Table 2: Newer insulin formulations and details of their respective experimental results

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]
LinjetaÖ (VIAjectÖ) 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 Ĺsmartĺ MPC algorithm allows more accurate glycaemic control ľ 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-lynÖ 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 DM▀CD) In vivo (rats) Relative bioavailabilities: [TDM] 0.34-0.84% [DM▀CD] 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% DM▀CD In vivo (rabbits) Prolonged insulin release. Maximum hypoglycaemic effect in insulin-CS gel + 5% DM▀CD. 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-▀-maltoside; DM▀CD: Dimethyl-▀-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.