69

The AERx Pulmonary Drug

Delivery System
Jeff Schuster and S. J. Farr
Aradigm Corporation, Hayward, California, U.S.A.

I.

INTRODUCTION

Delivery of aerosolized drugs to the lungs presents signicant opportunities, both

for the topical treatment of lung disease and for the noninvasive delivery of systemically active compounds. Unlike other noninvasive methodologies, such as
transdermal techniques, delivery via the lung takes advantage of a physiological
portal of entry to the systemic circulation [1].
A number of constraints need to be satised to achieve efcient and reproducible delivery systems that comply with regulatory demands, are reasonably
patient-friendly, and are economically viable. Aradigm Corporation has been
developing a family of pulmonary delivery systems [2] with these constraints in
mind.
To avoid the oropharynx and more central airways, particle diameters less
than approximately 3.5 m must be generated [3]. Particle sizes can be affected
by hygroscopic growth [4,5], and high relative humidity can cause signicant
increase in particle diameter on time scales similar to transit times for aerosols
through the oropharynx and bronchial airways [6]. Efcient deposition with a
minimum amount of exhaled aerosol requires particles larger than approximately
1 m [7]. Regional deposition of aerosols is also affected by inhalation ow rate
[8].
Recently, the U.S. Food and Drug Administration has mandated that liquid
aerosol delivery systems utilize sterile dosage forms [9].
This chapter describes a novel unit-dose liquid aerosol delivery technology,
the AERx system [2,10].
825

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II. THE AERx SYSTEM

The AERx aerosol drug delivery system was developed to efciently deliver
topical and systemically active compounds to the lung in a way that is independent of such factors as user technique or ambient conditions [10]. A single-use,
disposable dosage form ensures sterility and robust aerosol generation. This dosage form is placed into an electronically controlled mechanical device for delivery.

III. THE AERx DOSAGE FORM

The AERx dosage form (Fig. 1) is a multilayer laminate designed to both ensure
the stability of the pharmaceutical compound on storage and facilitate the robust
generation of the aerosol [11]. The formulation is packaged in a blister layer
consisting of polymer components that ensure stability of the pharmaceutical
compound and also provide a barrier to the loss of water during storage. After
the formulation is dispensed into the blister, a multilayer laminate is heat-sealed
to the top of the blister. This laminate, in addition to providing the same storage
and stability functions as the blister layer, also contains a single-use disposable
nozzle array.

Figure 1 The AERx dosage form.

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Figure 2 AERx nozzle array.

This nozzle array consists of hundreds of approximately 1-m holes lasermicromachined into a polymer lm (Fig. 2).
Prior to lling, the formulation is carefully ltered to remove particulates.
This, combined with the single-use nature of the nozzle array, ensures that the
aerosol generation process is not affected by nozzle blockage from particulates
or dried formulation.

IV. THE AERx DEVICE

Prior to a drug delivery event, the AERx dosage form is placed into an electronically controlled mechanical device (Fig. 3). This device is battery-powered and
handheld to allow complete portability. The device incorporates many features
designed to eliminate possible causes of dosing irreproducibility. To eliminate
variability due to uncontrolled inhalation rate, the device prompts and trains the
subject to inhale at the optimal rate by presenting multicolored, ashing, and
steady-light-emitting diodes. In addition to monitoring the inhalation ow rate,
the device calculates an inhaled volume, and will trigger the generation of aerosol
only if the inhalation rate is in the best range during a predetermined range early
in the inspiration, a technique that has been previously shown to optimize lung
deposition [12]. When the patient achieves this optimum ow/volume window,
an electronically controlled motor actuates a piston, which pressurizes the formu-

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Schuster and Farr

Figure 3 The AERx device (with dosage forms).

lation blister in the dosage form. When the formulation is pressurized, the heat
seal peels open in a controlled region, and the formulation ows from the blister
through the nozzle array, forming an aerosol. This aerosol is entrained in the
patients inhalation air, and is delivered to the lungs.
To generate an optimal aerosol size distribution across the range of expected in-use ambient conditions, the device provides an air-temperature-controlling module [13]. This module is electrically preheated prior to the drug delivery
event. During inspiration, the inhalation air is drawn through the module, warming the air. Because the air is warmed, the aerosol generation always occurs in
conditions of low relative humidity, eliminating the possibility of hygroscopic
growth (Tables 1 and 2).
Many optional features can be incorporated into the AERx device, depending on the requirements of the therapy. For asthma and other lung diseases,
an integrated instrument has been developed to measure indicators of lung function such as peak ow or FEV1 [14]. Compliance to critical dosing regimens can
be ascertained with onboard memory that monitors time and date of dosing event,
along with other required parameters. Applications, such as pain management,
that require multiple doses in a short period of time with minimal patient interven-

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AERx Pulmonary Drug Delivery System

Table 1

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The Effect of Ambient Conditions on Aqueous and Powder Aerosols

Temp.
(C)

RH
(%)

MMAD
(m)

GSD

FPF

2324

100

4.2 0.3

1.5 0.1

33%

2324

6575

2.7 0.3

1.5 0.1

73%

37 0.1
37 0.1

97 1
20 5

5.5 0.60
3.8 0.24

1.4 0.12
1.5 0.13

9%
42%

Aerosol
Isotonic saline [4], Hudson
updraft
Isotonic saline [4], Hudson
updraft
Fluorescein powder [29]
Fluorescein powder [29]

RH, relative humidity; MMAD, mass median aerodynamic diameter; GSD, geometric standard deviation; FPF, ne-particle fraction, % 3.5 m.

tion can be facilitated with an autoloading multidose cassette feature. Use by a

nonpatient can be eliminated with a patient identication feature that disables
the device until a special patient identication bracelet is placed in contact with
the device.
One particularly unique feature of the AERx system is the ability to titrate
fractional doses from a single dosage form [15]. This is accomplished by controlling the stroke of the piston, and retracting it when the desired dose is achieved.
This feature is valuable when the dose delivered needs to be tightly controlled,
and varies in time or between patients. An example is the control of diabetes
with insulin [16]. The required dose can vary with such factors as measured blood
glucose level, expected food intake, and body weight. Unlike any other aerosol
drug delivery system, this feature allows the AERx system to deliver controlled
fractions of the dosage form contents in accurate 10% increments (Fig. 4).

Table 2

The Effect of Ambient Conditions on AERx.

Temperature
(C)

RH
(%)

MMAD
(m)

GSD

ED (%)

FPD (%)

40
40
22

80
10
50

2.42
2.15
2.47

1.34
1.33
1.34

72.7
75.7
77.0

65.1
72.1
67.9

RH, relative humidity; MMAD, mass median aerodynamic diameter; GSD,

geometric standard deviation; ED, emitted dose (as a fraction of the loaded
dose); FPD, ne-particle dose (fraction of the loaded dose in particles 3.5
m).

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Figure 4 AERx dose titration accuracy.

Figure 5 AERx morphine plasma concentration curve.

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Schuster and Farr

AERx Pulmonary Drug Delivery System

V.

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CLINICAL DATA

The AERx system has been tested in the clinic with a wide variety of smallmolecule [17], protein and peptide drugs [1820], gene vectors [21], and diagnostic agents [22,23]. Pharmacokinetic studies with morphine sulfate [24,25] are
illustrative of the potential capabilities of the technology. Peak plasma concentrations are achieved in less than 1 min following inhalation, and greater than 90%
of the morphine emitted from the device appears in the systemic circulation.
Plasma concentration proles are indistinguishable from intravenous injection
(Fig. 5).
Another well-studied application of the AERx system is delivery of human
insulin for the management of diabetes [26,27]. Clinical data show that glycemic
control similar to subcutaneous injection is achievable. However, minimum glycemic levels are achieved in approximately 1 h, versus approximately 2 h for a
subcutaneous injection. This more rapid response is much more similar to the
glucodynamics in nondiabetics, and will allow insulin dosing at mealtime, as
opposed to dosing 3060 min prior to meals as is presently required with injections. Depth of inhalation has been shown to have a signicant effect on insulin

Figure 6 Glucodynamics following insulin administration with AERx.

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Schuster and Farr

bioavailability [28], suggesting the need for breath control like that demonstrated
with the AERx system (Fig. 6).

VI. CONCLUSIONS
Delivery of drugs by aerosol inhalation presents a signicant opportunity for
rapid, reproducible, noninvasive therapy. The AERx system takes advantage of
this opportunity by optimizing aerosol characteristics and patient compliance,
and by removing sensitivity to ambient conditions. Clinical data have shown that
inhalation therapy is capable of reproducing, or in some cases improving on,
injections.

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