1. Nutrition 26 (2010) 33–39
www.nutritionjrnl.com
Review article
Inhaled insulin—Intrapulmonary, intranasal, and other routes
of administration: Mechanisms of action
R. I. Henkin, M.D., Ph.D.*
Center for Molecular Nutrition and Sensory Disorders, The Taste and Smell Clinic, Washington, D.C., USA
Manuscript received April 17, 2009; accepted August 3, 2009.
Abstract Background: After discovery of insulin as a hypoglycemic agent in 1921 various routes of admin-
istration to control blood glucose were attempted. These included subcutaneous, oral, rectal, sublin-
gual, buccal, transdermal, vaginal, intramuscular, intrapulmonary and intranasal delivery systems.
While each delivery system controlled hyperglycemia the subcutaneous route was given priority until
2006 when the Federal Drug Administration (FDA) approved the first commercially available
pulmonary inhaled insulin.
Methods: A review of major publications dealing with intrapulmonary administration of insulin was
made to understand the physiological basis for its use, its efficacy in controlling hyperglycemia, its side
effects and a comparison of its efficacy with other delivery methods.
Results: The large surface area of the lung, its good vascularization, capacity for solute exchange and
ultra thin membranes of alveolar epithelia are unique features that facilitate pulmonary insulin deliv-
ery. Large lung surface area (w75 m2) and thin alveolar epithelium (w0.1–0.5 mm) permit rapid drug
absorption. First pass metabolism avoids gastrointestinal tract metabolism. Lung drug delivery
depends upon a complex of factors including size, shape, density, charge and pH of delivery entity,
velocity of entry, quality of aerosol deposition, character of alveoli, binding characteristics of aerosol
on the alveolar surface, quality of alveolar capillary bed and its subsequent vascular tree. Many studies
were performed to optimize each of these factors using several delivery systems to enhance pulmonary
absorption. Availability was about 80% of subcutaneous administration with peak activity within 40–
60 min of administration. Intranasal insulin delivery faces a smaller surface area (w180 cm2) with
quite different absorption characteristics in nasal epithelium and its associated vasculature. Absorption
depends upon many factors including composition and character of nasal mucus. Absorption of intra-
nasal insulin resulted in a faster absorption time course than with subcutaneous insulin.
Interpretation: After many studies the FDA approved Pfizer’s product, Exubera, for intrapulmonary
insulin delivery. While the system was effective its expense and putative side effects caused the drug
company to withdraw the drug from the marketplace. Attempts by other pharmaceutical companies to
use intrapulmonary insulin delivery are presently being made as well as some minor attempts to use
intranasal delivery systems. Ó 2010 Elsevier Inc. All rights reserved.
Keywords: Insulin; Hormones; Glucose metabolism; Inhalation; Lung; Nose; Insulin metabolism; Nasal mucus
Introduction administer this key agent to control blood glucose. Initial
attempts delivered the hormone intramuscularly, intrave-
Discovery of insulin as a hypoglycemic agent by Banting nously, and eventually subcutaneously. Other routes of
and Best in 1921 [1] and its subsequent purification indicated administration of the drug were explored. These included
that this hormone was of great value to patients with diabetes oral, rectal, sublingual, buccal, transdermal, vaginal, intra-
mellitus. The practical question at that time was how to muscular, intrapulmonary, and intranasal delivery systems.
The purpose of these latter studies was to determine a non-
injectable method to deliver insulin to patients with type 1
* Corresponding author. Tel.: þ202-364-4180; fax: þ202-364-9727. and 2 diabetes that would effectively lower blood sugar, con-
E-mail address: rihenkin@earthlink.net (R. I. Henkin). trol hemoglobin A1c (in much later studies), and allow
0899-9007/10/$ – see front matter Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.nut.2009.08.001

2. 34 R. I. Henkin / Nutrition 26 (2010) 33–39
patients a simpler, less invasive, and more direct control of Particle size
their underlying disease process. Only recently has interest
in alternative administration routes to the commonly used Absorption of particles by the lung has been shown to
subcutaneous and intravenous routes been forcefully revived. have an optimal aerodynamic diameter from 1 to 5 mm. To
However, there were no a priori concepts that would direct its target the alveolar region specifically, aerosol droplet diame-
delivery by one or another method. As clinical events ter has been determined to be no more than 3 mm with parti-
occurred it became clear that absorption of the insulin mole- cles >6 mm deposited in the oropharynx but <1 mm exhaled
cule by any route could be improved. Thus, absorption during normal tidal breathing [3].
enhancers were used to improve hormone absorption. In
this manner, protamine zinc was formulated early in the treat-
Delivery devices
ment process with significant improvement in hormone
action. Other enhancers were considered later.
Delivery depends on the character of the delivered drug as
In January 2006 the United States Food and Drug
liquid or powder. Devices are usually nebulizers that are me-
Administration approved Exubera (Pfizer Pharmaceuticals,
tered-dose inhalers or drug-powder inhalers. The problem
New York, NY) as the first pulmonary inhaled insulin. In
with liquid nebulizers is that 99% of generated droplets are
actuality attempts to explore various methods to deliver in-
recycled back into the reservoir to be redelivered during the
sulin using intrapulmonary delivery had occurred since
next dose [3]. In addition, droplets rendered by nebulizers
1925 [2]. Approval of Exubera was the result of many years
are heterogeneous, which results in poor drug delivery to
of work by many groups of scientists who had to overcome
the lower respiratory tract. These devices usually use a hydro-
many obstacles to obtain this event.
carbon propellant to atomize the drug solution, with a result-
In the present work some of the physiologic bases for
ing more-uniform spray, but these proteins and peptides are
intrapulmonary, intranasal, and other delivery routes are dis-
susceptible to denaturation when in contact with a propellant
cussed, in addition to advantages and disadvantages of each
or with large air–liquid water forces that are constantly gen-
approach and mechanisms of action.
erated during aerosolization [3].
Dry-powder inhalers are currently the most commonly used
devices to deliver pulmonary insulin and treat many pulmo-
Intrapulmonary insulin
nary conditions. This method improved drug delivery stability
and sterility [4] over liquid aerosols [5]. Although dose-to-dose
The lung has been considered a route for systemic deliv-
variations occur and delivered material is susceptible to envi-
ery of many therapeutic proteins and peptides [3]. This
ronmental humidity and moisture and is dependent on inhala-
system includes two major anatomical parts. The first
tion flow rates [3], this method was chosen because accurate
includes the upper airways, oral cavity, trachea, bronchi,
dosing and relatively complete drug delivery were ensured.
and all upper airways distal to the bronchioles. The second
This choice was based on development of a novel inhaler
includes the lower airways, conducting airways including
device, improved powder engineering technology, a functional
respiratory bronchioles, alveolar ducts, and alveolar sacs.
drug carrier, and knowledge of absorption enhancers, which
The large surface area of the lung, its good vascularization,
optimized drug delivery [5]. Mechanically a fixed volume of
immense capacity for solute exchange, and ultrathin mem-
air was used to aerosolize a pre-metered and sealed drug
branes of alveolar epithelia are unique features that facilitate
dose into a chamber. The patient inhales the drug into the
systemic delivery of these substances [3]. The lung offers
lung using a slow, deep breath, eliminating the complex motor
a large surface area for drug absorption (w75 m2). The
co-ordination required for liquid propellant devices.
very thin alveolar epithelium (w0.1–0.5 mm thick) permits
rapid drug absorption. The alveoli can be targeted for effec-
tive drug absorption by drug delivery by aerosol with Pulmonary barrier and pulmonary absorption
a mass medium aerodynamic particle diameter <5 mm.
First-pass metabolism in this route avoids gastrointestinal These parameters include the amount and character of
tract metabolism. Although metabolic enzymes are found respiratory mucus, amount and speed of mucociliary clear-
in the lung, their activities and metabolism are different ance, character and thickness of the alveolar lung layer, alve-
from those found in the gastrointestinal tract [3]. olar epithelium, basement membrane, pulmonary enzymes,
Drug delivery to the lung is defined by a complex of fac- macrophages, and cells that may act as barriers to pulmonary
tors including character of moieties to be transported and absorption [3]. Although alveolar and capillary epithelia may
absorbed, their size, shape, density, charge, pH of delivery be highly permeable to water permeation of many hydro-
entity, velocity of entry into the system, quality of deposition philic substances, absorption of moieties of large molecular
of aerosol in which the moiety is inhaled, character of alveoli, size and ionic species is limited [3]. Molecular weight cutoff
binding characteristics of the aerosol to the alveolar surface, of tight junctions for absorption by alveolar type I cells is
qualities of the alveolar capillary bed, character of the capil- 0.6 mm, although endothelial junctions allow passage of
lary bed, and its subsequent vascular tree. larger molecules (4–6 mm) [3].

3. R. I. Henkin / Nutrition 26 (2010) 33–39 35
After reaching the alveoli many proteins are degraded by insulin is absorbed, studies have suggested that the degree
proteases or are removed by alveolar macrophages that se- of inhaler absorption is reproducible.
crete short-lived peroxidases, inflammatory and immuno- Many clinical trials of various dry-powder preparations
modulatory mediators [including granulocyte colony have indicated that inhaled insulin had a faster onset of action
stimulating factor (GCSF), interleukins, leukotrienes, and than subcutaneous systems [25,26] and a clear dose–response
proteases], and other host-defense molecules. These mole- has been measured [18,19]. Availability of intrapulmonary
cules degrade inhaled peptides and proteins. insulin has been shown to be about 80% of that of subcutane-
Pulmonary mucus is the direct surface layer with which ous administration [8]. Efficiency of insulin delivery depends
insulin comes into contact. Pulmonary mucus varies from on many factors including losses related to delivery device,
1 to 10 mm in thickness. In the mucus is surfactant (0.1– environment of delivery, deposition of insulin in the mouth,
0.2 mm thick) that lines the alveoli and forms a barrier to throat, and bronchi with intrapulmonary administration, and
absorption [3]. incomplete absorption from alveoli when introduced into the
Much work has been done to develop insulin absorption lung. Through the lung maximum delivery efficacy is esti-
enhancers or promoters that increase dry-powder insulin ab- mated to be about 30%, with peak activity occurring within
sorption. These include multiple and different types of com- 40–60 min [19]. The technique was proved reproducible
pounds relating to various aspects of enhancing pulmonary and safe, with intra-subject variability not differing from
absorption [6,7]. Addition of these substances improved that observed with subcutaneous administration [17].
drug delivery reproducibility and decreased variability Efficacy of intrapulmonary insulin administration com-
[3,8–10]. pared with that of subcutaneous insulin has been evaluated
by many investigators in many studies in normal and diabetic
Human studies subjects [2,27,28]. Results have demonstrated that inhaled
insulin provides equivalent glucose control to that of subcu-
In 1925 Gansslen [11] reported the first study of efficacy
¨ taneous insulin as measured by hemoglobin A1C [17]. Some
of insulin administration by the pulmonary route; results investigators have indicated that inhaled insulin improves
indicated that inhalation of crude animal pancreas extract glycemic control over that of subcutaneous insulin. These
reduced blood glucose by 26% within 2.5 h. Many subse- results have indicated that the inhaled system is not only
quent studies up to the present have provided direct evidence efficacious but also well tolerated, well liked, and results in
of absorption of insulin after pulmonary inhalation [12–18]. reproducible results as acceptable or even more acceptable
Initial estimates have suggested that about 10–13% of than subcutaneous administration [29,30]. Indeed, treatment
aerosolized insulin product was delivered into the lung satisfaction was greater among patients receiving inhaled
(e.g., with a delivery efficacy of about 30%) [19]. Studies compared with subcutaneous insulin [29]. A potential advan-
have indicated that postprandial glucose levels could be tage of aerosol insulin is that it is more rapidly absorbed
maintained below diabetic levels by intrapulmonary insulin (serum peak a 5–60 min) and cleared than subcutaneous insu-
administration [12–19]. Some investigators have maintained lin (peak at 60–150 min), which provides a more relevant and
that inhaled insulin provides a more physiologic prandial in- convenient mealtime glucose control [17]. Because of this
take replacement than ‘‘regular’’ (i.e., subcutaneous) insulin rapid absorption the onset of action of inhaled insulin is faster
in patients with diabetes [20]. It is not simply a question of than that of subcutaneous injection [27]. Compared with sub-
insulin absorption through the lung but under what condi- cutaneous injection the relative efficiency of delivery by
tions this process can be maximized and controlled [9]. As aerosol has been estimated to be retained from 360–
noted, particle size and ventilation parameters including tidal 380 min dependent on dosage administered [29]. Some
volume, inspiratory flow rates, and lung functionality are sig- investigators have considered duration of action of intrapul-
nificant factors in determining particle deposition into the monary and subcutaneous administrations to be similar
lung with subsequent insulin absorption into the blood by [27], whereas others have considered action duration of
the alveolar capillary system [21]. Studies have suggested inhaled insulin to be longer [27]. As noted earlier, insulin
that moieties such as insulin are absorbed into the blood by binding antibody was increased in patients who used the
transcytosis, a process occurring at the alveolar capillary inhaled compared with the subcutaneous method of adminis-
membrane by transposition of tiny membrane ‘‘bubbles’’ or tration [24]. With respect to the primary mechanism of action
transcytotic vessels that are dependent on particle size, mo- of inhaled insulin, as noted earlier, it appears to be absorbed
lecular weight, solubility, charge, lipophilicity, pH, and by transcytosis across the alveolar–capillary membrane
membrane permeability [22,23]. This system has been mod- [22,23,27].
eled to evaluate the contribution of each of these and other However, the first drug approved to deliver intrapulmo-
factors separately and as a complex system [21]. As with nary insulin had its detractors [31]. Its usefulness was initially
subcutaneous insulin administration, over time, antibodies inhibited by its cost, which was significantly greater than that
to insulin develop and inhaled insulin has been reported to for subcutaneous administration. It was withdrawn from the
produce a larger antibody response than has subcutaneous market in 2008. Its death knell occurred with reports of sev-
insulin [24]. Despite the fact that only a fraction of inhaled eral cases of lung cancer attributed to its use [32,33], although

4. 36 R. I. Henkin / Nutrition 26 (2010) 33–39
the drug company marketing the drug denied this was the blood–brain barrier and can pass directly into the brain.
cause of the withdrawal [34]. The former method of absorption was measured indirectly
by comparing levels of endogenous insulin in blood, nasal
Intranasal insulin mucus, and saliva under varying conditions [36–38]. Results
of these studies have illustrated that the metabolism of insu-
Many of the same absorption issues related to intrapulmo- lin, insulin receptor, IGF-I, or IGF-R3 differ significantly in
nary insulin administration relate to intranasal inhalation of blood plasma, nasal mucus, and saliva, suggesting that mech-
insulin. Although this mode of administration has not been anisms that control insulin secretion and utilization differ in
studied as extensively as has intrapulmonary inhalation, it these three fluids. The latter method of absorption, using
has been used for the past 25 y. Although the surface area these same data, suggests that one aspect of these differences
for intrapulmonary insulin inhalation is quite large could relate to neural control of insulin metabolism through
(w75 m2), the surface area for intranasal insulin inhalation endogenous nasal absorption of insulin. This hypothesis sug-
is much smaller (w180 cm2) [3]. However, characteristics gests that intranasal administration of insulin may offer
of the upper airways may make intranasal insulin administra- a unique and useful method of insulin administration that
tion a more suitable surface for drug administration [35]. may provide an important and novel method that could tap
Insulin itself is secreted into nasal mucus by serous glands into important and heretofore unanticipated methods of con-
that line the nasal mucus membrane [35]. This secretion trol of insulin administration. This could not only control
changes physiologically with obesity, decreased food intake, blood glucose directly but also control insulin effects on
and in patients with type 2 diabetes [36]. Insulin receptors are central nervous system (CNS) metabolism and secretion of
also secreted into the nasal mucus [37] and are similarly substances by which insulin feedback mechanisms could be
responsive to obesity, decreased food intake, and in type 2 enhanced.
diabetes [37]. Similarly, insulin-like growth factor (IGF)-I Control of insulin metabolism by insulin replacement
and IGF receptor 3 (IGF-R3) are secreted into nasal mucus through inhalation and CNS processing is an important issue
and have been previously reported to be present in this that has not been fully addressed. Kern et al. [40] reported
fluid [38]. that intranasal insulin reduced amplitudes of auditory-evoked
Delivery of intranasal insulin, as with intrapulmonary potentials and increased latency of some waveforms that they
delivery, is dependent on many anatomic and physiologic interpreted as demonstrating direct insulin entry into the brain
factors that enhance and inhibit absorption. These include and directly influencing CNS function. Sigurdsson et al. [41]
nasal mucus concentration, character of the nasal mucus using I125-insulin demonstrated the transport of intranasally
[39], speed of mucociliary clearance, character and thickness administered insulin directly into the brain and systemic
of the mucociliary membrane, nasal mucus enzymes, macro- absorption. They concluded that insulin gains entry into the
phages, and other cells that may act as barriers to intranasal CNS from the olfactory region of the upper nose by a non-
absorption and—groups of moieties not present in pulmo- specific pathway [41]. Other studies suggesting direct CNS
nary secretions—xenobiotics, bacteria, fungi, and other effects of intranasal insulin administration relate to intranasal
active microbial and antimicrobial agents present in the insulin improving human memory [42,43], acting on adipos-
nose that are not present in the lower airways or in lung. In- ity signals [44], and improving several aspects of cognitive
deed, the nose, compared with the lung, is a ‘‘dirty’’ area in function [44]. Intranasal administration of IGF-I has also
which interactions among microbial, antimicrobial, and been shown to bypass the blood–brain barrier and have a di-
xenobiotic agents are present at all times; this type of interac- rect CNS effect protecting against focal cerebral ischemic
tion, although present to some extent in portions of the upper damage [45], reducing infarct volume after middle cerebral
airways, is not present in lung alveoli, which are usually artery occlusion [46], and improving neurologic function
sterile. after this procedure [46]. Intranasal insulin delivery of IGF-
The optimal particle size for intranasal insulin administra- I into the brain and spinal cord was considered to travel along
tion is not well characterized. However, it may be assumed olfactory and trigeminal pathways [47]. Transport into the
that similar-size or somewhat larger particles than those pre- brain, as with systemic absorption through the nose, was
sented to pulmonary alveoli would be absorbed. Intranasal dependent on molecular characteristics including size,
delivery devices may be similar with respect to intrapulmo- charge, solubility, lipophilicity, and other molecular charac-
nary drug presentation, with dry powder preferable to fluid teristics. Nasal delivery avoids the major action of liver me-
aerosol sprays. tabolism, as occurs with the subcutaneous route, although
What makes intranasal insulin administration more attrac- cytochrome P-450 activity in the olfactory region of the nasal
tive than intrapulmonary administration is that absorption airway is higher than in liver due to a higher content of
into the nose not only bypasses gastrointestinal inhibition nicotinamide adenosine dinucleotide phosphate/cytochrome
of insulin absorption but also offers two important physio- P-450 reductase. There are also peptidases and proteases in
logic processes for insulin absorption: 1) absorption by the nasal mucus that limit direct insulin delivery.
the large available complex plexus of small blood vessels That intranasal insulin acts similarly to subcutaneous insu-
in the nose and 2) absorption that is not limited by the lin administration in the control of blood glucose is well

5. R. I. Henkin / Nutrition 26 (2010) 33–39 37
known [48]. There have been many clinical studies of this in each route of administration, but nasal absorption was
route of insulin administration demonstrating long-term suc- induced the greatest, with the rank order effect changed
cessful control of plasma glucose [49–57]. such that nasal > rectal > sublingual, with nasal and rectal
As with intrapulmonary delivery composition, the intrana- being about half as efficacious as intramuscular insulin
sal delivery system has been reported to play a significant role [65]. In the absence of an absorption promoter substantial
in insulin absorption. Intranasal absorption has been amounts of buccal insulin were not absorbed, but with
improved by using absorption enhancers such as aminobor- absorption enhancers (sodium taurocholate, sodium laurel
onic acid derivatives, amastatin, and enzyme inhibitors sulfate, sodium methoxy salicylate, sodium dextran sulfate,
[58]. Surfactants, such as bile salts, have been reported to ethylenediaminetetra-acetic acid, and Brij-35) buccal insulin
increase absorption by inhibiting the action of proteolytic en- was absorbed and induced hypoglycemia, although pharma-
zymes present in nasal mucus [58]. The variety of the compo- cologic availability was dependent on the concentration of
sition of the intranasal delivery systems was reported to play the absorption promoter [66,68]. Bioavailability from buccal
a significant role in insulin absorption. Use of surfactants administration was about 12%, whereas it was about 4% from
[50,52], gelified insulin [53], bioadhesive microspheres oral administration [68].
[59], phospholipids [54], chitosan nanoparticles [59], and
other enhancers amplified absorption of intranasally deliv-
Summary
ered insulin. Administration of insulin as a dry powder was
considered more effective than as a liquid aerosol. However,
Insulin absorption can be obtained by many routes of
liquid nose drops containing insulin and alkyl glycerides [60]
administration dependent on the characteristics of the insulin
have also been proved effective.
molecule, its absorption enhancement promoters, formula-
Intranasal insulin absorption resulted in a faster time
tion of the delivery system, nature of the system into which
course of absorption than subcutaneous administered insulin
insulin is to be delivered, ease and convenience of adminis-
[54]. Its bioavailability was 8.3% compared with an intrave-
tration, and cost. These factors suggest that, although intra-
nous bolus [54] and a dose-dependent suppression of C-pep-
pulmonary insulin administration is not currently available,
tide and stimulation of glucagon secretion occurred after this
intranasal insulin administration may be a more effective
route of administration [54].
non-invasive method of administration [35]. Future studies
In general there has been little toxicity associated with
will establish whether or not this suggestion will be verified
intranasal insulin delivery [61]; it has been well tolerated
in the marketplace.
without any long-term side effects [61]. However, reports
of increased cough, nasal irritation, inflammation, or pruritus
from intranasal insulin delivery have been made [61], and References
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