Introduction: oral insulin has always fascinated scientists. History of

Introduction:Although insulin remains the single therapy toachieve glucose control in most patients with type-2 diabetes mellitus (T2DM) andall type-1 diabetes mellitus (T1DM) patients, for many patients and providers,it remains a last resort, with enormous negative connotations. Most currentlyavailable insulin are tailor-made for either subcutaneous or itravenous routes.So, a quest for relatively non-invasive routes of insulin delivery was alwayson.1 In general, the oral dosage form is the most preferable,convenient, easiest and safest route for drug delivery. Moreover, this route ofadministration closely mimics the physiological secretion of insulin.

So,developing oral insulin has always fascinated scientists.History of oralinsulin- the milestones: The concept of oral insulin is such a lucrative idea that attempts to create this panacea was started since 1922.2 In between the years of 1923-24 oral insulin was ?rst trialed, although with poor results.

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3,4 In 1965 first patent of oral insulin was won by Edgar Ferguson.5 First scientific publication of oral insulin formulation came out in 1981.6 In 2000 the first clinical trial with oral insulin was attempted.

7 In 2004 scientific paper regarding oral insulin with culture in vitro cell models was published.8 In 2014 FDA approved Phase III clinical trial of an oral insulin.9 Despite the limited success of these routes, the desirability of oral insulin encourages the continuation of research.Potential ClinicalBenefits of Oral Insulin:An oral route of insulin delivery bearsphysiologic implications. At the present time, evidence suggesting the possible advantages of oralinsulin10-12 can mostly be inferred from data generated from studieswith intraperitoneal13-20 and intraportal insulins21,which follow a similar route of absorption through the portal vein, and morerecently, hepato-preferential insulins22-24.1.

     Protection againstdiabetic hyperglycemia:- Sufficient hepaticinsulinization is indispensably needed to suppresshepatic glucose production and to reduce both fasting and postprandialhyperglycemia.25 Currently available parenteral insulin isabsorbed directly into the peripheral circulation without initial hepaticextraction, and fails to restore the portal-peripheral insulin gradient andphysiologic hepatic insulinization. An oral insulinproduct is predicted to have therapeutic advantages in the management ofhepatic glucose production, via its potential to mimic the natural routeof endogenous insulin secreted by the pancreas. After reaching the portal vein,the oral insulin is directly delivered to the liver and then to the peripheralcirculation, thereby reestablishing the physiologic portal–peripheral insulingradient and providing for adequate hepatic insulinization.262.     Reducing the risk ofhypoglycemia:- When injected insulin is administered, it gets distributedevenly throughout the body. On the other hand, secreted insulin displays acutepeaks (almost ~400 times higher) in the islets compared with the systemic concentration.27By a paracrine action, insulin secreted from ?-cells reciprocally regulates?-cell to secrete glucagon, and thus generating the insulin/glucagon ratio tomaintain optimal glycemic level.

28 Insulin injected in systemiccirculation can’t reach the islet cells and suppress glucagon and thus, exposes patients tohypoglycemia. However, the desired insulin/glucagon ratio can be achieved by increasing the insulin concentration in the portalvein.29 There are evidences that such a strategy can significantlyreduce the occurrence of hypoglycemic events.30,313.     Mitigating the risk ofglycaemic variability:- Glycemicvariability is an independent risk for diabetic complications.32 In fact,glycemic variability imposes greater risk on long term outcomes among diabeticsthan persistent hyperglycaemia.33 Studies on direct portaladministration of insulin and oral insulin have demonstrated significant attenuationof glycemic swings.34,35 4.

     Mitigating the risk ofweight gain:- One of the major adverse effects of parenteral insulin therapyis weight gain.36 Systemic hyperinsulinemia resulting from non-physiologicroute of insulin administration leads to a disproportional anabolic effect onmuscle and adipose tissue.37 Weight gain due to insulin therapyfurther accentuates insulin resistance.38 Adequate hepatic insulinizationwithout systemic hyperinsulinization, achieved by means of sulfonylureas,39peritoneally delivered insulin,40 or with hepatoselective insulin,41is associated with weight loss. These indirect evidences that the route ofinsulin delivery has a strong bearing on weight control.5.

     Effect on GH–IGF1–IGFBP axis:- Insulin increases the sensitivity of the liver to growth hormone(GH) by upregulating GH receptor expression and increasing insulin-like growthfactor-1 (IGF-1) production. It also downregulates IGF binding protein-1(IGFBP-1) production in the liver, thereby further augments circulating IGF-1bioactivity.42,43 Thus, in diabetes portal insulinopenia isimplicated in perturbations in GH bioactivity, leading to worsening glucoseintolerance and lipid metabolism.44 Administering insulin bycontinuous intraperitoneal insulin infusion (CIPII)45 orintraportally46 have beneficial effects on the GH– IGF1–IGFBP axis comparedto subcutaneously.6.     Effect on sex steroidbioactivity:- T1DM patients have a higher risk for hypogonadism, asreflected by lower free testosterone and higher steroid hormone bindingglobulins (SHBG) levels.47,48 In T2DM, a reduction in totaltestosterone and free testosterone, is observed.49 Portal insulinhas been shown to downregulate SHBG, independent of glycemic status.

50,517.     Attenuating the mitogeniceffects of systemic hyperinsulinemia:- Parenteral routes expose peripheral targetsto greater insulin concentrations relative to the liver, predisposing patients to thedeleterious effects of hyperinsulinemia which may trigger deleteriousoverstimulation of growth, cell division and other metabolic responses.528.     Protection of ? cells of thepancreas from autoimmune destruction:- Oral insulin plays a signi?cant role in protection of ?cells of the pancreas from autoimmune destruction.53,54 From findings from animal study, it has beenhypothesized that oral insulin might generate induction of oral tolerance orimmune modulating effect which is likely to help in prevention of diabetes. ThePre-POINT study, a phase1/2clinical pilot study done among children at high risk for T1DM, daily oral administration of 67.5mg of insulin, comparedwith placebo, resulted in an immune response without hypoglycemia.54 Unfortunatelya recent RCT refuted the idea of administering oral insulin among subjects withhigh risk for developing T1DM.

559.     Better quality of life:- The most lucrativeaspect from patients’ point of view is oral insulin therapy might improve theirquality of life.2 Oral insulin is devoid of the apprehension and distress associated withinsulin injections. The convenience of an oral pill might improve patient compliance to insulin therapy and thusachieving better metabolic control. Barriers to deliveryof oral insulin and strategies to overcome them:Insulin is not an easy choice to get absorbedvia enteral route due its physico-chemical properties and the hostile environmentof gastrointestinal tract.

56A.    Insulin’s physico-chemical characteristics: because of itsenzymatic instability, tendency to aggregate, hydrophilicity and high molecularweight (5808 Da) hinder its intestinal absorption, posing a challenge for itsoral delivery.57B.     Existing barriers57 could be categorized into three main sub- types, namelyphysical, biochemical and formulation-based.

1.     Physical barriers:i)                   Mucous layerii)                 Intestinal epitheliumiii)               Tight junctions2.     Biochemical barriers:i)                   Luminal pHii)                 Enzymatic degradation3.     Formulation barrier: The fabricationmethod could be the last barrier in formulation of peptide drugs. Being asensitive polypeptide hormone and any conformational changes to insulinstructure would affect its biological activity.

58The suggested strategies trialed for oral insulindelivery are-1.      PEGylation technique: The covalent attachment of polyethyleneglycol (PEG) to therapeutic peptides is called PEGylation. It has been used todecrease the rate of clearance and improve the pharmacological and biologicalproperties of peptides and eliminates the immunogenicity, allergenicity andantigenicity of insulin if compared with unmodi?ed subcutaneous insulin.59PEGylation techniquewas employed by NOBEX Corporation worked on the same principal to develop hexylinsulin mono-conjugate-2 (HIM2).

HIM2 showed increased solubility, absorption,good stability against enzymatic degradation.60 Although oralbioavailability of HIM2 was still 5%, it showed efficacy in both type I and typeII diabetic patients.61,62 Biocon, an Indian pharmaceutical companydeveloped the oral insulin candidate (IN-105) as a second- generation tablet.63,64IN-105 showed an improved stability pro?le in enteral route and enhancedabsorption. In comparison with normal insulin, it had lower immunogenicity,lower mitogenicity and the same pharmacological action.652.      Eligen technology: Emisphere’s Eligen technology employs non-covalentinteraction of the novel drug-carrier molecule monosodiumN-(4-chlorosalicyloyl)-4-aminobutyrate (4-CNAB) with insulin.66 4-CNABis organic/lipophilic in nature, thus expected to improve the lipophilicity ofinsulin and facilitates passive transcellular diffusion.

Despite the relativefast absorption rate obtained from the pharmacokinetic data, Emisphere did notshow a satisfactory bioavailability even in the presence of the large amount ofcarriers needed per dose.67,68 Acomparative proof-of-concept study69 comparing between subcutaneoushuman regular insulin and oral insulin tagged with (4-CNAB) showed that maximuminsulin concentration was greater and onset of action was faster with oralinsulin in fasting conditions, but higher between-subject variability inabsorption was a concern (relative bioavailability 7 +4%).3.      Receptor-mediated endocytosis: This principle has been adopted by AccessPharmaceuticals to develop CobOral, a peptide-loaded dextran nanoparticlecoated with cobalamin. Similarly, Apollo Life has developed Oradell, a carbohydrate-basednanoparticle coated with vitamin B12.70 Insulin, coatedwith vitamin B12-tagged dextran nanoparticles showed signi?cantprolonged hypoglycaemic effect in a streptozocin-induced diabetic rat model.714.

      Cell-penetrating peptides (CPPs):  In vitro studyinvolving a CPP, called HIV-1 transactivator of transcription (TAT) showed signi?cant improvement of thetransport of insulin/TAT conjugate across Caco-2 cells.725.      Nanoparticles of chitosan: Signi?cant protection of insulin encapsulatedwith chitosan against enzymatic degradation, and such nanoparticles were ableto cross the epithelium through Peyer’s patches.736.      Protease inhibitors: Although Iinsulin is degraded by trypsin, ?-chymotrypsinand carbxypeptidases, a speci?c insulin-degrading enzyme (IDE) on thebrush-border membrane is found.74 Although a potent IDE inhibitor(6bK) did not improve oral insulin delivery, IDE inhibition was associated withincreased amylin levels, which in turn slows the gastric emptying rate andimproves glucose tolerance.75 Co-administration of Na-glycocholate, aprotinin,bacitracin, soya bean trypsin inhibitor and camostat mesilate with insulindirectly into isolated intestines of normal rats showed improvement of thebioavailability of insulin.

The effect was more predominant in the largeintestine than the small intestine.76 Chicken ovomucoid and duckovomucoid also showed protective effect against degradation of insulin bytrypsin and ?-chymotrypsin.777.      Absorption enhancers/permeation enhancers (PEs): PEs are a group ofagents that promote absorption of therapeutics through perturbing the cellmembrane to improve transcellular transport or by selective action on tightjunctions to enhance paracellular permeability.78 Bile salts,ethylene diamine tetraacetic acid, surfactants, fatty acids and zonulaoccludens toxin (ZOT) are examples of permeation enhancers commonly used toimprove oral peptide bioavailability.

78 In-vivo result showed thatZOT increased insulin oral absorption 10-fold from rabbit ileum and jejunum andno effect was observed in colon.798.      Site-speci?c delivery: Low level of luminal and brush-borderproteases compared to duodenum and jejunum has made the colon an interestingtarget to circumvent harsh gastric conditions. Polyacrylic-coated gelatincapsules loaded with insulin showed signi?cant drop in the blood glucose levelcompared to intraperitoneal injection.

80 A colon-speci?c drugdelivery system, CODES incorporated the hormone with meglumine (a pH adjuster),citric acid (insulin solubilizer), Na-glycocholate (a permeation enhancer)along with polyethylene oxide. CODES showed sustained release of insulin in thecolon of dogs.81,82 Capsulin is an enteric-coated capsule loadedwith dry powder mixture of insulin, permeation enhancer and solubilizer.83It showed good gastric stability, reasonable safety pro?le with well-toleratedstatistically signi?cant hypoglycaemia.84 Oramed PharmaceuticalsInc. developed Protein Oral Delivery (POD) technology, which employed athree-pronged approach composed of encapsulation, protease inhibitors and a chelatingagent.

85 In subjects with T1DM, Oramed’s oral insulin has been shownto reduce postprandial glucose concentrations,86 and when administeredpreprandially, it reduces both fasting blood glucose levels and the requirementfor fast-acting insulin doses.87 In another system insulin  was incorporated in the core which was eitherattached to or embedded in the enteric-coated shuttle or conveyor of superporoushydrogel (SPH) and superporous hydrogel composite (SPHC) targeting proteins toa speci?c site of the intestine.88 Interpenetrating polymericnetworks of superporous hydrogels (SPH-IPNs) have been trialed to estimateinsulin transport across rat intestine and colon. No conformational changes toinsulin or alterations to its oral bioactivity was observed using SPH-IPNsfollowing administration to healthy animals.89 When it was comparedto the subcutaneous route, insulin-loaded SPH-IPNs delivery system achievedaround 4% pharmacological availability.

909.      Mucoadhesive and mucopenetrative systems: The mucoadhesiveproperties of some polymers prolongs the residence time of the drug at itsabsorption site.91Chitosan-4-thiobutylamidine insulin-loaded tablets showed controlled release innon-diabetic rats for over 8 hours.92 Mucuspenetration is another technology introduced to overcome the dynamic upstreammucus barrier.93-95 N-(2-hydroxypropyl methacrylamide (HPMA), a hydrophilicmucus inert polymer having mucus penetration characteristics was used to coatmucoadhesive insulin-loaded N-trimethyl chitosan (Ins-TMC) nanocarriers.

Uponoral administration to diabetic rats, remarkable hypoglycaemia was noted.9110.  Hydrogels: Hydrogels, with good insulin encapsulation efficiency96like cross-linked poly-(N-isopropyl acrylamide)-methacrylic acid-hydroxy ethylmethacrylate (NIPAAm- MAA-HEM) are able to prevent insulin release in thestomach. As the pH increases toward the small intestine, insulin is releasedfrom the hydrogel.97 Methyl-?-cyclodextrin complexed insulinencapsulated in the polymethacrylic acid- PEG-chitosan hydrogel microparticlesled to a better pharmacological response in diabetic animals compared withmicroparticles containing original insulin.98 11.

  Particulate carrier system: Formulations of drugs with colloidalparticulate carriers such as submicroemulsion, lipid suspension, liposomes,polymeric microparticles and nanoparticles and polymeric micelles are used toimprove peptide drug delivery.Insulin-loaded chitosan phthalate microsphere formulation,having improved oral bioavailability was found to lower the plasma glucoselevel at the prediabetic level.99 Another novel solid-in-oil-in-water(S/O/W) emulsion has been used to encapsulate insulin and showed apH-responsive release pattern mimicking gastroenteric niche.

Microemulsions entrappinginsulin showed 10-fold improvement in bioavailability compared to plain insulinsolution upon oral administration to healthy rats.100 A liposomalinsulin formulation known as hepatic direct vesicle insulin (HDV-I) has beensuccessfully delivered orally.101 Combined use of thiolated chitosanand self-nanoemulsifying drug delivery systems (SNEDDS) to produce nanospheres resultedin signi?cantly improved release pro?le, increased serum insulin level and remarkablehypoglycaemia.102,103 A novel SNEDDS was developed based uponhydrophobic ion pair of insulin with dimyristoyl phosphatidylglycerol (DMPG) toform insulin/DMPG complexes which had improved permeation characteristic, providedprotection from gastroenteral enzymes and prevented initial burst release ofinsulin.104 Results with polymer-based nanoparticles for oralinsulin delivery have showed promising results. For this purpose, eithernatural (gold105, gelatin, casein, chitosan, alginate, dextran,starch and pectin106) or synthetic polymers (polylactic acid, polylacticco-glycolic acid and poly ?-caprolactone)107 have been employed. Recent advancements: ·        Mucoadhesiveintestinal insulin device: A combination of intestinal devices, a permeation enhancer withpH-responsive enteric coating has shown to adhere to porcine intestinal mucosa,release their protein load unidirectionally, and prevent enzymatic degradationin the gut.

It has decreased blood glucose levels by 30 and 33% in diabetic andnondiabetic rats, respectively.108·        Intestinal insulin micropatch: Study has shown that intestinalmicropatches can adhere to the intestinal mucosa, release their drug loadrapidly within 30?min and are effective in lowering blood glucose levels (up to34%) in vivo.109 ·        Self-assembled polyelectrolyte complex nanoparticles:  Insulin-loaded dodecy-lamine-graft-?-polyglutamic acid micelles were developed and cross-linked withtrimethyl chitosan (TMC) in the form of nanoparticle complex. To improve theiraf?nity for the intestinal epithelium goblet cell targeting modification wasdone. Oral administration of this targeted nanoparticle had a relativebioavailability of 7.05% with prolonged hypoglycaemia in diabetic rats.

110·        Emergence of Seleniumnanoparticles as carriers for oral delivery of insulin: Insulin-loadedselenium nanoparticles were formulated by ionic cross-linking reductiontechnique. The produced Insulin-loaded Selenium nanoparticles(INS-SeNPs)had good insulin encapsulation ef?ciency, outstanding gastric stability and remarkablehypoglycaemic effect. The study also suggested that Selenium could potentiatethe antidiabetic effect of insulin, might alleviate diabetes-associatedoxidative stress and improve pancreatic ?-cell functions.111Data from Clinicaltrials and current status:The small number of clinical trials incomparison with published preclinical studies indicates that oral insulin isstill battling to move on from clinical testing.112,1131.     OramedORMD-0801 Entericcoating and absorption enhancersCompleted Phase IIa inT1DM; completed Phase IIb in T2DM; approved by US FDA for Phase IIb2.

     BioconIN-105 Chemicalmodification of insulin with a small PEG and penetration enhancersPhase III in T2DMfailed to clear the primary end point; planned Phase I and II studies incollaboration with Bristol Myers Squibb3.     NovoNordisk – MerrionNN1953, NN1954, NN1956Absorption enhancersthat activate micelle formationCompleted Phase I;planned Phase IIa4.      NovoNordisk – Emisphere EligenPenetration enhancers– salcaprozate sodiumPhase II in T2DM5.     DiabetologyCapsulinEnteric coating,absorption enhancers and a solubiliserCompleted Phase IIa inT1DM and Phase II in T2DM6.     Oshadi drug administrationOshadi oral insulinEnteric capsules withinsulin blended with silica nanoparticles and a polysaccharide suspended in oilCompleted Phase II inT1DM7.     DiasomeHDV-ILiposomes with hepatictargetingCompleted Phase II inT1DM and T2DM; approved by FDA for Phase IIIConclusion:Given thevaried heterogenous pathophysiology of diabetes, it is unlikely that any singledrug or delivery method will meet the needs of all patients.

So, oral insulin,if at all can be produced in clinically useful form, need be optimallypositioned to address the specific pathophysiologic aspects of glucoseintolerance.Even after relentless research obstacles for clinicallyeffective oral insulin remains because of  poor scale-up possibility, bad reproducibilityof particle production, no framed algorithm to predict the large-scale performanceof a product based on its small-scale behavior and high cost-benefit.112Food-drug interaction, which is an important subject as far as insulin’sbioavailability is concerned, is yet to be explored.114 Moreover,considerations and surveillance of the effects of the large amounts of unabsorbedinsulin, a growth factor with mitogenic potential115,116 and a recognizedmodulator of gastrointestinal physiology117 will be required tounfurl its safety on long-term use.