| Insulin formulation | Experimental model | Results | Reference | |
| Injectable | Insulinglargine 300 U/ml | Human studies (T2DM), randomized controlled trial | Less risk of nocturnal hypoglycaemia, with no increase in risk of daytime hypoglycaemia[vs. IGlar-100]. Similar extent of HbA1C control [IGlar-300 vs. IGlar-100]. | [12,13] |
| Insulin degludec | Human studies (T1DM, T2DM) | Better glycaemic control [vs. IGlar&IDet]. Less hypoglycaemic episodes, including nocturnal hypoglycaemia [vs. IGlar&IDet]. Flexibility in timing of doses. Non-inferior to IGlar in achieving HbA1C of 7%. May increase MACE risk. | [5,14-31] | |
| Linjeta™ (VIAject™) | Human studies (healthy, T1DM, T2DM | Faster onset [vs. human soluble insulin & LIS]. Less within-subject variability, less postprandial glycaemic excursions & oxidative stress, improved endothelial function [vs. RHI & LIS]. | [5,32-36] | |
| Artif icial pancreas | Delivery system involving CGM, CSII, and an algorithm (MPC) Using short- or ultrashort-acting insulin ± absorption enhancers | Human studies (T1DM) | A newer ‘smart’ MPC algorithm allows more accurate glycaemic control – faster response & less extreme glucose fluctuations [vs. PID algorithm]. Outpatient studies indicate CLC systems are safe & efficient for clinical practice. | [5,37-39] |
| Oral | Nanoparticle-based: CS & CS-derivatives, PLGA, acrylicbased, PLA, PCL, poly(allylamine), dextran, lipid-based (e.g. liposomes & SLNs), multi-layered NP | In vitro, in vivo (normal & diabetic mice/rats) | Improved absorption & bioavailability. Greater & prolonged hypoglycaemic effect. | [10] |
| Nanolayer encapsulation of insulin-CS complexes | In vitro, in vivo (STZ-induced diabetic mice) | Sustained-release of insulin. Improved insulin loading capacity [>90%], insulin stability, 74% less solubility at low pH [vs. non-encapsulated insulin]. Decreased fasting glucose levels by up to 50% [sustained &dosedependent]. Decreased postprandial hyperglycaemia, without risk of hypoglycaemia. | [40] | |
| Nanoparticulated insulin in multiple emulsion form | In vitro | Good release characteristics. Protectedinsulin at different pH levels. | [41] | |
| Insulin-loaded alginate/CS blend gel beads cross-linked by glutaraldehyde | In vitro | Greater stability in SGF & SIF. Reduced cumulative insulin release in SGF. Improved performance of gel beads in SIF | [42] | |
| IN-105 | Animal studies, human studies (Phase 2 trials) | Improved half-life & absorption. Lower immunogenicity &mitogenic effect. Similar pharmacological effect. Wide therapeutic window. Dose-dependent postprandial glycaemic effects. | [5,43,44] | |
| Buccal | Oral-lyn™ | Clinical trials (market available) | Dose-dependent absorption profile. Faster onset &shorter duration of action [vs. SC insulin]. | [5,45] |
| Insulin-coated NPloaded in ERL films | In vitro (EpiOral human buccal mucosa model) | Enhanced permeation through EpiOral model. | [46] | |
| Insulin-loaded NP embedded into CS films | In vitro (EpiOral human buccal mucosa model) | Enhanced permeation through EpiOral model by 1.8-fold [vs. pure insulin]. | [47] | |
| Insulin-bearing pelleted bioadhesive polymeric NP | In vivo (diabetic rats) | Significant hypoglycaemia after 7h. No risk of hypoglycaemia. | [48,49] | |
| Insulin in transferosome vesicles | In vivo (rabbits) | Improved insulin delivery [vs. conventional vesicles]. Relative pharmacological activity of 15.59% [vs. SC insulin]. | [48,50] | |
| Insulin + soybean lecithin + propanediol | In vivo (diabetic rabbits, diabetic rats) | Significant hypoglycaemic effect, lasting 4-5h. | [5,48,51] | |
| Insulin + PF-127 (containing unsaturated fatty acids) | In vivo (normal rats) | Improved insulin release with fatty acids. Continuous hypoglycaemia. Oleic acid showed best pharmacological availability of 15.9%. | [48,52] | |
| Insulin + lysalbinic acid | In vitro (hamster cheek pouch model) | Increased permeability to insulin. | [48,53,54] | |
| Pulmonary (inhaled) | Afrezza® | Clinical trials (market available) | Acceptable HbA1C reduction in T1DM when used pre-meals with another basal insulin, but less HbA1C reduction [vs. insulin aspart]. Greater HbA1C reduction in T2DM when used with other OHA [vs. placebo]. May cause bronchospasm in asthma & COPD. | [55] |
| Insulin microcrystals | In vivo (STZ-induced diabetic rats) | Prolonged hypoglycaemic effects over 7h. Addition of zinc increases hypoglycaemic effect [17% minimum reductions in blood glucose]. | [48,56,57] | |
| Insulin + HA dry powder + (Zn2+ or HPC) | In vivo (beagle dogs) | Addition of Zn2+& HPC improved mean residence time by >9-fold&>7-fold, respectively [vs. spray dried pure insulin]. | [48,58] | |
| Insulin + DPPC | In vivo (rats) | Greater hypoglycaemic effect [vs. insulin + liposome]. | [48,59] | |
| Insulin + (bacitracin, Span 85, or citric acid) | In vivo (rats) | Bacitracin & Span 85 improved insulin solution bioavailability to ~100% [not effective in dry powder forms]. Citric acid increased the hypoglycaemic effect, with bioavailabilities of 42-53% for dry powders. No acute toxicity to lung cells by citric acid. | [48,60] | |
| Insulin + (TDM or DMßCD) | In vivo (rats) | Relative bioavailabilities: [TDM] 0.34-0.84% [DMßCD] 0.19-0.48%. Both have reversible effects on respiratory epithelium [normalises 120min post-exposure]. | [48,61] | |
| Insulin + H-MAP | In vivo (rats) | Dose-dependent effect [maximum at 16mg/kg H-MAP & 1.3 U/kg insulin]. At maximum doses: relative bioavailability increased by>2.5-fold, maximum insulin concentration by 2-fold, blood glucosereductionby 2-fold [vs. same dose of insulin alone]. | [62] | |
| Insulin/liposome | In vivo (alloxan-induced diabetic rats) | Homogeneously distributed throughout lung. Increased drug retention times. Hypoglycaemic effect. | [48,63] | |
| Insulin-CAP-PEG particle suspensions | In vivo (rats) | Increased half-life & residence times [vs. insulin solution. Spray instillation was more efficient than intratracheal instillation. | [48,64] | |
| Insulin/PLGA nanospheres | In vivo (guinea pigs) | Substantial prolonged hypoglycaemic response over 48h[3.9 IU/kg insulin] [vs. 6h by aqueous insulin]. | [48,65] | |
| Insulin/PBCA NP | In vivo (healthy rats) | Improved bioavailability. Significant hypoglycaemic responses. Minimum blood glucose concentrations of 46.9/ 30.4/13.6% of initial levels for 5/10/20 IU/kg insulin in PBCA NP. | [48,66] | |
| Nasal | Insulin + alkylglycosides dodecylmaltoside, tridecylmaltoside, tetradecylmaltoside,ordodecylsucrose | In vivo (hyperglycaemic rats) | Improved insulin absorption. Rapid hypoglycaemic effects, maximum between 60-120min postadministration. Tetradecylmaltoside increases insulin absorption even when administered 15min before insulin. | [48,67,68] |
| Insulin + 0.5% sucrose cocoate | In vivo (rats) | Improved insulin absorption, with resulting hypoglycaemic effects. | [69] | |
| Insulin + carbopol-based gel | In vivo (rabbits) | Significant hypoglycaemic effect. Relative bioavailability of 20.6% [vs. IV insulin]. | [48,70] | |
| Insulin + 2% CS gel + EDTA | In vivo (diabetic rabbits) | Improved insulin absorption. Hypoglycaemic effect up to 46% of that caused by IV insulin. | [48,71] | |
| Insulin/CS microspheres 400mg CS + 70mg ascorbylpalmitate (as cross-linker) | In vivo (diabetic rats) | Absolute bioavailability of 44%. 67% decrease in blood glucose [vs. IV insulin] | [48,72] | |
| Insulin + AGMS | In vivo (rats) | Insulin released slower from AGMS [cumulative release of 18.4% within 30min, 56.9% within 8h], compared to GMS [cumulative release of 32.4% within 30min, 75.1% within 8h]. AGMS increased nasal insulin absorption significantly when given in dry powder form | [48,73] | |
| Insulin/CS-TBA microparticles + reduced glutathione (permeation mediator) | In vivo (rats) | Controlled-release of insulin over 6h. Absolute bioavailability of 7.24%[higher than using unmodified CS]. | [48,74,75] | |
| Insulin/PEGylated TMC NC | In vivo (rats) | Reduced blood glucose levels by 34-47%. Less toxic on nasal epithelium [vs. non-PEGylated]. | [76] | |
| Insulin/NC Amine-modified poly(vinyl alcohol)- graft-poly(L-lactide) | In vivo (healthy & STZinduced diabetic rats) | 50% decreaseinblood glucose within 50-80min [fasted healthy rats]. 30% decrease in blood glucose within 75-95min [STZ-induced diabetic rats]. No histological evidence of nasal mucosal damage 4h postadministration. | [77] | |
| Insulin/p(LAMA-r-AAPBA) NP | In vitro & in vivo (diabetic rats) | Modification of glycopolymers affects insulin release. Good cytocompatibility. NP internalisation via clathrin- &lipid raft/caveolae-mediated endocytosis. Significant hypoglycaemic effect. | [78] | Ocular | Insulin solution + (POELE, NaGC, NaTC, or NaDC) | In vivo (albino rabbits) | Bioavailability ranging from 3.6-12.6% [vs. 0.7-1.3% without absorption enhancers]. | [48,79] |
| Insulin solution + alkylglycosides tetradecylmaltoside,tridecylmaltoside, dodecylmaltoside, or dodecylsucrose | In vivo (rats) | Improved insulin absorption, at =0.125% conc. [vs. NaGCrequiring = 0.5% conc.]. | [48,80] | |
| Insulin + (fusidic acid or GC) | In vivo (rabbits) | Improved insulin absorption, especially at higher pH [pH 8 vs. pH 3.5]. | [81] | |
| Insulin + absorption enhancer saponin, POELE, Brij-78, fusidic acid, dodecylmaltoside, or tetradecylmaltoside | In vivo (healthy cats, healthy dogs) | Improved insulin absorption, with resulting hypoglycaemic effects [vs. native insulin]. | [48,82,83] | |
| Insulin-loaded liposomes | In vivo (healthy rabbits) | Significant hypoglycaemic effects 90-120min post-administration. | [84] | |
| Gelfoam® ocular insert containing insulin | In vitro & in vivo | Significant prolonged insulin delivery. Improvement in insulin activity & prolonged duration of action with the addition of Brij-78. No risk of hypoglycaemia. Return to near normoglycaemia 60min after device removal. 5% acetic acid or 1% HCl improved insulin absorption without enhancers. | [48,85-89] | |
| Rectal | Suppositories containing 50U insulin + DCA + NaTC + polycarbophil | In vivo (alloxan-induced hyperglycemic rabbits) | Relative hypoglycaemia of 38% [DCA], 34.9% [NaTC], 44.4% [DCA+NaTC], 56% [DCA+NaTC+polycarbophil] [vs. 40U SC insulin]. ~50% of the efficacy of SC insulin. | [48,90] |
| Suppositories (Witepsol W35 base) containing 5U/kg insulin + (50mg sodium salicylate or 1% POELE) | In vivo (diabetic beagle dogs) | Improved insulin absorption. Relative hypoglycaemia of 49-55% [vs. 4U/kg SC insulin]. | [48,91] | |
| Suppositories (Witepsol W35 base) containing 5U/kg insulin + (NaDC+NaC, NaTDC, or NaTC) | In vivo (diabetic beagle dogs) | Relative hypoglycaemia of ~50% [vs. SC insulin]. Adjusting insulin dose allows desirable hypoglycaemic effectaccordingto degree of hyperglycaemia. | [48,92] | |
| Insulin-CS gel + 5% DMßCD | In vivo (rabbits) | Prolonged insulin release. Maximum hypoglycaemic effect in insulin-CS gel + 5% DMßCD. Improves transvaginal insulin delivery as well. | [93] | |
| Suppositories containing 100U insulin + 200mg sodium salicylate | Human studies (healthy, T1DM) | Hypoglycaemic effects by 15min, lasting up to 90min postadministration | [94] | |
| Suppositories containing 200U insulin + 100mg NaC | Human studies (healthy, T1DM) | Maximum of 47.7% reduction in blood glucose levels at 90min postadministration [vs. 50.6% with 20U SC insulin]. Prevented significant postprandial rise in blood glucose in T1DM patients. | [95] | |
| Thermo-reversible insulin liquid suppository 100 IU/g insulin, 15% poloxamer P407, 20% poloxamer P188, 0.2% polycarbophil, and 10% sodium salicylate | In vivo (STZ-induced diabetic rats) | Improved insulin bioavailability Easy to deliver, painless, safe, remained at site of administration. | [48, 96] | |
| Mucoadhesive glycerol-gelatin suppository containing insulin + 7% snail mucin | In vivo(rats) | Sustained-release of insulin. 66% reduction of blood glucose levels within 2hpost-administration. | [48, 97] | |
| Transdermal | Insulin-loaded microemulsions Oleic acid as oil phase, Tween 80 as surfactant, isopropyl alcohol as cosurfactant | In vitro (goat skin) | Formulation of 10% oleic acid, 38% aqueous phase, 50% surfactant phase with 2% DMSO as permeation enhancer showed maximum permeation fluxthrough goat skin | [98] |
| Transferosomal gel containing insulin | In vitro (porcine ear skin), in vivo (diabetic rats) | Skin permeation followed zero-order kinetics. Prolonged hypoglycaemic effect [>24h]. | [99] | |
| Amidated pectin hydrogel matrix containing insulin | In vivo (diabetic rats) | Delivery of physiologically relevant amounts of insulin, with pharmacological activity. | [100] | |
| Insulin emulgel carbomer or HPMC (gelling agent) + polysorbate 80 (emulsifier) + emu oil (absorption enhancer) | In vitro & in vivo (albino rabbits) | Hypoglycaemic effect 250 to 185mg/dl at 120min.Adding iontophoresisincreasedhypoglycaemic effect [250 to 125mg/dl at 120min]. | [101] | |
Abbreviations:
T2DM: Type 2 Diabetes Mellitus; IGlar: Insulin Glargine; IGlar-300: Insulin Glargine 300 U/ml; IGlar-100: Insulin Glargine 100 U/ml; T1DM: Type 1
Diabetes Mellitus; IDet: Insulin Detemir; HbA1C: glycated haemoglobin; MACE: Major Adverse Cardiovascular Events; LIS: Insulin Lispro; RHI: Regular Human Insulin;
CGM: Continuous Glucose Monitoring; CSII: Continuous Subcutaneous Insulin Infusion; MPC: Model-Predictive Control; PID: Proportional-Integral-Derivative; CLC:
Closed-Loop Control; NP: Nanoparticles; CS: Chitosan; PLGA: Poly(lactide-co-glycolide); PLA: Poly(lactide); PCL: Poly(e-caprolactone); SLN: Solid-Lipid Nanoparticles;
STZ: Streptozotocin; SGF: Simulated Gastric Fluid; SIF: Simulated Intestinal Fluid;SC: Subcutaneous; ERL: Trimethylammonioethyl Methacrylate Chloride, Eudragit®
RLPO; OHA: Oral Hypoglycaemic Agents; COPD: Chronic Obstructive Pulmonary Disease; PF-127: Pluronic F-127; EDTA: Ethylenediaminetetraacetic Acid; AGMS:
Aminatedgelatin Microspheres; GMS: Gelatinmicrospheres; CS-TBA: Chitosan-4-Thiobutylamidine; PEG: Poly(ethylene) Glycol; TMC: Trimethyl Chitosan; NC:
Nanocomplexes; p(LAMA-r-AAPBA): Poly(2-lactobionamidoethyl methacrylate-random-3-acrylamidophenylboronic acid); HA: Hyaluronic Acid; Zn2+: Zinc Ions; HPC:
Hydroxypropyl Cellulose; DPPC: 1,2-Dipalmitoyl Phosphatidylcholine; TDM: Tetradecyl-ß-maltoside; DMßCD: Dimethyl-ß-cyclodextrin; H-MAP: Hydroxy-Methyl-
Amino-Propionic Acid; PLGA: Poly(lactide-co-glycolide); PBCA: Polybutylcyanoacrylate; POELE: Polyoxyethylene-9-lauryl Ether; NaGC: Sodium Glycocholate; NaTC:
Sodium Taurocholate; NaDC: Sodium Deoxycholate; GC: Glycocholate; Brij-78: Polyoxyethylene-20-stearyl ether; HCl: Hydrochloric Acid; DCA: Deoxycholic Acid;
NaTC: Sodium Taurocholate; NaDC: Sodium Deoxycholate; NaC: Sodium Cholate; NaTDC: Sodium Taurodeoxycholate; DMSO: Dimethyl Sulfoxide; CAP: Calcium
Phosphate; PEG: Polyethylene Glycol; HPMC: Hydroxypropyl Methylcellulose.