Kinesh V.P. et.al.

: Novel Approaches for Oral Delivery of Insulin and Current Status of Oral Insulin Products 1057
International Journal of Pharmaceutical Sciences and Nanotechnology
Volume 3 Issue 3 October - December 2010

Review Article
Novel Approaches for Oral Delivery of Insulin and Current Status of
Oral Insulin Products
Kinesh V. P.*, Neelam D. P., Punit. B. P., Bhavesh S.B., Pragna K. S.
Department of Pharmaceutics and Pharmaceutical Technology
K. B. Institute of Pharmaceutical Education & Research, Gandhinagar-India

ABSTRACT:

Diabetes mellitus is a serious pathologic condition that is responsible for major healthcare problems
worldwide and costing billions of dollars annually. Insulin replacement therapy has been used in the clinical management of
diabetes mellitus for more than 84 years. The present mode of insulin administration is by the subcutaneous route through
which insulin is presented to the body in a non-physiological manner having many challenges. Hence novel approaches for
insulin delivery are being explored. Challenges to oral route of insulin administration are: rapid enzymatic degradation in the
stomach, inactivation and digestion by proteolytic enzymes in the intestinal lumen and poor permeability across intestinal
epithelium because of its high molecular weight and lack of lipophilicity. Liposomes, microemulsions, nanocubicles, and so
forth have been prepared for the oral delivery of insulin. Chitosan-coated microparticles protected insulin from the gastric
environment of the body and released intestinal pH. Limitations to the delivery of insulin have not resulted in fruitful results
to date and there is still a need to prepare newer delivery systems, which can produce dose-dependent and reproducible
effects, in addition to increased bioavailability.

KEYWORDS: Insulin; Oral delivery; Challenges; Approaches; Market status

Introduction
Diabetes mellitus is a common disease and its
complications are responsible for excess morbidity
and mortality, loss of independence, and reduced
quality of life (Giriraj KG, 2003; Ahmed I, 2006).
Diabetes mellitus is a serious pathologic condition
that is responsible for major healthcare problems
worldwide and costing billions of dollars annually.
Currents routes for Insulin delivery and
their problems
The present mode of insulin administration is by the
subcutaneous route by which insulin is presented to
the body in a non-physiological manner. The
subcutaneous administration of insulin has many
challenges.
Insulin injected subcutaneously at least twice a
day is having many inherent disadvantages include
local pain, inconvenience of multiple injections, and
occasional hypoglycemia as a result of overdose,
itching, allergy, hyperinsulinemia, and insulin
* For correspondence: Kinesh V.P.
E-mail: kineshpatel29@gmail.com

lipodystrophy around the injection site. Lastly,

clinical trials have shown that even on injectable
insulin treatment, a significant percentage of patients
fail to attain lasting glycemic control due to noncompliance (Pamnani D, 2008).
Because of these problems, novel approaches for
insulin delivery are being explored, including oral,
transdermal, nasal, rectal, pulmonary, uterine, and
ocular delivery as well as s.c. implants. Delivery
options that use dermal, nasal, and oral approaches
have been explored (Cefalu WT, 2004; Haak T,
1999). This review describes various oral insulin
delivery systems.

Why oral delivery of insulin?

Making needles needless is gaining widespread
prominence,
to
offset
the
aforementioned
disadvantages by oral delivery of insulin. The oral
route is considered to be the most acceptable and
convenient route of drug administration for chronic
therapy. Due to knowledge explosion in the
biotechnology industry, extensive investigations are
being conducted to achieve successful control of
blood glucose by the oral delivery system.
1057

1058 International Journal of Pharmaceutical Sciences and Nanotechnology

Insulin if administered via the oral route will help

eliminate the pain caused by injection, psychological
barriers associated with multiple daily injections such
as needle anxiety (Korykowski M, 2002) and possible
infections (Lin YH et al., 2007). In addition, oral
insulin is advantageous because it is delivered
directly to the liver, its primary site of action, via the
portal circulation, a mechanism very similar to
endogenous insulin; subcutaneous insulin treatment
however does not replicate the normal dynamics of
endogenous insulin release, resulting in a failure to
achieve a lasting glycemic control in patients
(Morishita M, 2006; Agarwal V et al., 2001).

Challenges to Oral Insulin Delivery

Generally, peptides and proteins such as insulin
cannot be administered via the oral route due to rapid
enzymatic degradation in the stomach, inactivation
and digestion by proteolytic enzymes in the intestinal
lumen, and poor permeability across intestinal
epithelium because of its high molecular weight and
lack of lipophilicity (Nakamura K et al., 2004;
Sajeesh S et al., 2006; Jain D et al., 2005).The oral
bioavailability of most peptides and proteins
therefore is less than 1%. The challenge here is to
improve the bioavailability to anywhere between 30
50% (Lee VH, 1991).

Volume 3 Issue 3 October-December 2010

cannot diffuse across epithelial cells through lipidbilayer cell membranes to the blood stream (Lin YH
et al., 2007). In other words, insulin has low
permeability through the intestinal mucosa (Torisaka
E et al., 2005). There is no evidence of active
transport for insulin (Schilling RJ et al., 1999). It has
been found however that insulin delivery to the midjejunum protects insulin from gastric and pancreatic
enzymes and release from the dosage form is
enhanced by intestinal microflora (Schilling RJ et al.,
1999; Koosapur H et al., 1999). Various strategies
have been tried out to enhance the absorption of
insulin in the intestinal mucosa and in some cases;
they have proven successful in overcoming this
barrier.

Enzymatic Barrier
The harsh environment of the gastrointestinal tract
(GIT) causes insulin to undergo degradation. This is
because digestive processes are designed to
breakdown proteins and peptides without any
discrimination. (Tuesca A et al., 2006) Insulin
therefore undergoes enzymatic degradation by pepsin
and pancreatic proteolytic enzymes such as trypsin
and -chymotrypsin (Agarwal V et al., 2001; Patki
VP et al., 1996). Overall, insulin is subjected to acidcatalyzed degradation in the stomach, luminal
degradation in the intestine and intracellular
degradation. The cytosolic enzyme that degrades
insulin is insulin-degrading enzyme (IDE) (Chang LL
et al., 1999).Insulin is however not subject to
proteolytic breakdown by brush border enzymes
(Agarwal V et al., 2001). Insulin can be presented for
absorption only if the enzyme attack is either reduced
or defeated.
Intestinal Transport of Insulin
Another major barrier to the absorption of
hydrophilic macromolecules like insulin is that they

Fig. 1 Barriers to absorption of drug in the intestine

(Soltero et al., 2001).

Dosage form Stability

The activity of proteins depends on the threedimensional molecular structure. During dosage form
development, proteins might be subject to physical
and chemical degradation. Physical degradation
involves modification of the native structure to a
higher order structure while chemical degradation
involving bond cleavage results in the formation of a
new product (Agarwal V et al., 2001). Proteins must
be characterized for change in conformation, size,
shape, surface properties, and bioactivity upon
formulation processing. Changes in conformation,
size, shape can be observed by use of
spectrophotometric techniques, X-ray diffraction,
differential scanning calorimetery, light scattering,
electrophoresis, and gel filtration (Pearlman R et al.,
1991).

Kinesh V.P. et.al. : Novel Approaches for Oral Delivery of Insulin and Current Status of Oral Insulin Products 1059

Approaches for oral Insulin

Attempted Oral Insulin Delivery Systems
Most peptides are not bioavailable from the GIT after
oral administration (Cho YW et al., 1989). Therefore,
successful oral insulin delivery involves overcoming
the enzymatic and physical barriers (Tuesca A et al.,
2006) and taking steps to conserve bioactivity during
formulation processing (Agarwal V et al., 2001). In
developing oral protein delivery systems with high
bioavailability, three practical approaches might be
most helpful: (Morishita M et al., 2006)
1. Modification of physicochemical properties
such as lipophilicity and enzyme susceptiblity.
2. Addition of novel function to macromolecules.
3. Use of improved carrier systems.
The various oral delivery systems which have been
attempted to deliver insulin orally either singly or in a
synergistic approach can be categorized as follows:
Enzyme Inhibitors
Insulin is degraded in the GIT by pepsin and other
proteolytic enzymes. Enzyme inhibitors slow the rate
of degradation of insulin which increases the amount
of insulin available for absorption (Agarwal V et al.,
2001). The earliest studies involving enzyme
inhibitors were carried out with sodium cholate along
with aprotinin which improved insulin absorption in
rats (ziv E et al., 1987). Significant hypoglycemic
effects were also obtained following large intestinal
administration of insulin with camostat mesilate,
bacitracin (Yamamoto A et al., 1994). Other
inhibitors which have shown promise are leupeptin
(Liu H et al., 2003), FK-448 (Fujji S et al., 1985), a
potent and specific inhibitor of chymotrypsin and
chicken and duck ovomucoid (Agarwal V et al.,
2001). In one study, polymers cross-linked with
azoaromatic groups formed an impervious film to
protect insulin from digestion in the stomach and
small intestine (Saffran M et al., 1986). The use of
enzyme inhibitors in long-term therapy however
remains questionable because of possible absorption
of unwanted proteins, disturbance of digestion of
nutritive proteins and stimulation of protease
secretion (Shah RB et al., 2002).
Penetration Enhancers
Hydrophilic molecules like insulin are adsorbed to
the apical membrane and are internalized by

endocytosis (Agarwal V et al., 2001). Another theory

suggests absorption via paracellular transport. Tight
junctions between each of the cells in the epithelium
prevent water and aqueous soluble compounds from
moving past those cells. Hence, approaches for
modulating tight-junction permeability to increase
paracellular transport have been studied (SalamatMiller N et al., 2005). A number of absorption
enhancers are available that cause these tight
junctions to open transiently allowing water-soluble
proteins to pass. Absorption may be enhanced when
the product is formulated with acceptable safe
excipients (Soltero R et al., 2001). These include
substances like bile salts, surfactants, trisodium
citrates, chelating agents like EDTA (Li CL et al.,
2004), labrasol (Eaimtarakam S et al., 2002). The
drawbacks with penetration enhancers include lack of
specificity, i.e., they allow all content of the intestinal
tracts including toxins and pathogens the same access
to the systemic bloodstream (Rieux A et al., 2006),
and risk to mucous membranes by surfactants and
damage of cell membrane by chelators
(Gowthamarajan K et al., 2003). Mucoadhesive
polymers have been proven to be safe and efficient
intestinal permeation enhancers for the absorption of
protein drugs (Thanou M et al., 2001; Plate NA et al.,
2002).
Chemical modifications
Modifying the chemical structure of a peptide or
protein is another approach to enhance bioavailability
by increasing its stability against possible enzymatic
degradation or its membrane permeation. However,
this approach is more applicable to peptides rather
than proteins because of the structural complexity of
proteins. For example, substitution of D-amino acids
for L-amino acids in the primary structure can
improve the enzymatic stability of peptides. A diacyl
derivative of insulin maintains its biological activity
and also increases absorption from the intestine
(Giriraj KG et al., 2003).
Carrier Systems
Hydrogels
These are cross-linked networks of hydrophilic
polymers, which are able to absorb large amounts of
water and swell, while maintaining their threedimensional structure (Yupeng R et al.).
Complexation hydrogels are suitable candidates for
oral delivery of proteins and peptides due to their
abilities to respond to changes in pH in the GI tract

1060 International Journal of Pharmaceutical Sciences and Nanotechnology

and provide protection to the drugs from the harsh

environment of the GI tract (Nakamura K et al.,
2004).
Liposomes
Insulin-entrapped liposomes cause dose-dependent
hypoglycemia. Researcher have prepared liposomes
with varying composition by two methods: solvent
evaporation hydration and solvent spherule
evaporation (Choudhari KB et al., 1994). Liposomes
containing lecithin 100 mg, cholesterol 20 mg, insulin
150 units, and Tween 1% v/v were found to be most
effective. The effect of insulin-liposome was
prolonged in diabetes-induced rabbits than that of
normal rabbits. The pharmacodynamics of the
insulin-liposome system was comparable with the
action of 1 U/kg of insulin administered
subcutaneously.
Erythrocytes
Human red blood cells have been developed as oral
carrier systems for human insulin. In a study by AlAchi et al., male Wistar rats were made diabetic by a
single intraperitoneal injection of streptozocin (100
mg/kg) (Al-Achi A et al., 1998). Rats received orally
one of the following (100 U, 2 mL): an insulin
solution, a ghosts-insulin suspension, a vesiclesinsulin suspension, a liposomes-ghosts-insulin
suspension,
or
a
liposomes-vesicles-insulin
suspension. Free-carrier suspensions or sodium
chloride solution (0.9%) were given orally as
controls. Blood glucose concentration was
determined just before administration and at 1, 2,
3,4,5,6, and 7 h post administration. Results showed
that all treatment groups, except liposomes-ghostsinsulin, were significantly different statistically from
their respective controls (i.e., the free carriers).
Nanospheres
Damge et al. prepared insulin-loaded nanospheres by
polymerization of isobutyl cyanoacrylate (IBCA) in
an acidic medium (Damge C et al., 1997). These
nanospheres displayed a mean size of 145 nm and an
association rate of 1 U of insulin per milligram of
polymer. These nanospheres were dispersed in an
oily medium (Miglyol 812) containing surfactant
(Polox-amer 188 and deoxycholic acid) and evaluated
for in vitro and in vivo degradation. No degradation
due to proteolytic enzyme was observed in vitro.
When these nanospheres (100 U per kilogram of
body weight) were administered perorally in

Volume 3 Issue 3 October-December 2010

streptozotocin-induced diabetic rats, a 50% decrease

in fasted glucose levels from the second hour up to
10-13 days was observed. This effect was shorter (2
days) or absent when nanospheres were dispersed in
water. Using 14C-labeled nanospheres loaded with
(125I) insulin, it was found that nanospheres increased
the uptake of (125I) insulin or its metabolites in the
gastrointestinal tract, blood, and liver while the
excretion was delayed when compared to (125I)
insulin nonassociated to nanospheres.
Nanocubicles
A liquid formula that can be easily dispersed in water
to produce particles named "Nanocubicles" was
developed by Chung et al. (Chung H et al., 2004).
These nanocubicles containing insulin were
administered to fasted streptozotocininduced diabetic
rats. For comparison, an aqueous solution of insulin
in water was also administered. Nanocubicles without
insulin and insulin in phosphate buffer saline (PBS)
were administered as controls. Blood glucose
concentration and insulin concentration were
measured 1, 2, 3, 4, and 6 h after the administration
of the insulin formulations. In vitro experiments
showed that the particles were taken up by the Caco-2
cells at a high ratio. It was observed in these studies
that the serum glucose concentration was controlled
for more than 6 h after oral insulin administration but
returned to the basal concentration in 3 h when 1
IU/kg of insulin was injected, intravenously.
Other Approaches
Tablets
Thiolated chitosan insulin tablets: The efficacy of
orally administered insulin has also been improved
using thiolated chitosan. 2-Iminothiolane was
covalently linked to chitosan and the resulting
chitosan-TBA
(chitosan-4-thiobutylamidine)
conjugate exhibited 453.5 64.1 mol thiol groups
per gram of polymer (A.H. Krauland et al., 2004).
Two enzyme inhibitors Bowman-Birk-Inhibitor
(BBI) and Elastatinal were covalently linked to
chitosan. Chitosan-TBA conjugate (5 mg), insulin
(2.75 mg), the permeation mediator reducer
glutathione (0.75 mg), and the two inhibitor
conjugates (in each case 0.75 mg) were compressed
to make chitosan-TBA-insulin tablets. Control tablets
were also prepared using chitosan and insulin.
Chitosan-TBA-insulin tablets showed a controlled
release of insulin over 8 h. In vitro mucoadhesion

Kinesh V.P. et.al. : Novel Approaches for Oral Delivery of Insulin and Current Status of Oral Insulin Products 1061

studies showed that the mucoadhesive/cohesive

properties of chitosan were at least 60-fold improved
by the immobilization of thiol groups on the polymer.
Microemulsions
Cho and Flynn (Cho YW et al., 1989) developed
water-in-oil microemulsions in which the aqueous
phase is insulin and oil phase is lecithin, nonesterified fatty acids and cholesterol in critical
proportions. In vivo studies showed substantial
reduction in blood glucose. Recent studies have
focused on enteric-coated dry emulsion formulations
prepared from solid-in-oil-in-water emulsions. These
responded to changes in external environment
suggesting potential application for oral insulin
delivery (Torisaka E et al., 2005).
Oral insulin pills
Insulin administration in the form of a pill has always
been an attractive concept in research. Due to
numerous limitations of this mode of insulin
administration, efficacy has been hard to
demonstrate. Research has focused on overcoming
these limitations by stabilising the degradation,
improving the permeability, and adding absorption
promoters to protect the insulin as it passes through
the stomach.

pill has polymers added at specific locations in the B

chain of the insulin to prevent insulin from getting
destroyed in the stomach (insulin is made up of two
polypeptide chains namely, chain-A with 21 amino
acids and chain-B with 30 amino acids, which are
held together by two disulfide bonds). Biocon's R&D
group has successfully developed a carefully selected
formulation to give consistent absorption through the
intestines, delivering the glucose-lowering effect. In
the clinic, this molecule has completed phase I trials
and is expected to enter phase II in India later this
year to illustrate proof of concept. The encouraging
results of the phase Ia and Ib studies represent a
pivotal hurdle crossed in the development of IN-105
as a product. IN-105 will enter phase I trials in
Europe towards the end of the year.
Oral-lyn (Generex Biotechnology, Canada)

An alternative to injected insulin that is currently

being explored by researchers is a mouth spray
containing insulin that would be absorbed through the
lining of the mouth and throat. The liquid formulation
allows the insulin to be absorbed by the mucus
membranes in the cheeks, tongue, and throat. The
benefit from oral spray is identical to an insulin
injection in its ability to lower blood glucose levels.

Oral-lyn is the company's proprietary oral insulin

spray product. The liquid formulation is absorbed
into the body by the lining of the inner mouth using
the company's proprietary RapidMist device. Since it
is buccally absorbed, no insulin is deposited in the
lungs by the Oral-lyn RapidMist. August 2007 saw
the commercial launch of Oral-lyn in the Indian
market. Generex Biotechnology entered into Master
Product Licensing and Distribution Agreement of
Oral-lyn with Shreya Life Sciences, the fourth largest
distributor of insulin in India. In April 2008, Generex
entered into a similar agreement for the distribution
of Oral-lyn in China, Hong Kong, and the following
additional countries: Indonesia, South Korea,
Malaysia, the Philippines, Singapore, Thailand, and
Vietnam. Presently, Generex Oral-lyn is in phase III
clinical trials at several sites around the worldUS,
Canada and Ukraine.

Pulmonary or inhaled insulin

Transgene (Biotek, Andhra Pradesh)

The inhaled insulin system delivers a dose of insulin,

either in liquid or dry powder form, through the
mouth, directly into the lungs, where it enters the
blood circulation as rapid-acting insulin. With inhaled
insulin, the highly permeable alveolar epithelium and
large surface area of the lungs provide an effective,
efficient portal for macromolecular delivery.

Transgene has developed an oral delivery technology

which combines several oral delivery approaches into
a single drug delivery system. Unique in its approach,
this technology involves using biodegradable novel
polymeric nanoparticles loaded with insulin as a new
carrier to ferry the insulin across the intestinal
epithelial tissues. Nanoparticles are solid spherical
particles with a size range of 10 and 1,000 nm
containing dispersed drugs. Transgene has attempted
to improve the intestinal absorption of insulin and
other peptides. The technology has been well proven
in animal models, and human clinical studies are in
progress. Drug companies are obviously interested in

Oral spray

Market Status of Oral Insulin Products

IN-105 (Biocon, Bangalore)
Biocon is developing the IN-105 conjugated insulin
molecule, administered as a tablet. This oral insulin

1062 International Journal of Pharmaceutical Sciences and Nanotechnology

the potential of oral insulin to net a massive share of

the market, and therefore, investment in research is
substantial and ongoing. Biocon, Transgene Biotek
and Generex Biotechnology have proven to be
insightful in the race to enhance the treatment of
diabetes, and are definitely ahead of the pack.

Conclusion
Attempts have been made to achieve oral insulin
delivery using various systems. It has been proved
that insulin is subjected to acid catalyzed degradation
in stomach, luminal degradation in intestine, and
intracellular degradation. Scientists have been able to
protect the insulin delivery systems from acidic
environment of the stomach and target it to the
intestine. The maximum bioavailability of the insulin
has been reported to be very low because of the poor
absorption of insulin from the intestine. Attempts
have been made to increase the absorption of insulin
from intestine using absorption enhancers such as
aprotinin (protease inhibitor), tween, oligoarginine,
sodium glycol-cholate, deoxycholic acid, and
taurodeoxycholate.
Liposomes, microemulsions, nanocubicles, etc.,
have been prepared for the oral delivery of insulin.
Chitosan-coated microparticles protected insulin from
the gastric environment of the body and released it in
intestinal pH. Limitations to the delivery of insulin
have not resulted in fruitful results to date and there is
still a need to prepare newer delivery systems, which
can produce dose-dependent and reproducible effects
in addition to increased bioavailability.

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