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Introduction: oral insulin has always fascinated scientists. History of

Introduction:

Although insulin remains the single therapy to
achieve glucose control in most patients with type-2 diabetes mellitus (T2DM) and
all type-1 diabetes mellitus (T1DM) patients, for many patients and providers,
it remains a last resort, with enormous negative connotations. Most currently
available insulin are tailor-made for either subcutaneous or itravenous routes.
So, a quest for relatively non-invasive routes of insulin delivery was always
on.1 In general, the oral dosage form is the most preferable,
convenient, easiest and safest route for drug delivery. Moreover, this route of
administration closely mimics the physiological secretion of insulin. So,
developing oral insulin has always fascinated scientists.

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History of oral
insulin- 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.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 Clinical
Benefits of Oral Insulin:

An oral route of insulin delivery bears
physiologic implications. At the present time, evidence suggesting the possible advantages of oral
insulin10-12 can mostly be inferred from data generated from studies
with intraperitoneal13-20 and intraportal insulins21,
which follow a similar route of absorption through the portal vein, and more
recently, hepato-preferential insulins22-24.

1.     
Protection against
diabetic hyperglycemia:- Sufficient hepatic
insulinization is indispensably needed to suppress
hepatic glucose production and to reduce both fasting and postprandial
hyperglycemia.25 Currently available parenteral insulin is
absorbed directly into the peripheral circulation without initial hepatic
extraction, and fails to restore the portal-peripheral insulin gradient and
physiologic hepatic insulinization. An oral insulin
product is predicted to have therapeutic advantages in the management of
hepatic glucose production, via its potential to mimic the natural route
of endogenous insulin secreted by the pancreas. After reaching the portal vein,
the oral insulin is directly delivered to the liver and then to the peripheral
circulation, thereby reestablishing the physiologic portal–peripheral insulin
gradient and providing for adequate hepatic insulinization.26

2.     
Reducing the risk of
hypoglycemia:- When injected insulin is administered, it gets distributed
evenly throughout the body. On the other hand, secreted insulin displays acute
peaks (almost ~400 times higher) in the islets compared with the systemic concentration.27
By a paracrine action, insulin secreted from ?-cells reciprocally regulates
?-cell to secrete glucagon, and thus generating the insulin/glucagon ratio to
maintain optimal glycemic level.28 Insulin injected in systemic
circulation can’t reach the islet cells and suppress glucagon and thus, exposes patients to
hypoglycemia. However, the desired insulin/glucagon ratio can be achieved by increasing the insulin concentration in the portal
vein.29 There are evidences that such a strategy can significantly
reduce the occurrence of hypoglycemic events.30,31

3.     
Mitigating the risk of
glycaemic variability:- Glycemic
variability is an independent risk for diabetic complications.32 In fact,
glycemic variability imposes greater risk on long term outcomes among diabetics
than persistent hyperglycaemia.33 Studies on direct portal
administration of insulin and oral insulin have demonstrated significant attenuation
of glycemic swings.34,35

4.     
Mitigating the risk of
weight gain:- One of the major adverse effects of parenteral insulin therapy
is weight gain.36 Systemic hyperinsulinemia resulting from non-physiologic
route of insulin administration leads to a disproportional anabolic effect on
muscle and adipose tissue.37 Weight gain due to insulin therapy
further accentuates insulin resistance.38 Adequate hepatic insulinization
without systemic hyperinsulinization, achieved by means of sulfonylureas,39
peritoneally delivered insulin,40 or with hepatoselective insulin,41
is associated with weight loss. These indirect evidences that the route of
insulin 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 growth
factor-1 (IGF-1) production. It also downregulates IGF binding protein-1
(IGFBP-1) production in the liver, thereby further augments circulating IGF-1
bioactivity.42,43 Thus, in diabetes portal insulinopenia is
implicated in perturbations in GH bioactivity, leading to worsening glucose
intolerance and lipid metabolism.44 Administering insulin by
continuous intraperitoneal insulin infusion (CIPII)45 or
intraportally46 have beneficial effects on the GH– IGF1–IGFBP axis compared
to subcutaneously.

6.     
Effect on sex steroid
bioactivity:- T1DM patients have a higher risk for hypogonadism, as
reflected by lower free testosterone and higher steroid hormone binding
globulins (SHBG) levels.47,48 In T2DM, a reduction in total
testosterone and free testosterone, is observed.49 Portal insulin
has been shown to downregulate SHBG, independent of glycemic status.50,51

7.     
Attenuating the mitogenic
effects of systemic hyperinsulinemia:- Parenteral routes expose peripheral targets
to greater insulin concentrations relative to the liver, predisposing patients to the
deleterious effects of hyperinsulinemia which may trigger deleterious
overstimulation of growth, cell division and other metabolic responses.52

8.     
Protection of ? cells of the
pancreas 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 been
hypothesized that oral insulin might generate induction of oral tolerance or
immune modulating effect which is likely to help in prevention of diabetes. The
Pre-POINT study, a phase1/2
clinical pilot study done among children at 
high risk for T1DM, daily oral administration of 67.5mg of insulin, compared
with placebo, resulted in an immune response without hypoglycemia.54 Unfortunately
a recent RCT refuted the idea of administering oral insulin among subjects with
high risk for developing T1DM.55

9.     
Better quality of life:- The most lucrative
aspect from patients’ point of view is oral insulin therapy might improve their
quality of life.2 Oral insulin is devoid of the apprehension and distress associated with
insulin injections. The convenience of an oral pill might improve patient compliance to insulin therapy and thus
achieving better metabolic control.

Barriers to delivery
of oral insulin and strategies to overcome them:

Insulin is not an easy choice to get absorbed
via enteral route due its physico-chemical properties and the hostile environment
of gastrointestinal tract.56

A.    Insulin’s physico-chemical characteristics: because of its
enzymatic instability, tendency to aggregate, hydrophilicity and high molecular
weight (5808 Da) hinder its intestinal absorption, posing a challenge for its
oral delivery.57

B.     Existing barriers57 could be categorized into three main sub- types, namely
physical, biochemical and formulation-based.

1.     
Physical barriers:

i)                   
Mucous layer

ii)                 
Intestinal epithelium

iii)               
Tight junctions

2.     
Biochemical barriers:

i)                   
Luminal pH

ii)                 
Enzymatic degradation

3.     
Formulation barrier: The fabrication
method could be the last barrier in formulation of peptide drugs. Being a
sensitive polypeptide hormone and any conformational changes to insulin
structure would affect its biological activity.58

The suggested strategies trialed for oral insulin
delivery are-

1.      PEGylation technique: The covalent attachment of polyethylene
glycol (PEG) to therapeutic peptides is called PEGylation. It has been used to
decrease the rate of clearance and improve the pharmacological and biological
properties of peptides and eliminates the immunogenicity, allergenicity and
antigenicity of insulin if compared with unmodi?ed subcutaneous insulin.59
PEGylation technique
was employed by NOBEX Corporation worked on the same principal to develop hexyl
insulin mono-conjugate-2 (HIM2). HIM2 showed increased solubility, absorption,
good stability against enzymatic degradation.60 Although oral
bioavailability of HIM2 was still 5%, it showed efficacy in both type I and type
II diabetic patients.61,62 Biocon, an Indian pharmaceutical company
developed the oral insulin candidate (IN-105) as a second- generation tablet.63,64
IN-105 showed an improved stability pro?le in enteral route and enhanced
absorption. In comparison with normal insulin, it had lower immunogenicity,
lower mitogenicity and the same pharmacological action.65

2.      Eligen technology: Emisphere’s Eligen technology employs non-covalent
interaction of the novel drug-carrier molecule monosodium
N-(4-chlorosalicyloyl)-4-aminobutyrate (4-CNAB) with insulin.66 4-CNAB
is organic/lipophilic in nature, thus expected to improve the lipophilicity of
insulin and facilitates passive transcellular diffusion. Despite the relative
fast absorption rate obtained from the pharmacokinetic data, Emisphere did not
show a satisfactory bioavailability even in the presence of the large amount of
carriers needed per dose.67,68 A
comparative proof-of-concept study69 comparing between subcutaneous
human regular insulin and oral insulin tagged with (4-CNAB) showed that maximum
insulin concentration was greater and onset of action was faster with oral
insulin in fasting conditions, but higher between-subject variability in
absorption was a concern (relative bioavailability 7 +4%).

3.      Receptor-mediated endocytosis: This principle has been adopted by Access
Pharmaceuticals to develop CobOral, a peptide-loaded dextran nanoparticle
coated with cobalamin. Similarly, Apollo Life has developed Oradell, a carbohydrate-based
nanoparticle coated with vitamin B12.70 Insulin, coated
with vitamin B12-tagged dextran nanoparticles showed signi?cant
prolonged hypoglycaemic effect in a streptozocin-induced diabetic rat model.71

4.      Cell-penetrating peptides (CPPs):  In vitro study
involving a CPP, called HIV-1 transactivator of transcription (TAT) showed signi?cant improvement of the
transport of insulin/TAT conjugate across Caco-2 cells.72

5.      Nanoparticles of chitosan: Signi?cant protection of insulin encapsulated
with chitosan against enzymatic degradation, and such nanoparticles were able
to cross the epithelium through Peyer’s patches.73

6.      Protease inhibitors: Although Iinsulin is degraded by trypsin, ?-chymotrypsin
and carbxypeptidases, a speci?c insulin-degrading enzyme (IDE) on the
brush-border membrane is found.74 Although a potent IDE inhibitor
(6bK) did not improve oral insulin delivery, IDE inhibition was associated with
increased amylin levels, which in turn slows the gastric emptying rate and
improves glucose tolerance.75 Co-administration of Na-glycocholate, aprotinin,
bacitracin, soya bean trypsin inhibitor and camostat mesilate with insulin
directly into isolated intestines of normal rats showed improvement of the
bioavailability of insulin. The effect was more predominant in the large
intestine than the small intestine.76 Chicken ovomucoid and duck
ovomucoid also showed protective effect against degradation of insulin by
trypsin and ?-chymotrypsin.77

7.      Absorption enhancers/permeation enhancers (PEs): PEs are a group of
agents that promote absorption of therapeutics through perturbing the cell
membrane to improve transcellular transport or by selective action on tight
junctions to enhance paracellular permeability.78 Bile salts,
ethylene diamine tetraacetic acid, surfactants, fatty acids and zonula
occludens toxin (ZOT) are examples of permeation enhancers commonly used to
improve oral peptide bioavailability.78 In-vivo result showed that
ZOT increased insulin oral absorption 10-fold from rabbit ileum and jejunum and
no effect was observed in colon.79

8.      Site-speci?c delivery: Low level of luminal and brush-border
proteases compared to duodenum and jejunum has made the colon an interesting
target to circumvent harsh gastric conditions. Polyacrylic-coated gelatin
capsules loaded with insulin showed signi?cant drop in the blood glucose level
compared to intraperitoneal injection.80 A colon-speci?c drug
delivery 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 the
colon of dogs.81,82 Capsulin is an enteric-coated capsule loaded
with dry powder mixture of insulin, permeation enhancer and solubilizer.83
It showed good gastric stability, reasonable safety pro?le with well-tolerated
statistically signi?cant hypoglycaemia.84 Oramed Pharmaceuticals
Inc. developed Protein Oral Delivery (POD) technology, which employed a
three-pronged approach composed of encapsulation, protease inhibitors and a chelating
agent.85 In subjects with T1DM, Oramed’s oral insulin has been shown
to reduce postprandial glucose concentrations,86 and when administered
preprandially, it reduces both fasting blood glucose levels and the requirement
for fast-acting insulin doses.87 In another system insulin  was incorporated in the core which was either
attached to or embedded in the enteric-coated shuttle or conveyor of superporous
hydrogel (SPH) and superporous hydrogel composite (SPHC) targeting proteins to
a speci?c site of the intestine.88 Interpenetrating polymeric
networks of superporous hydrogels (SPH-IPNs) have been trialed to estimate
insulin transport across rat intestine and colon. No conformational changes to
insulin or alterations to its oral bioactivity was observed using SPH-IPNs
following administration to healthy animals.89 When it was compared
to the subcutaneous route, insulin-loaded SPH-IPNs delivery system achieved
around 4% pharmacological availability.90

9.      Mucoadhesive and mucopenetrative systems: The mucoadhesive
properties of some polymers prolongs the residence time of the drug at its
absorption site.91
Chitosan-4-thiobutylamidine insulin-loaded tablets showed controlled release in
non-diabetic rats for over 8 hours.92 Mucus
penetration is another technology introduced to overcome the dynamic upstream
mucus barrier.93-95 N-(2-hydroxypropyl methacrylamide (HPMA), a hydrophilic
mucus inert polymer having mucus penetration characteristics was used to coat
mucoadhesive insulin-loaded N-trimethyl chitosan (Ins-TMC) nanocarriers. Upon
oral administration to diabetic rats, remarkable hypoglycaemia was noted.91

10.  Hydrogels: Hydrogels, with good insulin encapsulation efficiency96
like cross-linked poly-(N-isopropyl acrylamide)-methacrylic acid-hydroxy ethyl
methacrylate (NIPAAm- MAA-HEM) are able to prevent insulin release in the
stomach. As the pH increases toward the small intestine, insulin is released
from the hydrogel.97 Methyl-?-cyclodextrin complexed insulin
encapsulated in the polymethacrylic acid- PEG-chitosan hydrogel microparticles
led to a better pharmacological response in diabetic animals compared with
microparticles containing original insulin.98

11.  Particulate carrier system: Formulations of drugs with colloidal
particulate carriers such as submicroemulsion, lipid suspension, liposomes,
polymeric microparticles and nanoparticles and polymeric micelles are used to
improve peptide drug delivery.

Insulin-loaded chitosan phthalate microsphere formulation,
having improved oral bioavailability was found to lower the plasma glucose
level at the prediabetic level.99 Another novel solid-in-oil-in-water
(S/O/W) emulsion has been used to encapsulate insulin and showed a
pH-responsive release pattern mimicking gastroenteric niche. Microemulsions entrapping
insulin showed 10-fold improvement in bioavailability compared to plain insulin
solution upon oral administration to healthy rats.100 A liposomal
insulin formulation known as hepatic direct vesicle insulin (HDV-I) has been
successfully delivered orally.101 Combined use of thiolated chitosan
and self-nanoemulsifying drug delivery systems (SNEDDS) to produce nanospheres resulted
in signi?cantly improved release pro?le, increased serum insulin level and remarkable
hypoglycaemia.102,103 A novel SNEDDS was developed based upon
hydrophobic ion pair of insulin with dimyristoyl phosphatidylglycerol (DMPG) to
form insulin/DMPG complexes which had improved permeation characteristic, provided
protection from gastroenteral enzymes and prevented initial burst release of
insulin.104 Results with polymer-based nanoparticles for oral
insulin delivery have showed promising results. For this purpose, either
natural (gold105, gelatin, casein, chitosan, alginate, dextran,
starch and pectin106) or synthetic polymers (polylactic acid, polylactic
co-glycolic acid and poly ?-caprolactone)107 have been employed.

Recent advancements:

·        
Mucoadhesive
intestinal insulin device: A combination of intestinal devices, a permeation enhancer with
pH-responsive enteric coating has shown to adhere to porcine intestinal mucosa,
release their protein load unidirectionally, and prevent enzymatic degradation
in the gut. It has decreased blood glucose levels by 30 and 33% in diabetic and
nondiabetic rats, respectively.108

·        
Intestinal insulin micropatch: Study has shown that intestinal
micropatches can adhere to the intestinal mucosa, release their drug load
rapidly within 30?min and are effective in lowering blood glucose levels (up to
34%) in vivo.109

·        
Self-assembled polyelectrolyte complex nanoparticles:  Insulin-loaded dodecy-
lamine-graft-?-polyglutamic acid micelles were developed and cross-linked with
trimethyl chitosan (TMC) in the form of nanoparticle complex. To improve their
af?nity for the intestinal epithelium goblet cell targeting modification was
done. Oral administration of this targeted nanoparticle had a relative
bioavailability of 7.05% with prolonged hypoglycaemia in diabetic rats.110

·        
Emergence of Selenium
nanoparticles as carriers for oral delivery of insulin: Insulin-loaded
selenium nanoparticles were formulated by ionic cross-linking reduction
technique. The produced Insulin-loaded Selenium nanoparticles
(INS-SeNPs)
had good insulin encapsulation ef?ciency, outstanding gastric stability and remarkable
hypoglycaemic effect. The study also suggested that Selenium could potentiate
the antidiabetic effect of insulin, might alleviate diabetes-associated
oxidative stress and improve pancreatic ?-cell functions.111

Data from Clinical
trials and current status:

The small number of clinical trials in
comparison with published preclinical studies indicates that oral insulin is
still battling to move on from clinical testing.112,113

1.     
Oramed

ORMD-0801 Enteric
coating and absorption enhancers

Completed Phase IIa in
T1DM; completed Phase IIb in T2DM; approved by US FDA for Phase IIb

2.     
Biocon

IN-105 Chemical
modification of insulin with a small PEG and penetration enhancers

Phase III in T2DM
failed to clear the primary end point; planned Phase I and II studies in
collaboration with Bristol Myers Squibb

3.     
NovoNordisk – Merrion

NN1953, NN1954, NN1956

Absorption enhancers
that activate micelle formation

Completed Phase I;
planned Phase IIa

4.     
 NovoNordisk –

Emisphere Eligen

Penetration enhancers
– salcaprozate sodium

Phase II in T2DM

5.     
Diabetology

Capsulin

Enteric coating,
absorption enhancers and a solubiliser

Completed Phase IIa in
T1DM and Phase II in T2DM

6.     
Oshadi drug administration

Oshadi oral insulin

Enteric capsules with
insulin blended with silica nanoparticles and a polysaccharide suspended in oil

Completed Phase II in
T1DM

7.     
Diasome

HDV-I

Liposomes with hepatic
targeting

Completed Phase II in
T1DM and T2DM; approved by FDA for Phase III

Conclusion:

Given the
varied heterogenous pathophysiology of diabetes, it is unlikely that any single
drug 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 optimally
positioned to address the specific pathophysiologic aspects of glucose
intolerance.

Even after relentless research obstacles for clinically
effective oral insulin remains because of  poor scale-up possibility, bad reproducibility
of particle production, no framed algorithm to predict the large-scale performance
of a product based on its small-scale behavior and high cost-benefit.112
Food-drug interaction, which is an important subject as far as insulin’s
bioavailability is concerned, is yet to be explored.114 Moreover,
considerations and surveillance of the effects of the large amounts of unabsorbed
insulin, a growth factor with mitogenic potential115,116 and a recognized
modulator of gastrointestinal physiology117 will be required to
unfurl its safety on long-term use. 

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