Alternative Insulin Delivery Systems

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Harish Dureja

Harish Dureja

A large number of patients with diabetes worldwide require daily doses of
insulin. Insulin therapy, using the vial and syringe method is complicated
and time consuming. The quest to find an alternative way to deliver insulin
still eludes the researchers to replace injectable insulin by a more comfortable,
noninvasive and less sternuous delivery method, which can provide insulin
in pharmacokinetically consistent manner. The present article reviews the
various alternatives for insulin delivery.

1. Introduction

Insulin marked a tremendous advancement in the treatment of diabetes since
its discovery by Banting and Best in 1921 [1] and still remains a crucial
component for controlling both type I and type II diabetes today. Historically,
patients were injected insulin using glass syringes with needles, which needed
to be boiled and then soaked in alcohol between injections to keep them sterile.
Parenteral drug delivery via subcutaneous or intramuscular route, although
is not as fast as intravenous administration but still achieves therapeutically
effective drug levels rapidly if the drugs are administered in aqueous solution.
Subcutaneous insulin has been in used to treat diabetes from the past 80 years
[2]. Subcutaneously, insulin is injected beneath the skin, though poor blood
supply to region delays insulin absorption and makes absorption unpredictable
[3]. Absorption of insulin is generally complete for intramuscular route.
The rate of absorption via intramuscular route depends on vascularity of muscle
site, lipophilicity and degree of ionization of the drug. Intravenous insulin
is suitable for short – term clinical conditions such as thrombosis
and septicemia. The intraperitoneal insulin delivery is more reliable and
predictable as incidence of variable absorption and local degradation is minimal
[4]. Moreover, reduced fluctuations in blood glucose levels, minimal alteration
by lipid metabolism and less stronger immune response makes this route more
advantageous than other parenteral routes [5]. Though injectable insulin is
very effective and has many benefits but it is not well accepted by all patients
because of the problems associated with using a needle. This difficulty with
needles represents more than just a problem of pain or patient convenience.
One of the reasons for poor diabetic control is the fact that patients are
required to inject themselves every day. Not only has this reduced patient
compliance it also leads to complications. There is some reluctance by both
patients and healthcare professionals to initiate insulin therapy. This reluctance
has been termed 'psychological insulin resistance'. Barriers to the initiation
of insulin therapy include patients' fear of disease progression and needle
anxiety; mutual concerns about hypoglycemia and weight gain; and health professionals'
use of insulin as a threat to encourage compliance with earlier therapies
[6]. Since 1920s, several researchers are looking for new methods of delivering
this crucial medication. Ever since insulin was identified as the key to restore
normal glucose levels in diabetic patients, doctors and patients, both have
been hoping for an alternative to insulin injections. This article reviews
various alternative insulin delivery systems beneficial to both patients and
health care professionals.

2. Alternative Routes of Insulin Delivery

2.1 Oral Delivery

Insulin molecule is too large to be absorbed from gastrointestinal tract
and is broken down before it is absorbed. The possibility of delivering insulin
orally is attractive, but is often limited by poor bioavailability. The poor
bioavailability of orally administered insulin is attributed to its degradation
or inactivation by presystemic metabolism due to highly acidic gastric fluid,
gastrointestinal pancreatic enzymes and intestinal proteolytic enzymes [7-9].
Furthermore, poor permeability of insulin across intestinal barrier adds a
detrimental impact on its oral absorption, thus making insulin inaccessible
by this route. It has been reported that only a very small fraction of an
oral insulin dose becomes available for absorption through the gastrointestinal
membrane [10]. A desire to deliver insulin orally has prompted many scientists
to explore the various possibilities of improving oral bioavailability of
insulin by in vitro and in vivo studies in animal models. In the last several
decades, various strategies have been employed to overcome the formidable
barriers of enzymatic digestion and poor absorption to improve permeability
and to facilitates absorption by concurrent administration with protease inhibitors
and entrapping insulin within microparticles [11-14], liposomes [15, 16],
ethosomes [17], and nanoparticles [18] etc. Trotta et al., reported that solid
lipid microparticles also appear to have interesting possibilities as delivery
systems for oral administration of insulin [14]. The feasibility of using
liposomes as potential oral delivery systems for the systemic delivery of
insulin has also been studied. Moufti et al., [15] were able to produce a
50% reduction in blood glucose levels in normal rats by an insulin-containing
liposome. Dobre et al., [16] also illustrated a lowering of blood glucose
levels in normal rats following the oral administration of insulin entrapped
in phosphatidylcholine/cholesterol liposomes. Preliminary studies with plasmids
and insulin revealed that the ethosomal carrier might be used for enhanced
delivery of these agents [17]. Positive developments in coating soft gelatin
capsules containing insulin with enhancers and/or enzyme inhibitors like sodium
salicylate and sodium cholate have also been reported. The insulin nanoparticles
might represent a promising formulation for oral delivery of insulin when
prepared by a water-in-oil-in-water emulsification and evaporation method
using blends of biodegradable poly-epsilon-caprolactone and of Eudragis RS
[18]. A novel oral dosage formulation of insulin consisting of a surfactant,
a vegetable oil, and a pH-responsive polymer has been developed. The insulin
release from the resultant dry emulsion responded to the change in external
environment simulated by gastrointestinal conditions, suggesting that the
new enteric-coated dry emulsion formulation is potentially applicable for
the oral delivery of peptide and protein drugs [19]. It is evident from these
studies that the inclusion of enhancers/promoters and/or enzyme inhibitors
and other advancements do expedite the diffusion of insulin molecule across
the epithelial membrane, but achieving the higher oral bioavailability still
remains an unmet need.

2.2 Pulmonary Administration

Pulmonary route is a non-invasive route for systemic delivery of proteins/peptides
based therapeutic agents because lungs provide a vast (50–140 m2, 500
million alveoli) and well-perfused surface for absorption [20, 21]. This delivery
of insulin may result in improved patient compliance, may facilitate intensified
therapies and avoid the delay of initiating insulin administration because
of patient’s reluctance [22]. The inhalation of insulin was conceptualized
by the mid-1920s, but the first successful testing of inhaled insulin occurred
in the mid-1990s [23]. Inhaled insulin appears to be suitable because of its
better bioavailability than oral insulin and a pharmacokinetic profile that
mimics the time kinetics of insulin secretion after a meal [24]. Another advantage
with lung as a site of drug delivery is that it lacks peptidases that are
present in the gastrointestinal tract and hepatic "first pass metabolism"
is also avoided. Moreover, very thin alveolar-capillary barrier facilitates
a rapid uptake of peptides in the bloodstream resulting in and a rapid onset
of action after inhalation [21]. The use of enzyme inhibitors (proteases and
peptidases) in improving drug therapeutic activity through the lungs has also
been reported [25, 26]. In addition, some studies have concluded that a combined
approach using absorption enhancers (sodium glycocholate) with enzyme inhibitors
(bacitracin and bestatin) can effectively deliver insulin and salmon calcitonin
via the lungs [27]. Chitosan/tripolyphosphate nanoparticles have been developed
that promote peptide absorption across mucosal surfaces [28]. Recent clinical
studies suggest a possible role for inhaled insulin in fulfilling meal-related
insulin requirements in persons with Type 1 and Type 2 diabetes [29]. A new
drug delivery system, technosphere was developed to facilitate the absorption
of technosphere/insulin via pulmonary administration [23, 30]. Among various
difficulties of the pulmonary insulin delivery, the use of an effective promoter,
which is capable of increasing the bioavailability of insulin, is a crucial
issue. The cost of such insulin administration might also be a problem. Moreover,
aerosol delivery requires six times as much insulin for the same effective
dose as subcutaneous injection, which may create a cost barrier to widespread
use. Also, the long-term safety of delivering large amounts of insulin to
the alveoli is not known. The careful studies concerning the safety of this
kind of administration, particularly potential long-term pulmonary toxicity,
are mandatory [22]. Until recently, inhalation therapy focused primarily on
the treatment of asthma and chronic obstructive pulmonary disease, and the
pressurized metered-dose inhaler was the delivery device of choice. However,
the role of aerosol therapy is clearly expanding beyond that initial focus.
This expansion has been driven by the Montreal protocol and the need to eliminate
chlorofluorocarbons from traditional metered-dose inhalers, by the need for
delivery devices and formulations that can efficiently and reproducibly target
the systemic circulation for the delivery of proteins and peptides [31].

2.3 Transdermal Delivery

The delivery of large peptides through the skin poses a significant challenge,
and various strategies are under active investigation for enhancing the transdermal
permeation [32]. Transdermal iontophoresis is a physical enhancement strategy
primarily for charged molecules and offers a number of advantages for the
delivery of peptides and proteins. The singular advantage of iontophoresis
lies in the precise control of dose by manipulating the current protocol.
A low-level electrical current is used to enhance the delivery of drug ions
into the skin and surrounding tissues. The permeation of insulin was found
to increase as a function of current strength and duration of current application.
Skin barrier integrity and electrochemical stability of insulin was dependent
on the charge applied during iontophoresis [33]. Iontophoretically delivered
bovine insulin has been observed to produce a concentration-dependent reduction
in plasma glucose levels in depilated diabetic rats [34]. When carriers are
employed to administer macromolecules epicutaneously, the drugs must be associated
with specifically designed vehicles in the form of highly deformable aggregates
and applied on skin non-occlusively [35]. Using optimized carriers, transfersomes,
ensures reproducible and efficient transcutaneous carrier and drug transport.
Transfersomes transport the insulin with at least 50% of the bioefficiency
of a subcutaneous injection. The application of insulin-laden transfersomes
over a skin area 40 cm2 would provide the daily basal insulin needs of a typical
patient with type 1 diabetes [36]. Insulin loaded transferosomes can deliver
the drug through the non-compromised skin barrier with a reproducible drug
effect that resembles closely to that of an ultra lente insulin injected under
the skin. Transfersome mediated drug delivery through the skin is little affected
by the molecular size of the carrier associated active ingredient. Skin penetration
experiments done with transferosomes in vivo revealed that the preferred path
of the vesicle transport through the barrier always involves the regions of
lowest skin penetration resistance [35]. The data also confirm the essential
role of hydration gradient across the skin that provides the necessary energy
for the skin penetration by transferosomes [37]. To further improve patient
compliance, carrier-mediated transdermal insulin and inhaled insulin [38]
offer an attractive combination for truly non-invasive diabetes therapy. Transdermal
insulin, which acts for at least 24 h after a single application [39], could
become a replacement for basal insulin injections whereas inhaled insulin,
with its fast onset and relatively short duration of action [38], could eliminate
the need for preprandial insulin injections. An ultrasound-mediated transdermal
drug delivery offers a promising potential for noninvasive drug administration.

The feasibility of low-cost, lightweight cymbal array for enhanced transdermal
insulin delivery using ultrasound has also been studied by Lee et al., [40].
The skin poration with acoustic [41], electrical [42], photomechanical [43,
44] or thermal [35], means can yield excellent delivery results, but generally
suffers from the problem of temporary barrier destruction [45] and potentiality
of dermal immunization [46].

2.4 Intranasal Route

Nasal drug administration has been used as an alternative route for the systemic
availability of drugs, which were earlier, restricted to intravenous administration.
The concept of nasally administered insulin first appeared in 1935 [47] and
became popular due to large surface area of nasal cavity, its porous endothelial
membrane, large blood flow, avoidance of hepatic first-pass metabolism and
ready accessibility [48]. The nasal administration is quite an easy method
for patients and most successful among all the mucosal routes of drug delivery.
McMartin et al., [49] suggested that the nasal route is suitable for the delivery
of drugs with molecular weight less than 1000 Da without the aid of an absorption
enhancer and at least 6000 Da with the aid of absorption enhancer. Insulin
administered nasally is delivered rapidly that makes it useful for prandial
administration [50]. Significant bioavailability can be attained depending
on the factors like dose, timing, and frequency of insulin administration
[51]. Permeability enhancers may also be incorporated in nasal formulations
of insulin to augment the low bioavailability [51, 52]. Sucrose cocoate (SL-40),
ester containing a mixture of sucrose esters of coconut fatty acids in aqueous
ethanol solution, has also been emerged as an effective enhancer of nasal
peptide drug absorption [53]. Several approaches have been discussed for increasing
the residence time of drug formulations in the nasal cavity, resulting in
improved nasal drug absorption. The nasal mucosa presents an ideal site for
bioadhesive drug delivery systems. Bioavailability and residence time of the
drugs that are administered via the nasal route can be increased by bioadhesive
drug delivery systems. Drug delivery systems, such as microspheres, liposomes
and gels have been demonstrated to have good bioadhesive characteristics and
swell easily when in contact with the nasal mucosa [48]. Since, nasal route
is very sensitive to irritation, therefore, the excipients and other material
used to fabricate the system should not have serious irritant or adverse effects
[54].

2.5 Ocular Route

The eye presents unique opportunities and challenges when it comes to the
delivery of pharmaceuticals, and is most accessible to the application of
topical medications. Insulin, because of its high molecular weight, is one
of the most challenging drugs to deliver reproducibly via the ocular route
[55-59]. Eye drop formulations yielded only low bioavailability. Viscous aqueous
solutions, oil solutions, and emulsions can be drained from the eye by the
lachrymal system. Yamamoto et al., [60] conducted an extensive study on eye
drop delivery in rabbits and suggested that an ocular insert would be another
feasible approach to prolong and thus enhance the delivery of insulin via
the ophthalmic route. Simamora et al., introduced an ocular insert for the
delivery of insulin using Gelform® as a drug carrier to deliver sodium
insulin with the aid of Brij-78 as an absorption enhancer [61]. Conjunctival
cul-de-sac has been targeted as potential route for insulin delivery. Factors
like local irritation, loss in drainage, blinking limits bioavailability of
the drug through this route. To overcome this limitation, novel polymeric
systems are being investigated. Permeation enhancers such as BL-9, Brij-78
and alkylpolysaccharides have been found to be safe and stimulate systemic
absorption of insulin [62-64].

2.6 Rectal Route

Insulin administered via rectum successfully avoids the hepatic first pass
metabolism, is independent of intestinal motility, gastric emptying time,
and presence of diet and encounters less degrading enzymes. Insulin is probably
the most investigated polypeptide with regard to rectal administration. Yamasaki
et al., examined the effectiveness of insulin administration by rectal suppository
in normal and non-insulin dependent nonobese diabetic subjects.100-IU insulin
suppository 15 minutes after meals, three times daily significantly reduced
postprandial hyperglycemia and urine glucose [65]. A thermo-reversible insulin
liquid suppository was developed, which was able to undergo a phase transition
to bioadhesive gels at body temperature and enhance the bioavailability of
insulin. It was concluded to have a potential to be developed as a more convenient,
safe and effective rectal delivery system of insulin [66]. Ritschel et al.,
delivered insulin using rectal gels made of emulsion system prepared from
pH 8 buffer solution containing insulin, an oleaginous phase, a surfactant
(bile salt) and viscosity enhancer [67]. Water-in-oil-in-water multiple emulsions
incorporating 2% Docosahexaenoic acid or eicosapentaenoic acid administered
directly into the colonic and rectal loops dose dependently decreased serum
glucose levels. Insulin-loaded W/O/W multiple emulsions composed of medium-chain
triglycerides have been shown to decrease the blood glucose level after oral
administration to diabetic rats [68].

2.7 Others

2.7.1 Vaginal/Uterine Route

Insulin delivery through vaginal mucosa also prevents presystemic degradation.
Attempts have been made with lysophosphatidylcholine-containing insulin as
an aqueous solution and as lyophilized powder with bioadhesive starch microspheres
[69]. Insulin has also been administered through intrauterine delivery in
rats and found to be absorbed in biologically active form in the uterus of
rats [70].

2.7.2 Buccal Route

Buccal or delivery into the mouth involves a device that delivers a spray
of insulin, which is absorbed in the lining at the back of the mouth and throat.
It avoids problems from putting large amounts of insulin in the lungs. Drugs
are absorbed through thin mucosa into the reticulated veins and enter into
the systemic circulation directly, thus bypassing the hepatic metabolism.
Nagai and Machida have improved systemic bioavailability of insulin by buccal
delivery using sodium glycocholate as absorption promoter into a mucosal adhesive
delivery system [71]. Xu et al., from the rabbit and rat experimental results
showed that insulin buccal spray, a formulation with soybean lecithin and
propanediol combined as absorption enhancer, is an effective buccal delivery
system, which is promising for clinical trial and the future clinical application
[72].

2.7.3 Transmucosal Route

High vascularity, easy accessibility and absorptive mucosa make it a potential
and reliable route for insulin delivery. This route is also a noninvasive
and bypass presystemic metabolism. A Transmucosal insulin, Intesulin-A (Coremed)
had extremely rapid insulin peak absorption at 5 min and does not have sustained
hyperinsulinemia [73]. New transmucosal insulin, Intesulin-B (25 units insulin/ml,
Coremed) shows extremely rapid insulin peak absorption at 5 min. in both diabetic
and non-diabetic rats. It lowers glucose linearly over many hours and has
profound hypoglycemic action [74].

3. Conclusion

The formidable task of administering insulin non-invasively has been pursued
over the last several decades with a view to ease pain and stress of multiple
daily injections to the millions of diabetic patients worldwide. Needle phobia
and stress led to the investigation and exploitation of all promising routes,
ranging from oral to rectal, by a wide variety of devices and delivery systems.
Several pharmaceutical companies are also involved actively in developing
a non-injectable insulin delivery system. Some of the companies are mentioned
in Table 1. Among the various routes of insulin administration, each has its
own set of favorable and unfavorable properties. Most of the approaches described
above represent long-term possibilities for insulin delivery, but difficulties
in securing adequate blood insulin concentrations are yet to overcome. The
quest for a permanent cure of diabetes still continues and the advent of time
will show some promising light on the new horizon on the insulin therapy.

Table 1. Some of the companies involved in Insulin formulation

 

Insulin dosage form

Name and address of Manufacturer
Oral Ariad Pharmaeutical, Cmbridge, Massachusetts, USA

AutoImmune, Pasadena,
California, USA

BioSante Pharmaceuticals, Lincolnshira, Illinois, USA

Cortecs, Flintshire, UK

Elan, Dublin, Ireland

Emisphere Technology, Inc., Tarrytown, New York, USA

Endorex, Lake Buff, Illinois, USA

Nobex Corporation, Raleigh, North Carolina, USA

Transgene Biotek Ltd., India

Unigene Laboratories, Inc., Fairfield, New Jersey, USA

Pulmonary AeroGen Inc., Mountain View, California, USA

Alkermes, Cambridge,
Massachusetts, USA

Aradigm Corporation, Hayward, CA

Aventis, Bridgewater, NJ, Pfizer, NY

Dura Pharmaceuticals, Menlo Park, California, USA

Epic Therapeutics Inc., Norwood, Massachusetts, USA

ImaRx Therapeutics, Tucson, Arizona, USA

Inhale Therapeutics, San carlos, CA

Nektar Therapeutics Inc., San Carlos, CA

NovoNordisk, Bagsvaerd, Denmark

Transdermal Altea Development Corporation, Altanta, Georgia, USA

Cygnus Pharmaceuticals, Redwood city, California, USA

Helix Biopharma Corporation, Aurora, Ontario, CA

IDEA, Munich, Germany

ImaRx Therapeutics, Tucson, Arizona, USA

Noven Pharmaceuticals, Miami, FL

Sontra Medical Corporation, Cambridge, Massachusetts, USA

Vector Medical Technologies Inc., Miami, FL

Intranasal Bentley Pharmaceutical Inc., North Hampshire, USA

ML Laboratories, Warrington, UK

Odem Ltd., Cambridge, Massachsetts, USA

Pari GmbH, Midlothian, Virginia, USA

Vectura Ltd., Cambridge, UK

West Pharmaceutical Services, Lionville, Pennysylvenia, USA

Ocular

BioSante Pharmaceuticals, Lincolnshira, Illinois, USA.

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About Authors:

Ritu Gilhotra

Ritu Gilhotra

Ritu Gilhotra has earned her Bachelor and Masters of Pharmacy (Pharmaceutics)
from Guru Jambeshwar University (India). She has published her work in National
and International Journals and coauthored in abstracts as well. She is currently
working as Lecturer at Jaipur college of Pharmacy, Jaipur, India.

Neeraj Gilhotra

Neeraj Gilhotra

Neeraj Gilhotra obtained his Masters Degree in Pharmacology from Punjabi
University (India). Neeraj Gilhotra is working as Asst. professor at Jaipur
college of Pharmacy, Jaipur, India. He has worked as Principal Investigator
in the field of Pharmaceutical care and rational medicine use, as an advisor
in India for International Pharmaceutical Students Federation, Netherlands.
He has published the work in National and International Journals and in abstracts.
He is also engaged with Young Pharmacist Group of India (YPG-FIP) in India
as Director, Community Services. He is Life Member of various Indian professional
associations.

Deepak Kaushik

Deepak Kaushik obtained his Bachelor of Pharmacy from M. D. University, India
and Masters of Pharmacy in Industrial Pharmacy from S.G.S.I.T.S., Indore (India).His
research area include Formulation Development of Tablet Dosage Forms and Dissolution
Enhancement of Poorly Soluble Drugs. He has published his work on development
of melt-in-mouth tablets in national and international journals. He is currently
working as Lecturer at Department of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak. His current job responsibilities include teaching UG /
PG classes as well as guiding research.

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Meenal Gupta

Meenal Gupta earned her Bachelor in Pharmacy from M.D. University (India)
and her Master in Pharmaceutics from Punjabi University (India). Her research
areas include Chemical Computation, Transdermal Drug Delivery Systems and
Dissolution Enhancement of Poorly Soluble Drugs. She has published her work
in international journals and has presented at the Indian Pharmaceutical Congress
Conference. She has also coauthored abstracts, research articles and review
articles. She is currently working as a Lecturer in the Department of Pharmaceutical
Sciences, Maharshi Dayanand University, Rohtak. Her current job responsibilities
include teaching UG/PG classes as well as guiding research. She is a Life
Member of the Indian Pharmaceutical Association.

Harish Dureja

Harish Dureja

Harish Dureja studied Pharmacy at C. C. S. University (India) and obtained
Masters Degree in Pharmaceutics from Punjabi University (India). His research
areas include Transdermal Drug Delivery Systems, Pharmaceutical Process Development
and Chemical Computation. He has published the work in more than 30 publications
in National and International Journals. He is currently working as Lecturer
at Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak.
His current job responsibilities include teaching UG/PG classes as well as
guiding research. He is Life Member of Indian Pharmaceutical Association.

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