-modified oligoamine sensitive to monosaccharides and carbon dioxide under physiological conditions. Colloids and Surfaces A: Physicochemical and Engineering Aspects 2018; 553:312–6. https://doi.org/10.1016/j.colsurfa.2018.05.084.

Nguyen T, Magda JJ, Tathireddy P. Manipulation of the isoelectric point of polyampholytic smart hydrogels in order to increase the range and selectivity of continuous glucose sensors. Sensors and Actuators B: Chemical 2018; 255:1057–63. https://doi.org/10.1016/j.snb.2017.08.022.

Li L, Jiang G, Yu W, et al. A composite hydrogel system containing glucose-responsive nanocarriers for oral delivery of insulin. Materials Science and Engineering: C 2016;69:37–45. https://doi.org/10.1016/j.msec.2016.06.059.

Zhao F, Wu D, Yao D, et al. An injectable particle-hydrogel hybrid system for glucose-regulatory insulin delivery. Acta Biomaterialia 2017;64:334–45. https://doi.org/10.1016/j.actbio.2017.09.044.

Gao W, Hu Y, Xu L, Liu M, Wu H, He B. Dual pH and glucose sensitive gel gated mesoporous silica nanoparticles for drug delivery. Chinese Chemical Letters 2018;29(12):1795–8. https://doi.org/10.1016/j.cclet.2018.05.022.

Magda J, Cho S, Streitmatter S, Jevremovic T. Effects of gamma rays and neutron irradiation on the glucose response of boronic acid-containing “smart” hydrogels. Polym Degrad Stab 2014;99:219–22. https://doi.org/10.1016/j.polymdegradstab.2013.11.002.

Matsumoto A, Tanaka M, Matsumoto H, et al. Synthetic "smart gel" provides glucose-responsive insulin delivery in diabetic mice. Sci Adv 2017; 3(11):eaaq0723. https://doi.org/110.1126/sciadv.aaq0723.

Byrne ME, Park K, Peppas NA. Molecular imprinting within hydrogels. Advanced Drug Delivery Rev 2002;54(1):149–61. https://doi.org/10.1016/S0169-409X(01)00246-0.

Peng M, Xiang H, Hu X, Shi S, Chen X. Boronate affinity-based surface molecularly imprinted polymers using glucose as fragment template for excellent recognition of glucosides. J Chromatogr A 2016;1474:8–13. https://doi.org/10.1016/j.chroma.2016.10.059.

Brownlee M, Cerami A. A glucose-controlled insulin-delivery system: Semisynthetic insulin bound to lectin. Science 1979;206(4423):1190–1. https://doi.org/10.1126/science.505005.

Yin R, Bai M, He J, Nie J, Zhang W. Concanavalin A-sugar affinity based system: Binding interactions, principle of glucose-responsiveness, and modulated insulin release for diabetes care. Int J Biol Macromol 2019;124:724–32. https://doi.org/10.1016/j.ijbiomac.2018.11.261.

Kawamura A, Hata Y, Miyata T, Uragami T. Synthesis of glucose-responsive bioconjugated gel particles using surfactant-free emulsion polymerization. Colloids Surf B Biointerfaces 2012;99:74–81. https://doi.org/10.1016/j.colsurfb.2011.10.008.

Park YS. Novel route of insulin delivery using an implant-mediated drug delivery system. Drug Deliv Transl Res 2017;7(2):286–91. https://doi.org/10.1007/s13346-016-0354-3.

Rieger C, Kurz K, Mueller-Hoffmann W, Gehr B, Liebl A. New design of a percutaneous port system for continuous intraperitoneal insulin infusion. J Diabetes Sci Technol 2019;13:1158–60. https://doi.org/10.1177/1932296819855425.

Taylor MJ, Tanna S, Sahota TS, Sawicka K. Closed loop glucose control of diabetic rats. J Pharmacy Pharmacol 2007;59(S1):A15.

Taylor MJ, Tanna S, Sahota T. In vivo study of a polymeric glucose-sensitive insulin delivery system using a rat model. J Pharm Sci 2010;99(10):4215–27. https://doi.org/10.1002/jps.22138.

Taylor MJ, Gregory R, Tomlins P, Jacob D, Hubble J, Sahota TS. Closed-loop glycaemic control using an implantable artificial pancreas in diabetic domestic pig (Sus scrofa domesticus). Int J Pharm 2016;500(1-2):371–8. https://doi.org/10.1016/j.ijpharm.2015.12.024.

Lin K, Yi J, Mao X, Wu H, Zhang L, Yang L. Glucose-sensitive hydrogels from covalently modified carboxylated pullulan and concanavalin A for smart controlled release of insulin. Reactive and Functional Polymers 2019;139:112–9. https://doi.org/10.1016/j.reactfunctpolym.2019.01.016.




DOI: https://doi.org/10.15277/bjd.2020.248

Refbacks

  • There are currently no refbacks.


The Journal of the Association of British Clinical Diabetologists