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Spiros Inhaler Technology


Clyde Witham and Elaine Phillips
Elan Pharmaceutical Technologies, San Diego, California, U.S.A.

I.

INTRODUCTION

Dura Pharmaceuticals has developed a small handheld, breath-actuated, batteryoperated powder inhaler (Spiros). The inhaler has an impeller that is actuated,
when the patient inhales, to disperse and deliver the powder aerosol for inhalation.
The breath actuation eliminates the patient coordination problems typically seen
with pressurized metered-dose inhalers. The absence of propellants, such as the
internationally restricted chlorouorocarbons used in many such metered-dose
inhalers, makes the Spiros inhaler environmentally safe.
The Spiros technology differs from rst-generation dry powder inhalers
(DPIs) including the Spinhaler, Rotahaler, and Turbuhaler. These earlier DPIs
(and most others in development) rely on the patients inspiratory rate to disperse
particles, leading to variable powder dispersion because of inter- and intrapatient
variability in inspiratory effort.
The core technology was initially developed to overcome the patient coordination required for metered-dose inhalers and the inspiratory effort required
for rst-generation dry powder inhalers in treating asthma. Since then, the technology has been recognized to have applicability for both topical and systemic
delivery of both small molecules and proteins and peptides. The Spiros system
is not yet commercially available. The rst product will be inhaled insulin in
partnership with Eli Lilly and Co. Several asthma drugs were in development
with Spiros, but owing to decreasing market economics, were abandoned in mid2000.

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II. SPIROS TECHNOLOGY


All motorized Spiros powder inhaler platforms use the same core technology [1],
described in Figure 1, to achieve powder dispersion that is relatively independent
of inspiratory ow rate over a broad range. The high-speed rotating impeller
provides mechanical energy to disperse the powder. The impeller and battery
power enable the powder dispersion to be independent of the ability of the patient
to inhale vigorously.
The core technology is housed in the blisterdisk inhaler (Fig. 2), which is
being utilized by Eli Lilly and Company for the delivery of pulmonary insulin.
The Spiros DPI blisterdisk powder storage system (Fig. 3) is designed for
potentially moisture-sensitive substances (e.g., some proteins, peptides, and live
vaccines). The blisterdisk powder storage system contains 16 unit doses. Powder
formulation is lled and then sealed into a foil blister that protects the powder
from exposure to high humidity and ultraviolet light, and reduces the risk of
contamination. Capabilities for lling range from small scale (200 powder storage
systems/batch) to automated cassette and blister assembly machines. Both automated systems are capable of lling up to 120 blisterdisks/min. Filling for GMP
purposes is conducted in class 100-10,000 environments.
The inhaler is designed to actuate the motor 1500 times at which point a
microprocessor causes a light-emitting diode (LED) on the inhaler to ash red,
indicating to the patient that he can use the contents of up to two more blisterdisks.
At 1500 actuations, the LED is solid red and the motor will no longer activate

Figure 1 Aerosol generator core technology.

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Figure 2 Spiros inhalation platform.

Figure 3 (A) Blisterdisk powder storage system. (B) The interior of a well in a blisterdisk.

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the impeller. This feature is designed to limit the lifetime of a given inhaler to
a period of optimal performance.
A.

Mechanism of Drug Delivery

Pulmonary drug delivery systems are intended for either topical or systemic delivery. To target the different regions of the lung, the formulation is designed such
that the aerodynamic particle size distribution is controlled to a target size. Typically, to target the tracheobronchial regions of the lung to treat asthma, the aerodynamic size is targeted on the order of 510 m. For systemic delivery, empirical models indicate that aerodynamic diameters on the order of 23 m are
preferred [2,3]. The aerodynamic particle size distribution is a function of the
primary particle size of the material and the degree to which the material can be
dispersed into discrete particles.
Once deposited, the solid particles dissolve and are absorbed. Typically,
the plasma proles for inhaled drugs have shorter times to maximum concentrations versus the subcutaneous and oral routes. Some investigation has been conducted to extend the release of drug from a solid matrix delivered to the lung.
Here, however, consideration must be given to the potential involvement of the
mucociliary escalator, alveolar macrophages, and various proteases. To extend
the release of drugs, the active ingredient must rst be incorporated into a matrix
either physically, chemically, or both. The solid matrix must then be size-reduced
to the target primary size. If the active ingredient is quite potent, then the sizereduced drug or drug matrix must be blended with a bulking agent, typically
lactose, for accurate metering into the blisterdisk.
Formulations lled into the Spiros blisterdisk inhaler can consist of materials that have been formulated by any of the techniques shown in Figure 4. The
most typical approach involves the active pharmaceutical ingredient being provided in a bulk crystalline or lyophilized form. The material is size-reduced by
jet milling and, if necessary, blended with lactose prior to lling into the blisterdisk. Of the nominal dose lled into the blister well, a certain percentage is emitted from the inhaler. The emitted dose (ED) contains discrete drug particles of
varying aerodynamic size. This aerodynamic particle size distribution is characterized in relationship to the target region of the lung.
B.

Particle Size Reduction

A number of size reduction techniques are available including spray drying, precipitation from supercritical uids, and jet milling. Jet milling differs from the
other two techniques in that the active ingredient has been isolated in the solid
state (e.g., by lyophilization) prior to the size reduction step [4]. Therefore, the

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Figure 4 Preparation of dry powder formulation.

molecular mobility of the protein in the solid state is much reduced compared
to that in the liquid state. This may help to protect the molecule during the size
reduction step when high shear forces are used to isolate the particles. Duras
experience with jet milling indicates that milled proteins and peptides exhibit
minimal to no detectable degradation or loss of activity [5].
A typical example of size distribution data obtained by jet milling a lyophilized peptide is shown in Figure 5. These data demonstrate that the size reduction
process produces a narrow distribution, is reproducible, and generates particles
in the target range for optimal pulmonary delivery. Dura has been very successful
with milling as a size reduction technique. Bioactivity has been maintained in
95% of the macromolecules evaluated to date. This includes a live attenuated
vaccine.

Figure 5 Size distribution of a peptide milled under the same conditions.

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Blending

Typical formulations for the Dura powder inhaler use 100M lactose as a carrier
for the drug particles. The lactose particles are large (100 m) and they facilitate the handling and dispersion of the smaller drug particles. The total mass of
each dose is usually on the order of 612 mg, of which some percentage is the
active drug. In some instances, drug concentration may be as low as 2% and in
other cases may be as high as 100%. The target blend concentration is determined
from the desired systemic dose and the estimated efciency of pulmonary delivery.
III. AEROSOL PERFORMANCE EVALUATION
A.

Aerosol Performance Parameters

Two key measures of aerosol performance are assessed for a powder for inhalation. The rst is the emitted dose, that is, the total quantity of active material
that exits from the mouthpiece of the inhaler and is available for dosing to the
patient. Figure 6 shows that emitted doses over consecutive shots are consistent
using different inhalers.
The second aerosol performance parameter is the respirable dose, that is,
the quantity of protein that is expected to deposit in the lungs based on particle
size. Andersen cascade impactors (ACI) are used to determine the mass median
aerodynamic diameter (MMAD) of particles dispersed from the inhaler. The respirable fraction (RF) is often dened as the percent of the emitted dose that is
less than 5.8 m MMAD. For systemic delivery of proteins and peptides the
desired MMAD is in the range of 13 m. Figure 7 shows ACI data for three
model peptides and a protein that were milled and blended with lactose in concentrations ranging from 2 to 50%.
B.

Stability/Activity Assessment

Proteins and peptides can be sensitive to preparation processes and may lose
activity by aggregation (or other degradation routes). A goal of preformulation
work is to stabilize the protein during processing and storage, at concentrations
appropriate for attaining the nal target dose. Physical and chemical stability is
evaluated at several storage temperatures and relative humidities at various time
points, consistent with ICH guidelines. Representative data demonstrating aerosol
stability of a micronized peptide blended with lactose are shown in Figure 8.
Analytical methods that assess the chemical purity and strength of the drug,
such as high-performance liquid chromatography, are generally transferred from
the partner and implemented at Dura. Throughout formulation development, the
activity of the protein is assessed using various in vitro/in vivo technologies.

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Figure 6
tein.

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Consistency of emitted doses with different inhalers for a representative pro-

Figure 7 Aerosol performance of protein and peptide formulations with Spiros.

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Figure 8 Aerosol stability of a micronized peptide blended with lactose.

Figure 9 Pulmonary imaging with radiolabeled albuterol slow inspiration (15 L/min).
(See color insert.)

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Dura develops additional physical and chemical tests to assess the performance of the formulation as needed.

IV. HUMAN CLINICAL STUDIES


Clinical trials through phase III have been completed for two asthma drugs, albuterol sulfate and beclomethasone diproprionate. For these programs, over 500,000
clinical doses were given with the Spiros cassette inhaler. These formulations
are intended to provide a topical dose to the lungs. Scintigraphy results show
uniform deposition of radiolabeled albuterol throughout the tracheobronchial region and signicant and uniform deposition in the alveolar region (Fig. 9) [6].

(A)
Figure 10 Bioavailability (A) and bioactivity (B) of inhaled salmon calcitonin for intrapulmonary (IP) versus intramuscular (IM) administration.

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(B)
Figure 10 Continued

To demonstrate the potential of Spiros with macromolecules in vivo, Dura


provided clinical trial materials for a phase I study with salmon calcitonin (sCT),
a polypeptide used to treat osteoporosis and other bone diseases. A stable dry
powder formulation of sCT was produced under Good Manufacturing Practices
(GMP) for the study. In a random crossover design, all 10 subjects received 100
IU of sCT (Miacalcin) by intramuscular injection, for comparison with pulmonary delivery of sCT. Five of the 10 subjects received 160 IU (1 puff) by inhalation, and the remaining ve received 320 IU (2 puffs) by inhalation. Blood levels
of sCT and biochemical markers, such as total serum calcium, were measured.
The study indicated that sCT is absorbed from the lung (Fig. 10A), and is active
systemically in lowering serum calcium (Fig. 10B). In addition, a single exposure
to inhaled calcitonin appeared to be well tolerated.

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Figure 11 Multidose S2.

Figure 12 Unit-dose S2.

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Witham and Phillips

NEXT-GENERATION TECHNOLOGY

The Spiros motorized system works well to overcome the dose-to-dose variability
due to patient variance, but for low-cost drugs, the inhaler may be too expensive.
Therefore, Dura embarked on a project to design and build an inhaler that retains
the benets of the motorized system (low ow, low effort, high efciency) yet
does not require a motor or batteries. The result of that effort is the Spiros S2
platform.
Spiros S2 is a motorless powder inhalation technology. Its simple design
includes a unique powder dispersion mechanism incorporating free-oating beads
and a dosing chamber congured to precisely control airow characteristics (Figs.
11 and 12).
Spiros S2 is designed to achieve efcient aerosol performance with low
inspiratory ow rates and minimal effort on behalf of the patient, and to deliver
a wide range of drugs and dose strengths. In addition, by interfacing with Duras
replaceable blisterdisk powder drug storage system, this new design also leverages existing commercial manufacturing capabilities. The S2 technology is costeffective, simple, easy to use, and is intended for development as both unit-dose
and multidose drug applications.

REFERENCES
1. DR Williams, MB Mecikalski, DO Thueson. Apparatus for aerosolizing powdered
medicine and process and using. US patent 5,327,883, 1994.
2. PR Byron. The prediction of drug residence times in regions of the human respiratory
tract following aerosol inhalation. J Pharm Sci 75:433438, 1986.
3. L Adjei, J Garren. Pulmonary delivery of peptide drugs: effect of particle size on
bioavailability of leuprolide acetate in healthy male volunteers. Pharm Res 7:565
569, 1990.
4. RM Platz, A Ip, CL Witham. Process for preparing micronized polypeptide drugs.
US patent 5,354,562, 1994.
5. E Phillips, E Allsopp, T Christensen, M Fitzgerald, L Zhao. Size reduction of peptides
and proteins by jet-milling. In: RN Dalby, PR Byron, SJ Farr, eds. Respiratory Drug
Delivery VI. Buffalo Grove, IL: Interpharm Press, 1998, pp. 161168.
6. M Hill, L Vaughan, M Dolovich. Dose targeting for dry powder inhalers. In: RN
Dalby, PR Byron, SJ Farr, eds. Respiratory Drug Delivery V. Buffalo Grove, IL:
Interpharm Press, 1996, pp. 197208.

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