Oral Insulin Delivery - Challenges and Current Status

Jikku Kurien Raju

The oral route is considered to be the most convenient and desired route of
drug delivery, especially when repeated or routine administration is necessary
¹.

Insulin is usually administered to diabetic patients through subcutaneous
injection. However, the problems encountered with subcutaneous insulin injections
are pain, allergic reactions, hyperinsulinemia, and insulin lipodystrophy around
the injection site ². 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 ³ and possible
infections ⁴. 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
^{5, 6}. In light of the above distinct benefits, pharmaceutical technologists
have been trying to design an oral delivery system for insulin. Such is the
interest in oral insulin delivery that some pharmaceutical companies are solely
focused on it.

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 ^{7, 8, 9}.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%.¹⁰

Enzymatic Barrier: ¹¹

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.
Insulin therefore undergoes enzymatic degradation by pepsin and pancreatic proteolytic
enzymes such as trypsin and α-chymotrypsin ^{6, 12}. Overall,
insulin is subjected to acid-catalyzed degradation in the stomach, luminal
degradation in the intestine and intracellular degradation. The cytosolic
enzyme that degrades insulin is insulin-degrading enzyme (IDE) ¹³. Insulin
is however not subject to proteolytic breakdown by brush border enzymes ⁶.
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 cannot diffuse across epithelial cells through lipid-bilayer
cell membranes to the blood stream ¹⁴. In other words, insulin has
low permeability through the intestinal mucosa ¹⁵. There is no evidence
of active transport for insulin ¹⁶. It has been found however that
insulin delivery to the mid-jejunum protects insulin from gastric and pancreatic
enzymes and release from the dosage form is enhanced by intestinal microflora
^{16, 17}. 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.

Dosage form stability:

The activity of proteins depends on the three-dimensional 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 ⁶. If a protein needs to
survive transit through the stomach and intestine, knowledge and assessment
of stability parameters during formulation processing is of utmost importance.

Attempted Oral Insulin Delivery Systems:

Most peptides
are not bioavailable from the GIT after oral administration ¹⁸. Therefore,
successful oral insulin delivery involves overcoming the enzymatic and physical
barriers ¹¹ and taking steps to conserve bioactivity during
formulation processing ⁶. In developing
oral protein delivery systems with high bioavailability, three practical
approaches might be most helpful: ¹⁹

(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:

Insulinis 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 ⁶. The earliest studies
involving enzyme inhibitors were carried out with sodium cholate along with
aprotinin which improved insulin absorption in rats ²⁰. Significant
hypoglycemic effects were also obtained following large intestinal administration
of insulin with camostat mesilate, bacitracin ²¹. Other inhibitors
which have shown promise are leupeptin ²², FK-448 ²³,
a potent and specific inhibitor of chymotrypsin and chicken and duck ovomucoid
²⁴. In one study, polymers cross-linked with azoaromatic groups formed
an impervious film to protect insulin from digestion in the stomach and small
intestine. Upon reaching the large intestine, the indigenous microflora degraded
the polymer film, thereby releasing the drug into the lumen of the colon for
absorption ²⁵. 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
²⁶.

Penetration Enhancers:

Another strategy for oral insulin delivery is to promote absorption through
the intestinal epithelium by permeation enhancement. Hydrophilic molecules like
insulin are adsorbed to the apical membrane and are internalized by endocytosis
⁶. 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 ²⁷. 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 ²⁸. These include substances like bile
salts, surfactants, trisodium citrates, chelating agents like EDTA ²⁹,
labrasol ³⁰. Insulin transport across Caco-2 cells was shown to be
dramatically increased by conjugation of insulin with TAT, a cell penetrating
peptide (CPP) ³¹. 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 ³²,
and risk to mucous membranes by surfactants and damage of cell membrane by chelators
². Mucoadhesive polymers have been proven to be safe and efficient
intestinal permeation enhancers for the absorption of protein drugs ^33,
34. The zonula occludens toxin, chitosan, thiolated polymers, and Pz-peptide
have all demonstrated capacity to increase macromolecular drug absorption ¹⁹.

Combinational strategies involving
enzyme inhibitors and absorption enhancers have been effective in increasing
bioavailability of insulin. Combinations like sodium cholate and soybean
trypsin inhibitor ²⁰, sodium lauryl sulphate and aprotinin ³⁵
have resulted in reduction in blood glucose in dogs.

Carrier Systems:

The oral bioavailability of insulin
can be enhanced by the use of novel carrier systems which deliver insulin to
the target site of absorption ². Liposomes, microspheres and
nanoparticles have been developed for use as carrier systems for insulin.

Liposomes:

These are tiny spheres formed when phospholipids are combined with water ².

Encapsulating
insulin in liposomes results in enhanced oral absorption of insulin.
However, the high doses of liposome-entrapped insulin required
coupled with variability in glycemic response limits its use ³⁶.
Other drawbacks include instability, leakage of entrapped drug, and low drug
carrying capacity ².

Encapsulation of insulin in liposomes

Microspheres:

Insulin can be encapsulated in a microcapsule or dispersed in a polymer matrix.
Microspheres are prepared by emulsification using natural (gelatin or albumin)
or synthetic polymers (polylactic or polyglycolic acid) ². Morishita
et al ³⁷ used microspheres for insulin delivery in rats. Their
study showed that L-microspheres carrying insulin and aprotinin enhanced insulin
absorption. Insulin-loaded alginate microspheres complexed with cyclodextrins
have an absorption enhancing effect leading to increase in bioavailability ³⁸.
Qi and Ping ³⁹ studied the oral coadministration of insulin enteric
microspheres with sodium N-(8-2-hydroxybenzoyl amino) caprylate (SNAC). EDTA
was administered before the insulin oil solution was given to rats. A decrease
in glucose levels, which primarily resulted from EDTA's enzyme inhibiting properties
was observed ⁴⁰. In a recent study, Eudragit S100 microspheres on
oral administration protected insulin from proteolytic degradation in the GIT
and produced hypoglycemic effect ⁹. Microspheres encapsulated with
chitosan phthalate polymer protect the insulin from enzymatic degradation with
an insulin-loading capacity of 62% and may be a potential carrier for oral insulin
delivery ⁴¹.

Nanoparticles :

Nanoparticles have been
extensively studied as carriers for oral insulin delivery ⁴².
Polymeric nanoparticles (nanocapsules and nanospheres) are of special interest
from a pharmaceutical point of view. The biological effect of insulin
nanocapsules depends on the amount of both insulin and polymer. The nature of
polymers strongly influences the nanoparticle size and release profile ³².
The intensity and duration also depends on the site of administration (65%
ileum, 59% stomach, 52% duodenum and jejunum, 34% colon). The nanoparticles
protect insulin against enzymatic degradation in vitro ⁴³. Synthetic polymers used for nanoparticle formulation
include polyalklylcyanoacrylate ⁴⁴, polymethacrylic acid ⁸,
polylactic-co-glycolic acids (PLGA) ⁴⁵.

Insulin encapsulation with nanoparticles

Natural polymers used
include chitosan ⁴, alginate, gelatin, albumin ³² and
lectin ⁴⁰. Chitosan has been the proven to have good permeation
enhancing abilities via the paracellular pathway ³³. A recent study
showed that insulin-loaded nanoparticles shelled with chitosan could
effectively reduce the blood glucose level in a diabetic rat model ⁴.
An exhaustive review of nanoparticles as a potential oral delivery system for proteins
has been done by Rieux et al ³².

Chemical Modification:

Modifying the chemical structure and thus increasing its stability is another
approach to enhance bioavailability of insulin. An example of chemical modification
is that of hexyl-insulin monoconjugate 2 (HIM-2) wherein a short chain polyethylene
glycol (PEG) linked to an alkyl group is in turn linked to LYS-29 of the beta
chain of insulin ²⁸. Alteration of the physicochemical characteristics
leads to enhanced stability and resistance to intestinal degradation of oral
insulin ⁵⁰. Shen et al ⁵¹ recently demonstrated
improved efficacy of orally administered insulin by conjugating insulin with
transferrin through disulfide linkages.

Bioadhesive Systems:

Mucoadhesive delivery systems adhere to the mucous gel layer covering mucosal
membranes. A high drug concentration is therefore present for absorption due
to the intimate contact with the mucosa. As a result, numerous mucoadhesive
delivery systems like chitosan ⁵², sodium salicylate, and polyoxyethylene-9-lauryl
ether ⁵³ have been proposed. The bioadhesive systems may however
be affected by the mucous turnover of the GIT, which varies based on the site
of absorption ^{2, 19, 34}.

Emulsions:

Cho and Flynn ¹⁸ developed water-in-oil microemulsions in which
the aqueous phase is insulin and oil phase is lecithin, non-esterified fatty
acids and cholesterol in critical proportions. Invivo 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 ¹⁵.

Hydrogels:

These are cross-linked networks of hydrophilic polymers, which are able to
absorb large amounts of water and swell, while maintaining their three-dimensional
structure ⁵⁴. 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 and provide protection to the drugs from the harsh
environment of the GI tract ⁷.

Mechanism of Complexation Hydrogels ¹¹

Complexation
hydrogels such as poly (methacrylic acid-g-ethylene glycol) P(MAA-g-EG) ^{7, 55}, P(PAA-g-EG) have been used for
this purpose. Tuesca et al ¹¹
modified the network of the P(MAA-g-EG) hydrogel and combined it with a chemically
modified insulin species in an attempt to improve bioavailability. Poly (ethylene
glycol) dimethacrylates (PEGDMA) have been used as pH-sensitive hydrogels ⁵⁶.
Oral administration of insulin entrapped in amidated pectin hydrogel beads in
streptozotocin (STZ)-diabetic rats resulted in a concomitant reduction in
plasma glucose concentration ⁵⁷.

Developments in oral insulin delivery:

The oral delivery of insulin has always been a significant challenge for pharmaceutical
researchers. The development of oral insulin is at different stages for different
companies and covers a broad spectrum from pre clinical testing to Phase II clinical
trials ⁵⁸. A notable advancement is the completion of phase II trials
of oral insulin product, hexyl-insulin monoconjugate 2 (HIM 2) which has been
found to be safe and well tolerated ⁵⁹. Human clinical trials with
conjugated insulin are a clear demonstration that proteins can be developed
into therapeutically viable products ²⁸. In October 2006, Emisphere
announced preliminary results of Phase II trials of oral insulin product developed
with Eligen™ technology. Emisphere’s Eligen™ technology makes
use of small hydrophobic organic compounds that interact noncovalently with
macromolecules, increasing their lipophilicity and enhancing absorption. Covalent
and non covalent drug modifications for increasing membrane permeability are
currently employed by two companies, Nobex (now Biocon) and Emisphere Technologies.
Clinical trials with type 1 and type 2 diabetic patients have demonstrated initial
efficacy, but low bioavailability (estimated at 5%) continues to be a problem
¹⁹.

Conclusion:

The oral route for insulin delivery might be possible in
the near future with the use of using superior materials as carriers for
insulin delivery systems. However, only further research into delivery systems
can make it possible for the oral route to represent a viable route of
administration. Maximization of the absorptive
cellular intestinal uptake and stabilization of insulin at all stages before it
reaches its target will determine its final efficiency. The chances for
a market launch will depend on several factors such as efficacy and safety as
well as economic reasons. Although considerable
efforts have been already made to deliver insulin orally, extensive and
continuous comparison of in-vitro and in-vivo studies are essential to develop
oral insulin delivery systems in the foreseeable future.

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About Authors:

Jikku Kurien Raju
Department of Pharmaceutics, Sri Ramachandra College of Pharmacy, Sri Ramachandra
University, Porur, Chennai

A.T. Ashik Rafi
Department of Pharmaceutics, Sri Ramachandra College of Pharmacy, Sri Ramachandra
University, Porur, Chennai

M. Sathiyanarayanan
Department of Pharmaceutics, Sri Ramachandra College of Pharmacy, Sri Ramachandra
University, Porur, Chennai

S. Shanmuganathan, Uma Maheswara Reddy
Department of Pharmaceutics, Sri Ramachandra College of Pharmacy, Sri Ramachandra
University, Porur, Chennai