(Chest. 2001;120:99S-106S.)
© 2001
American College of Chest Physicians
Treating Diabetes With Aerosolized Insulin*
Beth L. Laube, PhD
*
From The Johns Hopkins University, Baltimore, MD.
Correspondence to: Beth L. Laube, PhD, Pediatric Pulmonary Department, Johns Hopkins University Hospital, Park 316, 600 North Wolfe St, Baltimore, MD 1287–2533; e-mail: blaube{at}welchlink.welch.jhu.edu
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Abstract
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Because of the pain, inconvenience, and disruption of lifestyle
associated with the injection of insulin, many patients with diabetes
are noncompliant in terms of treatment regimens that require daily
multiple injections. To eliminate the pain and to improve treatment
outcome, there has been increasing interest in the development of
aerosolized insulin to replace subcutaneously (SC) delivered
formulations. Recent studies in human volunteers have shown that when
aerosolized insulin is effectively delivered to the alveolar region of
the lung, absorption rates and decreases in glucose levels are similar
to those achieved with SC-delivered insulin during the fasting state.
Other human trials have shown that inhaled insulin also effectively
controls postprandial glucose levels. Aerosolized insulin is
well-tolerated, and there is no evidence of irritation, hypoglycemia,
or changes in pulmonary function when administered over short periods.
At present, limitations in the delivery device result in less efficient
administration of insulin aerosol compared to SC dosing. However, new
devices and different formulations of insulin, which are currently
under development, should improve the efficiency. It is likely that the
treatment of diabetes with aerosolized insulin will provide an
effective alternative means for controlling plasma glucose levels in
diabetic individuals. Aerosolized insulin also will serve as a
developmental model for this route of administration for a number of
other therapeutic peptides that are currently administered by injection
only.
Key Words: aerosol • diabetes • insulin • intrapulmonary delivery
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Introduction
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Of
the 8 million individuals in the United States with diagnosed diabetes
mellitus, between 500,000 and 1 million have type I, or
insulin-dependent diabetes mellitus. Type I patients require injections
of insulin for glycemic control from the time of diagnosis, and it is
now recommended that they self-inject three or more times each day for
optimal glucose control.1
An additional 7.5 million
patients have type II, or non-insulin-dependent diabetes mellitus
(NIDDM). Initially, their diabetes can be controlled with oral
hypoglycemic drugs, changes in diet, and exercise. However, as their
disease progresses, they too will require the injection of insulin to
control their glucose levels. Thus, there is a large population of
patients with diabetes who require, or will require, insulin by
injection at some point in their lives. Many patients, particularly
those who must inject themselves several times each day, find this
regimen inconvenient, disruptive, and painful. As a result, patient
compliance with treatment regimens that require insulin injection is
often compromised, leading to potentially suboptimal treatment
outcomes. Since inhaling an aerosolized drug is not associated with
pain, beginning as early as 1925,2
a number of
investigators have examined the possibility of administering insulin by
aerosol as an alternative to injection for delivery to the systemic
circulation.
While the delivery of insulin by inhalation has been most frequently
and thoroughly studied, the same rationale of improving patient
compliance, convenience, and comfort has led to research into
inhalational therapy for other drugs that can be administered only by
injection. These include the following proteins and peptides:
calcitonin for Paget’s disease and osteoporosis; leuprolide acetate
for prostate cancer, breast cancer in postmenopausal women, and
infertility; growth hormone-releasing factor for the treatment of
pituitary short stature; and morphine for analgesia. Along with
insulin, these peptides appear to be good candidates for aerosol
delivery and systemic treatment of diseases because of their relatively
high bioavailability after inhalation compared to other proteins, and
the degree of bioavailability seems to be associated with molecular
weight. This relationship is demonstrated in Figure 1 , which shows the bioavailability of a number of therapeutic peptides in
terms of their molecular weight. Bioavailability in the plasma is shown
as a percentage of the dose of the drug that is deposited in the lungs
of various animals and humans after inhalation, relative to
subcutaneous (SC) injection. In the human studies, bioavailability
decreases as molecular weight increases, such that the bioavailability
of leuprolide is greater than that of calcitonin, which is greater than
that of insulin.
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Figure 1. The bioavailability of several therapeutic
peptides of increasing molecular weight (MW) relative to SC injection
is shown. Bioavailability is expressed as a percentage of the dose of
the drug that is deposited in the lungs of various animal
species (solid symbols) and human volunteers (open symbols). The solid
squares and circles represent data obtained from rodents. The solid
triangles represent data obtained from monkeys.
G-CSF = granuloctye-colony-stimulating factor; hGH = human growth
hormone; PTH = parathyroid hormone. Source: R.K. Wolff, PhD; personal
communication (July 11, 2000).
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Intranasal vs Intrapulmonary Administration of Insulin Aerosol
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From a historical point of view, investigators have focused on the
possibility of developing aerosolized drugs that could be delivered by
either intranasal or intrapulmonary administration. Intranasal
administration often appears particularly promising because of the
accessibility of the nasal cavity. The disadvantage to intranasal
delivery for systemic absorption is that the surface area for
absorption is relatively small (approximately 150
cm2)3
compared to that of the
alveolar region of the lung, which has a resorptive surface of
approximately 75 m2.4
The other
disadvantage to intranasal administration is that the drug needs to be
absorbed quickly (in approximately 15 to 20 min) or it will be removed
to the back of the nasopharynx by the rapid mucociliary clearance
mechanisms in the nose and swallowed. This is again in contrast to the
fate of drugs that are deposited in the alveolar region of the lungs
where drugs have a longer residence time because mucociliary clearance
mechanisms are minimal.5
Although suboptimal in terms of the systemic administration of most
drugs, some investigators6
7
have reported significant
reductions in the plasma glucose levels of patients with diabetes
following intranasal delivery of insulin aerosol. Moses et
al6
and Salzman et al7
showed that a dose of
0.5 to 1.0 U/kg insulin aerosol delivered to the nose lowered plasma
glucose levels by approximately 50%. However, because of the need to
overcome the rapid mucociliary clearance mechanisms of the nose, these
doses were effective only when a surface-active material was added to
the aerosolized solution. These compounds enhanced absorption but also
resulted in patient complaints of irritation to the nose and nasal
congestion. For this reason, intranasal administration does not appear
to be the route of choice for delivering aerosolized insulin.
As noted above, optimal systemic delivery of aerosolized drugs by the
intrapulmonary route requires that the aerosol be targeted for
deposition in the alveolar region of the lungs. In addition to having
minimal mucociliary clearance mechanisms and comprising 95% of the
resorptive surface of the lungs, the alveolar region has an extremely
thin (0.1 µm) and vesiculated cell barrier to promote the absorption
of drugs that are deposited there.4
8
9
Targeting of the alveolar region is best accomplished by oral
inhalation of an aerosolized medication. However, the oral
administration of aerosolized drugs also has disadvantages because
particles > 5 µm typically impact at the back of the mouth and do
not penetrate to the lower airways. In addition, particles associated
with high aerosol velocities, such as those that are generated by
propellants, and particles that are inhaled during high inspiratory
flow rates (ie, > 30 L/min) also will impact at the back
of the mouth and be lost to the lower airways. These hurdles to drug
delivery to the lung could explain why early studies involving the
delivery of insulin by the intrapulmonary route demonstrated little in
the way of efficacy. For example, in 1987 Elliott et al10
found that insulin aerosol was absorbed through the respiratory
epithelium of human volunteers and was biologically active because
plasma insulin levels increased and glucose levels decreased. However,
the effect on plasma glucose levels was not statistically significant,
and only one subject demonstrated a therapeutic effect. These findings
were similar to those reported in earlier studies by
Gaensslen2
and Wigley et al11
Again, in each
of those studies, only one subject achieved normal plasma glucose
levels following the intrapulmonary delivery of aerosolized insulin.
It is likely that these failures to achieve euglycemia with
intrapulmonary delivery of insulin were due to underdosage, probably
arising from the loss of drug in the oropharynx or in the delivery
device. For technical reasons, none of these studies quantified the
dose of insulin that was available for inhalation at the mouth of the
patient, or the amount of insulin that deposited within the respiratory
tract. In the study by Wigley et al,11
250 U insulin was
nebulized to dryness and was delivered via a traditional jet-type
nebulizer. The researchers assumed at that time that they were
delivering 100% of the drug to the lungs. However, it later became
apparent that only about 10% of a nebulized drug is actually delivered
and deposited in the lungs.12
13
14
Elliott and
coworkers10
quantified the drug dosage that was available
for inhalation at the outport of the nebulizer but did not account for
possible losses between the nebulizer and patient (ie,
losses in the spacer device they used or in the delivery system
tubing).
By the late 1980s, it was clear that aerosol particle size, aerosol
velocity, and inspiratory flow rate were major determinants of aerosol
delivery to the lungs. Taking these factors into account, we decided to
reexamine the possibility of normalizing plasma glucose levels in
patients with diabetes by intrapulmonary delivery of aerosolized
insulin.15
In that study, aerosolized insulin or placebo
was generated by a raindrop nebulizer (Puritan Bennett; Lenexa, KS) and
was administered by oral inhalation following a 12-h fast. The raindrop
nebulizer was chosen because it produced particles small enough to
avoid impaction in the mouth, thus minimizing oropharyngeal deposition
and maximizing delivery to the lung. The outport of the nebulizer was
attached to a spacer device that increased the distance between the
subject’s mouth and the nebulizer. This reduced aerosol velocity and
additional losses in the mouth. The insulin dose was approximately 1.0
U/kg of 500 U/mL regular pork insulin. Patients inspired the aerosol
from residual volume to total lung capacity to promote deposition in
the lung periphery. The inspiratory flow rate was regulated to
approximately 17 L/min to further minimize impaction and loss of
insulin in the mouth and larger conducting airways.
Prior to inhaling aerosolized insulin, six patients with NIDDM inhaled
a saline solution aerosol containing the radioisotope technetium-99m,
which was generated and inhaled as described above. This procedure
provided a method for quantifying how much aerosol deposited in the
oropharynx and lungs with this delivery system. Gamma camera scans of
the oropharynx and lungs indicated that losses in the oropharynx were
low and that most of the drug penetrated into the lung (Fig 2
). Deep penetration of the drug into the smaller airways and alveoli was
evidenced by well-defined lung margins. For these study subjects, the
deposited fraction below the larynx ranged from 50 to 93% of the
inhaled dose, and the mean (± SD) deposition was
79 ± 17%.15
A total of 10 patients with NIDDM then inhaled a dose of 1 U/kg insulin
aerosol that was generated and delivered in the same way as the
radiolabeled saline solution aerosol. The mean age of the NIDDM
patients was 52 years, and their mean body mass index was 26.90. All
patients were naive to insulin. Nine of the patients were receiving
oral hypoglycemic agents, which were discontinued 4 days prior to the
patients’ arrival at the laboratory. Patients fasted for 12 h
before each study visit. All subjects were nonsmokers and had normal
pulmonary functions. Blood was collected for approximately 3 h
after the inhalation of the insulin in order to measure changes in
plasma insulin and glucose levels. Figure 3
shows a typical time-response curve for one of the study subjects. At
baseline, the glucose level for this subject was approximately 300
mg/dL. The level declined and was within the normal range
(ie, < 120 mg/dL) at 160 min after drug administration. In
this subject, insulin levels reached their peak in the plasma at
approximately 20 min postinhalation.
The mean maximal decrease from baseline in plasma glucose levels for
all 10 patients was 52 ± 9% (Table 1
). This was significantly greater than the decrease that was observed in
seven of the patients who inhaled a placebo aerosol. The average
maximal decrease in glucose following placebo inhalation was
14 ± 7%. Nine of the 10 patients also demonstrated normal glucose
levels after inhaling this dosage of insulin aerosol (Table 1)
. No
patients showed any signs or symptoms of airway irritation after either
placebo or insulin aerosol inhalation, and there were no signs or
symptoms of hypoglycemia.
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Control of Postprandial Glucose With Inhaled Insulin
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The results indicated that fasting glucose levels could be
normalized by the intrapulmonary delivery of 1.0 U/kg insulin aerosol
in patients with NIDDM. Nevertheless, the dose of aerosolized insulin
needed to regulate postprandial glucose levels below diabetic levels
(ie, < 200 mg/dL) was unknown. For this reason, we
undertook another study16
that tested the hypothesis that
1.5 U/kg aerosolized insulin administered when glucose levels are
within the normal range and 5 min before a meal will control
postprandial glucose levels below diabetic levels.
Seven nonsmoking patients with NIDDM and normal pulmonary functions
participated in the study. After blood glucose levels had been
normalized by the inhalation of 1.0 U/kg insulin aerosol, subjects
inhaled 1.5 U/kg insulin aerosol 5 min before ingesting a test meal
containing 681 calories (Table 2
). Aerosol was generated from 500 U/mL regular pork insulin and was
delivered to the mouth (Medicator delivery system; Healthline Medical;
Baldwin Park, CA). During aerosolization, subjects inspired slowly and
deeply to promote penetration of the aerosol into the lung periphery.
Blood samples were collected for 3 h after inhalation
and were analyzed for plasma glucose, insulin, and
C-peptide levels. On another visit, subjects inhaled a
placebo aerosol, which was generated and delivered in the same way as
the insulin aerosol, 5 min before the same test meal.
Figure 4
shows that a dose of 1.5 U/kg aerosolized insulin was significantly
more effective in controlling postprandial glucose levels at 1, 2, and
3 h after the test meal than placebo aerosol. The greatest
disparity between placebo and inhaled insulin occurred at 2 h. At
that time point, six of the seven patients had achieved glucose levels
of < 200 mg/dL, which is considered to be below the diabetic level,
while four of the seven patients achieved glucose levels within the
normal postprandial range (ie, < 145
mg/dL).16
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Figure 4. Mean (± SD) glucose levels at 1, 2, and 3 h
postmeal for seven patients with NIDDM who inhaled 1.5 U/kg insulin
aerosol (solid bars) or placebo aerosol (open bars) 5 min before
ingesting the test meal. Glucose levels were significantly lower at
each of the time points after inhaling insulin compared to placebo
aerosol.
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It is likely that these decreases in glucose level were
attributable to the exogenous administration of insulin aerosol rather
than to postprandial pancreatic stimulation for the following two
reasons: 1-h insulin levels were significantly higher following
aerosolized insulin administration compared with placebo (Fig 5
); and C-peptide levels at 1, 2, and 3 h postinhalation were
significantly lower after inhalation of insulin aerosol compared to
placebo (Fig 6
). Since insulin and C-peptide are cosecreted by pancreatic ß-cells in
equimolar amounts, the C-peptide level is considered to be an indicator
of endogenous insulin secretion.17
The reduction in
C-peptide levels following aerosolized insulin
administration indicated that endogenous insulin had been suppressed by
the intrapulmonary delivery of insulin aerosol in these patients.
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Figure 5. Mean (± SD) insulin levels at 1, 2, and 3 h
postmeal for seven patients with NIDDM who inhaled 1.5 U/kg insulin
aerosol (solid bars) or placebo aerosol (open bars) 5 min before
ingesting the test meal. Insulin levels were significantly higher at
the 1-h time point after inhaling insulin compared to placebo
aerosol.
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Figure 6. Mean (± SD) C-peptide levels at 1, 2, and 3
h postmeal for seven patients with NIDDM who inhaled 1.5 U/kg insulin
aerosol (solid bars) or placebo aerosol (open bars) 5 min before
ingesting the test meal. C-peptide levels were significantly lower at
each of the time points after inhaling insulin compared to placebo
aerosol.
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Intrapulmonary vs SC Delivery of Insulin
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A few investigators18
19
have measured the time to
peak insulin level in healthy fasted volunteers after intrapulmonary
delivery of nebulized insulin. In those studies, the average time to
peak insulin levels varied between 50 and 60 min18
and 15
to 20 min.19
When compared with the results from a
different group of healthy subjects who were injected SC with insulin,
it appeared that insulin was absorbed more rapidly through the lungs,
as the average time to peak insulin levels with SC delivery was 144
min.20
Heinemann and colleagues21
extended
those earlier findings by comparing the time to peak insulin levels
after the inhalation of a dry powder insulin aerosol vs SC injection of
insulin in matched healthy subjects. Confirming what had been reported
previously in unmatched groups of subjects, they found that the time to
maximal insulin levels averaged 24 min with the inhalation of the
powder vs an average of 106 min for SC injection.21
A
similar comparison was recently completed22
in matched
healthy volunteers using a liquid formulation of insulin aerosol.
Twelve volunteers inhaled the insulin aerosol (Humulin Regular U-500;
Eli Lilly and Company; Indianapolis, IN). On another day, the
volunteers were injected SC with insulin (Humulin U-100 Ultralente; Eli
Lilly and Company). The time to peak insulin levels
was earlier with inhaled insulin, averaging approximately 50 min
compared to SC injection, which averaged 85 min. Taken together, these
data suggest that insulin absorption through the lungs may be faster
than absorption after SC injection in healthy subjects.
We have examined the time to peak insulin levels after intrapulmonary
delivery of nebulized insulin aerosol in patients with
diabetes.15
In one study, 15
we found that
the time to the peak insulin level in patients with NIDDM averaged 40
min. That time was similar to what has been reported by Jendle and
Karlberg23
in another group of patients with NIDDM. The
time to peak insulin levels after SC injection of insulin was not
quantified in either of these studies. However, we have completed that
comparison in another group of patients. 24
Seven fasting
patients with NIDDM inhaled 1.0 U/kg nebulized regular pork insulin
aerosol by the intrapulmonary route on one occasion and were injected
SC with 0.1 U/kg insulin on another occasion.24
SC and
aerosol administration of insulin resulted in similar decreases in
glucose levels. The average maximum decrease in glucose levels was
54 ± 16% after insulin inhalation and 40 ± 20% after SC
injection. Although there was a trend toward a faster time to peak
insulin level with the inhaled drug, the mean times to peak insulin
levels were not statistically different for the two modes of insulin
administration, averaging 43 ± 16 min for the aerosol and 64 ± 40
min for SC dosing.24
These data suggest that insulin
absorption through the lungs may not be faster than absorption after SC
injection in patients with NIDDM.
It is unclear why the time to peak insulin levels after the two modes
of administration appears to be similar in patients with NIDDM, whereas
the peak in plasma insulin seems to occur earlier following inhalation
of insulin in healthy subjects. One explanation could involve
intersubject variability. It has been shown that intersubject
variability in terms of time to peak insulin level is high for both
inhaled and injected insulin.25
Therefore, comparisons
between different groups of subjects who are dosed by different modes
of delivery may not be appropriate. Another explanation may be that
absorption of regular pork insulin (which was used in the studies of
patients with diabetes) across the respiratory epithelium differs from
that of recombinant human insulin (which, presumably, was used in the
studies of healthy volunteers). Alternatively, it may be that the
number of patients with NIDDM in the most recent study (n = 7) was
too small to detect a significant difference between the two treatment
modalities.24
Finally, it could be that the disease
affects the absorption mechanism such that the absorption of insulin
across the lung epithelium takes longer in patients with the disease
than in healthy individuals. Additional studies in matched patients
with NIDDM are necessary to clarify these findings.
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Relative Bioavailability of Aerosolized Insulin
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Three of the studies10
19
24
of aerosolized insulin
in human subjects have reported mouth-to-blood efficiencies ranging
from 15 to 25%. This means that the average bioavailability of the
inhaled dose of aerosolized insulin in these studies was approximately
20%, relative to the dose delivered by SC injection. It is important
to note that these results reflect the relative bioavailability of
nebulized insulin. It is not known how bioavailability is affected by
changes in formulation (eg, reformulating liquid insulin as
insulin powder). These bioavailability studies also were conducted in
nonsmokers. This is important because it appears that smoking
significantly affects the bioavailability of nebulized insulin aerosol.
Kohler et al19
reported that the bioavailability of
nebulized insulin was significantly enhanced in smokers compared to
nonsmokers. This may have been due to damage to the lung mucosa as a
result of smoking, making the lung more "leaky" and allowing more
drug to enter the systemic circulation. It is also interesting to note
that although the relative bioavailability was increased as a result of
smoking, the time to peak insulin levels did not differ between smokers
and nonsmokers.19
The reduced bioavailability for aerosolized insulin relative to SC
delivery may increase the cost of aerosolized insulin delivery.
However, increases in cost may be offset by an increased demand for
aerosolized insulin compared to SC delivery because of the elimination
of the pain and discomfort associated with injection and because of
potentially better control of blood glucose levels. Moreover, insulins
with a higher bioavailability than regular pork insulin, which are also
suitable for inhalation, should become available over time.
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Safety of Inhaled Insulin
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To my knowledge, there have been no reports of toxicity due to
inhaled insulin either in patients treated acutely or for short
periods. In the treatment studies cited above, no respiratory or
hypoglycemic adverse events were reported in patients who inhaled one
or two doses of insulin. Also, Jendle and Karlberg18
23
have examined the effect of the short-term administration of
aerosolized insulin on the pulmonary functions of both healthy
volunteers and patients with NIDDM. They found that
postadministration measurements of peak expiratory flow did not differ
significantly from values obtained before aerosol treatment.
In terms of treatment with inhaled insulin for longer periods of time,
Ogden and colleagues26
reviewed data from studies
completed before 1996 and found no reports of adverse lung effects that
were attributable to inhaled insulin that was administered in the long
term for up to several weeks. In addition, the abstracts of three phase
II studies, 27
28
29
each lasting 3 months, indicate that
there were no changes in pulmonary function test results for the users
of inhaled insulin in those studies.
Further studies will be needed to assess the possible development of
immunogenicity and toxicity from prolonged exposure to the lung.
However, it should be noted that long-term intrapulmonary delivery of
insulin by the SC route has resulted in no detectable abnormalities in
rats receiving chronic supraphysiologic doses.30
Thus, the
lung appears to tolerate such exposure from the vascular side. In
addition, the lung has been shown to be relatively immunotolerant in
comparison to the more reactive SC compartment.31
Therefore, immunogenicity could be expected to be lower. Clearly,
additional research in humans will be required to assess the safety of
long-term inhalational dosing from the standpoint of immune reactions.
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Future Research
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Several issues must be addressed in order to make intrapulmonary
delivery of insulin aerosol a feasible alternative to SC delivery. One
of the most significant is that of the delivery system. The current
generation of delivery devices, which includes conventional jet-type
nebulizers with and without spacer devices or holding chambers, limits
the efficient delivery of aerosolized insulin because most of the drug
remains in the device and is not delivered to the lung. In addition,
these devices require compressors and electricity to generate the
aerosol particles. Portable devices that do not require electricity and
that deliver a high percentage of the drug to the lung will
significantly enhance patient convenience and demand for this route of
delivery.
New formulations for insulin aerosols are currently under development
by several companies. Typically, these are either dry powder
formulations or new formulations of solubilized insulin. Both
formulations can be generated as particles of the optimal size for
absorption into the alveoli (ie, 1 to 3 µm in diameter).
The dry powder or liquid insulin is loaded into unit packets and is
released either mechanically or electronically into new portable and
compact delivery systems.32
33
With the mechanical system,
the insulin is released prior to inspiration into a small holding
chamber from which the patient then inhales slowly and
deeply.32
With electronic delivery, the insulin is
released early during the patient’s inspiration at a predetermined
flow rate of inspired air.33
The effect of the patient’s baseline pulmonary functions on the
deposition of aerosolized insulin within the lungs is another factor
that will require further study. So far, most studies have enrolled
subjects with normal pulmonary functions. Further data are needed
regarding the delivery of aerosolized therapeutics to patients with
compromised lung function since the degree of obstruction may determine
how much of the inhaled dose deposits in the alveolar region and how
much impacts and deposits in obstructed airways. This issue is
likely to be of particular importance in patients who have both
diabetes and cystic fibrosis, COPD, or asthma, since these diseases and
the possibility of exacerbations may compromise drug delivery.
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Summary
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Aerosolized insulin is an important model for the systemic
delivery of other types of therapeutic proteins. Like insulin,
successful treatment outcomes with other peptides and proteins will
hinge on the determination of the correct dosage and formulation for
aerosolized delivery of each agent, as well as the development of
optimal devices for maximizing the delivery of aerosolized
medication to the alveolar region of the lung.
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Footnotes
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Abbreviations:
NIDDM = non-insulin-dependent diabetes mellitus; SC = subcutaneous,
subcutaneously
This research was supported by grants from the National Institutes of
Health NCRR (M01-RR00052), the Diabetes Foundation and Healthline
Medical.
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Abstract
Introduction
