Method and device for delivering aerosolized medicaments

A device for accurately delivering aerosolized doses of a medicament disperses a measured amount of drug in a measured volume of carrier gas and transfers the resulting aerosol to a chamber prior to inhalation by a patient. The chamber is filled efficiently with the aerosol, and inhalation by the patient draws the aerosol dose into the lungs. This is followed by the inhalation of atmospheric air that will push the initial dose well into the lung interiors. The apparatus optimally includes a dose regulator, a counter, a clock, a dose memory and a signal to indicate when a dose is ready for inhalation. Optimal chamber designs are disclosed.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a structure and method of administering precisely 
measured doses of a therapeutic by inhalation. 
An accurate mechanism for delivering precise doses of aerosol drugs into 
the interior of human lungs has been an objective of many workers in the 
art. One of the most popular aerosol delivery devices is the 
propellent-driven metered dose inhaler (MDI), which releases a metered 
dose of medicine upon each actuation. Although these devices may be useful 
for many medicines, only a small variable percentage of the medicine is 
delivered to the lungs. The high linear speed with which the dosage leaves 
the device, coupled with incomplete evaporation of the propellants, causes 
much of the medicine to impact and stick to the back of the throat. This 
impacting and sticking creates a local concentration of drugs much of 
which is eventually swallowed. In the trade, this impact area is called a 
"hot spot" and can cause local immuno-suppression and the development of 
fungal infections with bronchosteriods. With broncodilators, for instance, 
the swallowed dose can contribute to unwanted systemic side effects such 
as tremor and tachycardia. 
MDI's also require a degree of coordination between activation and 
inhalation. Many patients are incapable of this task, especially infants, 
small children and the elderly. In an effort to overcome some of the above 
limitations of MDI's, others have interposed "spacers" between the 
conventional MDI and the patient. The primary function of these spacers is 
to provide extra volume to allow time for increased propellent droplet 
evaporation prior to inhalation and to reduce the velocity and impact of 
the medicine at the back of the throat. Although spacers do compensate for 
some of the inadequacies in the conventional MDI, it has been found that 
much of the medicine that may have ordinarily been deposited on the throat 
remains in the spacer and the total dose deposited in the lungs is small. 
It has been found that only approximately 8% of the medicine reaches the 
interior of the lung with conventional MDI's. Approximately 13% of the 
medicine reaches the lung when it is equipped with a spacer. 
Other workers in the art have attempted to provide a metered dose of a 
medicant by using dry powder inhalers (DPI). Such devices normally rely on 
a burst of inspired air that is drawn through the unit. However, these 
units are disadvantaged in that the force of inspiration varies 
considerably from person to person. Some patients are unable to generate 
sufficient flow to activate the unit. DPI's have many of the disadvantages 
of MDI's in that a large percentage of the medicant is deposited in the 
throat because of incomplete particle dispersion and the impact at the 
rear of the throat. Although pocket size MDI's and DPI's are very 
convenient they have disadvantages some of which are cited above. 
Other workers in the art have refined aqueous nebulization delivery 
systems. Although such systems require a continuous gas compressor, making 
them less portable than the MDI's and the DPI's, many nebulizers provide a 
low velocity aerosol which can be slowly and deeply inhaled into the 
lungs. Precision of dosage delivery, however, remains a serious problem 
and it is difficult to determine how much medicament the patient has 
received. Most nebulizers operate continuously during inhalation and 
exhalation. Dosage is dependent on the number and duration of each breath. 
In addition to breath frequency and duration, the flow rate, i.e., the 
strength of the breath that is taken from a nebulizer can effect the 
particle size of the dose inhaled. The patient's inhalation acts as a 
vacuum pump that reduces the pressure in the nebulizer. A strong breath 
can draw larger unwanted particles of medicant out of the nebulizer. A 
weak breath, on the other hand, will draw insufficient medicant from the 
nebulizer. 
Electro-mechanical ventilators and devices have also been used in recent 
years to deliver inhalable materials to a patient. These devices permit 
mixing of a nebulized medicant into breathing circuit air only during 
pre-set periods of a breathing cycle. An example of this type of machine 
is the system taught by Edgar et al., in their U.S. Pat. No. 4,677,975, 
issued in July of 1987 where a nebulizer is connected to a chamber which 
in turn is connected to a mouthpiece, an exhaust valve, and an inlet 
valve. A breath detector and timer are used to deliver nebulized materials 
to the patient during a portion of the breathing cycle. However, in Edgar 
and others of this type, the patient's intake strength can effect the 
nebulizer operation with many of the consequences heretofore mentioned. 
Moreover, the amount of nebulized material delivered in each breath can 
vary significantly, contributing to inaccurate total dosages. In a 
modification of Edgar et al. (Elliott, et al. (1987) Australian Paediatr. 
J. 23:293-297), filling of the chamber with aerosol is timed to occur 
during the exhalation phase of the breathing cycle so that the patient is 
not inhaling through the device during nebulization. This design, however, 
requires that the patient maintain a constantly rhythmic breathing pattern 
into and out of the device, which is inconvenient and can contaminate the 
device with oval microbes. Moreover, no provision is made on the devices 
to efficiently capture the aerosol in the chamber so that as many as 80 
breaths or more must be taken to obtain a dose of medication. 
The delivery of therapeutic proteins and polypeptides by inhalation 
presents additional problems. Many protein drugs are produced 
recombinantly and can thus be very expensive. It is therefore important 
that loss of a protein drug within the delivery device be reduced or 
preferably eliminated. That is, substantially all drug initially charged 
within the device should be aerosolized and delivered to the patient 
without loss within the device or released externally of the device. The 
protein drugs should further be delivered to the patient under conditions 
which permit their maximum utilization. In particular, protein drugs 
should be completely dispersed into small particles in the preferred 1 
.mu.m to 5 .mu.m size range which is preferentially delivered to the 
alveolar region of the lungs. The amount of protein drug delivered to the 
patient in each breath must also be precisely measured so that the total 
dosage of drug can be accurately controlled. Finally, it will be desirable 
to permit the delivery of highly concentrated aerosols of the protein drug 
so that the number of breaths required for a given dosage can be reduced, 
thus increasing accuracy and reducing the total time required for 
administration. 
2. Description of the Background Art 
U.S. Pat. Nos. 4,926,852 and 4,790,305, describe a type of "spacer" for use 
with a metered dose inhaler. The spacer defines a large cylindrical volume 
which receives an axially directed burst of drug from a propellant-driven 
drug supply. U.S. Pat. No. 5,027,806, is an improvement over the '852 and 
'305 patents, having a conical holding chamber which receives an axial 
burst of drug. U.S. Pat. No. 4,624,251, describes a nebulizer connected to 
a mixing chamber to permit a continuous recycling of gas through the 
nebulizer. U.S. Pat. No. 4,677,975, is described above. European patent 
application 347,779 describes an expandable spacer for a metered dose 
inhaler having a one-way valve on the mouthpiece. WO 90/07351 describes a 
dry powder oral inhaler having a pressurized gas source (a piston pump) 
which draws a measured amount of powder into a venturi arrangement. 
SUMMARY OF THE INVENTION 
The present invention provides methods and apparatus for producing an 
aerosolized dose of a medicament for subsequent inhalation by a patient. 
The method comprises first dispersing a preselected amount of the 
medicament in a predetermined volume of gas, usually air. The dispersion 
may be formed from a liquid, for example by injecting an air stream 
through a liquid reservoir of the drug, or from a dry powder, for example 
by drawing the powder into a flowing air stream from a reservoir using a 
venturi or other dispersion nozzle. The present invention relies on 
flowing substantially the entire aerosolized dose into a chamber which is 
initially filled with air and open through a mouthpiece to the ambient. 
The aerosolized dose of medicament flows into the chamber under conditions 
which result in efficient displacement of the air with the aerosolized 
material. By "efficient displacement," it is meant that at least 40% by 
weight of the aerosolized material entering the chamber will remain 
aerosolized and suspended within the chamber, thus being available for 
subsequent inhalation through the mouthpiece. It is further meant that 
very little or none of the aerosolized material will escape from the 
chamber prior to inhalation by the patient. Efficient displacement of air 
and filling of the chamber can be achieved by proper design of the 
chamber, as discussed below. 
After the aerosolized medicament has been transferred to the chamber, the 
patient will inhale the entire dose in a single breath. Usually, the total 
volume of aerosolized medicament and air within the chamber will be 
substantially less than an average patient's inspiratory capacity, 
typically being about 100 ml to 750 ml. In this way, the patient can first 
inhale the entire amount of drug present in the dose and continue in the 
same breath to take in air from the ambient which passes through the 
chamber and which helps drive the medicament further down into the 
alveolar region of the lungs. Conveniently, the steps of aerosolizing the 
medicament, filling the chamber, and inhalation of the chamber contents 
may be repeated as many times as necessary to provide a desired total 
dosage of the medicament for the patient. 
Apparatus according to the present invention comprise both a dispersion 
device for aerosolizing the medicament, either from a liquid or dry powder 
formulation of the medicament, and a chamber having an air inlet and 
patient mouthpiece for receiving the aerosolized medicament from the 
dispersion device. The chamber is designed and connected to the dispersion 
device in such a way that the aerosolized medicament will flow into the 
chamber and efficiently displace the internal air volume, as described 
above. The volume of the chamber will be at least as large as the maximum 
expected volume of aerosolized medicament to be transferred from the 
dispersion device. Usually, the chamber volume will be greater than the 
aerosol volume in order to reduce losses through the mouthpiece, with 
exemplary chamber volumes being in the range from 100 ml to 750 ml, as 
described above. The volume of aerosolized medicament will usually be in 
the range from 50 ml to 750 ml when the dispersion device is a liquid 
nebulizer and from 10 ml to 200 ml when the dispersion device is a dry 
powder disperser, as described in more detail below. In order to enhance 
efficient filling, the chamber will preferably define an internal flow 
path so that the entering aerosolized medicament will follow the path and 
displace air within the chamber without substantial loss of the medicament 
through the mouthpiece. Alternatively, the chamber may include a baffle 
which acts to entrap a high velocity aerosol, particularly those 
associated with dry powder dispersions. 
In a preferred aspect, the chamber is generally cylindrical and is 
connected to the dispersion device by a tangentially disposed aerosol 
inlet port located at one end of the cylinder The mouthpiece is then 
located at the opposite end of the cylinder, and aerosolized medicament 
flowing into the chamber will follow a generally vortical flow path 
defined by the internal wall of the chamber. By also providing an ambient 
air inlet at the same end of the cylindrical chamber, the patient can 
first inhale the medicament and thereafter breath in substantial amounts 
of ambient air, thus sweeping the interior of the chamber to efficiently 
remove substantially all aerosolized medicament present and help drive the 
medicament further into the patient's lungs. 
In further preferred aspects, the ambient air inlet of the chamber will be 
protected, typically through a one-way valve structure which permits air 
inflow but blocks aerosol outflow, so that aerosol will not be lost as it 
enters the chamber. The chamber may also comprise vortical baffles, 
typically in the form of an axially aligned tube or conical cylinder 
within the interior of the chamber, to restrict dispersion of the aerosol 
within the chamber and improve delivery efficiency. 
In an alternate preferred aspect, the chamber is generally cylindrical with 
an axially oriented aerosol inlet port located at one end. The mouthpiece 
is located at the other end of the cylinder, and an internal baffle is 
located between the aerosol inlet and the mouthpiece to prevent direct 
passage of the aerosol to the mouthpiece (which could result in loss of 
medicament well before the chamber has been efficiently filled). The 
internal baffle is preferably hemispherical in shape with a concave 
surface oriented toward the aerosol inlet. Such a construction has been 
found particularly useful in initially containing dry powder dispersions 
which are often introduced using a high velocity (frequently sonic) gas 
stream. The chamber further includes a tangential ambient air inlet port 
disposed in the chamber wall between the aerosol inlet and the internal 
baffle. By inhaling through the mouthpiece, the patient is able to 
establish a vortical flow of ambient air which will sweep the contained 
aerosol past the baffle and through the mouthpiece. 
In yet another aspect of the present invention, the apparatus for producing 
aerosolized doses of a medicament comprises the dispersing device, means 
for delivering pressurized gas to the dispersing device, the aerosol 
chamber, and a controller capable of selectively controlling the amount of 
pressurized air delivered to the dispersing device in order to produce the 
desired single doses of medicament and deliver said doses to the chamber. 
The controller may include means for timing the actuation of a compressor 
or means for controlling the amount of gas released from a pressurized 
cylinder, as well as a mechanism for counting and displaying the number of 
doses delivered from the chamber during a particular period of use. Still 
further, the controller may include a microprocessor and a keypad for 
inputting information to the microprocessor. 
In exemplary devices, the controller may comprise a timer connected to 
selectively actuate a valve, such as a solenoid valve, on a gas cylinder. 
Alternatively, the timer may turn on and off an air compressor to regulate 
the amount of air delivered to the dispersing device. In portable and 
hand-held apparatus, the controller may simply be a release button or 
mechanism that actuates a spring or air driven piston to deliver a 
specific amount of gas. The controller could also be a metered valve which 
could release a fixed amount of liquid propellant to the dispersing device 
(in a manner similar to a metered dose inhaler). 
The method and the apparatus of the present invention are particularly 
effective for delivering high value drugs, such as polypeptides and 
proteins, to a patient with minimal loss of the drug in the device. 
Moreover, the method and device provide for a very accurate measurement 
and delivery of the doses, while employing relatively simple and reliable 
equipment. Further advantages of the present invention include the ability 
to vary the total dosage delivered, either by controlling the number of 
breaths taken or by controlling the amount of medicament in each breath. 
Still further, the method and device of the present invention permit the 
delivery of relatively concentrated doses of the medicament in order to 
reduce the amount of time and number of breaths required for the delivery 
of a total dosage of the medicament, particularly when using dry powder 
medicament formulations.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS 
The method and device of the present invention are useful for delivering a 
wide variety of medicaments, drugs, biologically active substances, and 
the like, to a patient's lung, particularly for systemic delivery of the 
medicament or the like. The present invention is particularly useful for 
delivering high value medicaments and drugs, such as proteins and 
polypeptides, where efficient delivery and minimum loss are of great 
concern. 
The apparatus of the present invention will usually comprise the following 
basic components: a means for producing a metered volume of gas, a mixing 
chamber for generating an aerosol bolus from either a liquid or a powder, 
a reservoir that contains the medicament, and a holding chamber that 
efficiently captures the aerosol bolus to maintain the aerosolized 
particles in suspension and allow a patient to inhale the aerosol by a 
slow, deep inspiration, thereby effectively distributing the aerosolized 
medicament to the distal region of the lungs. 
A gas source will usually deliver a preselected volume of gas at greater 
than about 15 psig in order to produce a sonic velocity jet in an aerosol 
producing region (although sonic velocity is not always necessary). The 
pressurized gas is required to efficiently atomize the liquid or break 
apart the powder producing an aerosol having particles that are 
predominantly 1 to 5 .mu.m in diameter. In addition, the volume of the gas 
bolus must be less than a fraction of a patient's inspiratory volume, 
preferably between 100 to 750 ml. Suitable gas sources include: 
1) an air compressor with a timer to control the operating period of the 
compressor (where the timer comprises at least a portion of the controller 
discussed hereinafter); 
2) a compressed gas cylinder with a solenoid valve controlled by a timer; 
3) a liquid propellant with a metering valve and an evaporation chamber; 
4) a spring piston pump; and 
5) a pneumatic pump. 
The means for producing the aerosol will usually consist of a constricted 
orifice that produces a high velocity gas flow to atomize a liquid or 
break apart powder agglomerates. The present invention is designed to be 
used with a conventional jet nebulizer that operate with airflow rates in 
the range from 3 to 13 L/min at about 15 psig, with the flow rate 
depending largely on the nozzle geometry of the nebulizer. The present 
invention further provides a means of controlling the volume of air 
delivered to the nebulizer in order to produce an aerosol bolus having a 
specific volume that can be contained in the aerosol holding chamber. By 
controlling the gas source to deliver a specific volume of gas, the system 
can employ a variety of nebulizers available from commercial vendors, such 
as Marquest, Hudson, Baxter, and Puritan Bennett. 
The present invention can also operate with a powder jet disperser as a 
means of generating an aerosol. A pressurized gas jet produces a highly 
turbulent gas flow that serves to break apart powder agglomerates 
producing an aerosol having single particles of the preformed powder. An 
example of a suitable powder/gas mixing chamber is a simple nozzle with a 
venturi ejector, as shown in FIG. 7. An advantage of this type of powder 
mixer is that the gas flow through the nozzle is only a fraction of the 
entrained airflow through the venturi. This reduces the air capacity so 
that the required volume of gas for dispersing the powder could be 
delivered from a small "pocket-sized" gas source. 
In addition, the powder dispersing apparatus must produce a pressure pulse 
having a long enough duration (typically 0.01 to 1 second) to adequately 
fluidize the powder and efficiently dispense the powder from the 
reservoir. A small diameter nozzle, less than 0.020 inch is acceptable and 
less than 0.015 inch is preferable, in order to achieve an acceptable 
duration of the pressure pulse at peak pressures exceeding 15 psig with a 
volume of gas that is small enough to be contained in a small holding 
chamber. 
Referring now to the drawings wherein like numerals indicate like parts, 
the numeral 10 generally indicates an exemplary apparatus constructed in 
accordance with the principles of this invention. The apparatus is powered 
by an electrical source 12 that provides energy for a controller, 
typically in the form of a microprocessor 18. The present invention, 
however, does not require the use of an electrical or digital controller, 
so long as some means is provided for supplying preselected gas volumes 
for aerosol bolus. 
The microprocessor 18 is a general purpose microcontroller unit (MCU) such 
as that sold by Motorola under their Model Number 68HC05. This unit has 
on-chip peripheral capabilities and the on-board memory system 30. The 
on-chip peripheral capability of the Motorola unit includes multiple input 
ports, one of which receives the input data from the keypad 13 via line 
16. The microprocessor 18 has a plurality of output ports and its 
functioning will be more fully understood as the components of the 
invention are described. 
Keypad 13 has six input keys that are important to performance, namely; 
13a, 13b, 13c, 13d, 13e and 13f. The volume or amount of each aerosolized 
dose is selected by controlling the length of time a compressor 22 is 
turned on by pressing the "puff size" button 13a. The keypad 12 is 
programmed so that a first press of button 13a will display a choice of 
puff sizes on an LCD 32. Additional pressings of the button will select 
the desired size. A "puff counter actuator" button 13b is pressed which 
will cause the LCD 32 display "00". A second press of 13b energizes the 
air compressor 22 via output line 38 for a 13a. This produces the first 
aerosolized dose or bolus of a medicament for inhalation. The LCD display 
32 will change from 00 to 01 and the LCD will increase by one upon each 
additional activation of the compressor. The patient will continue 
activating puffs with button 13b until the prescribed number of puffs have 
been taken. As these puff events are occurring, the time and number are 
stored in memory 30. 
To view a record of previous uses of the device, a dosage recall button 13c 
is pressed which causes LCD 32 to display prior dates, times, puff sizes 
and number of puff formation events. Successive pressings of the button 
13c will enable scrolling of the patient's dosage history. Reversal of 
scroll direction is accomplished by pressing button 13d and then 
continuing to scroll with 13c. The button 13e is a clock/calendar button. 
Pressing the button 13e causes the LCD 32 to display the current date and 
time. After the device is used and a series of puffs have been taken, the 
system will automatically default five minutes after the last puff to 
display the actual time and date on the LCD display. Thus, the device is a 
clock/calendar when not in actual use and during the use and date or time 
can be viewed by pressing 13e. 
Air from compressor 22 is communicated to a mixer 40. The mixer 40 may be a 
nebulizer, a dry powder dispenser or other type of nebulizer known to the 
prior art. When unit 40 is a dry powder dispenser, the compressed air from 
compressor 22 may optionally be first subjected to coalescing filter 41 
and a desiccant filter 41a. When unit 40 is a nebulizer, a particle filter 
21 may optionally be placed at the intake 23 of the compressor to filter 
out articles before the air is compressed. In either case, the medicament 
or drug will preferably be in the form of a small particulate, usually 
having an aerodynamic size in the range from 1 .mu.m to 5 .mu.m. It is 
known that particles in this size range are most efficiently delivered to 
the alveolar regions of the lungs. 
An exemplary dry powder venturi nozzle 200 is illustrated in FIG. 7. The 
venturi nozzle 200 includes a side port 202 which receives an initial 
charge of powder medicament M, typically a lyophilized protein or 
polypeptide. The powder is drawn into dispersion chamber 204 at the point 
where nozzle orifice 206 introduces a high velocity gas stream in the 
direction of arrow 208. The high velocity gas stream will result from 
pressurized gas or air in plenum 210, which may be provided by a separate 
air compressor 22 (FIG. 1) or an air or gas cylinder (not illustrated). 
The low pressure caused by the air or gas stream will draw the powder 
continuously into the dispersion chamber 204 where agglomerates of the 
powder are broken into smaller sizes within the preferred 1 .mu.m to 5 
.mu.m range by the turbulent shear effect in the chamber. 
In any event, unit 40 is of a type that will nebulize or mix a defined 
amount of medicant with the preselected amount of compressed air received 
from compressor 22. This defined amount, referred to as a dosage or bolus, 
flows into a chamber 42 via the conduit 39. The chamber 42 is transparent, 
typically having a glass, transparent plastic, or similar wall 44. 
A critical aspect of the present invention is the ability to transfer the 
aerosolized medicament from the mixer 40 into the chamber 42 without 
substantial loss of medicament through the mouthpiece or within the 
chamber. Such losses will be minimized so that at least about 40% by 
weight of the medicament delivered to the chamber will remain aerosolized 
and suspended within the chamber after the entire volume has been 
transferred. Preferably, at least bout 55% will remain suspended, more 
preferable at least about 70%. Such low losses are desirable since the 
total amount of drug which may be introduced into the chamber for each 
transfer is maximized, and thus the amount which may be inhaled in each 
breath by a patient is increased. Additionally, even small losses of high 
valued drugs, such as proteins and polypeptides, can become significant 
over time. Still further, the ability to deliver a concentrated aerosol 
dispersion of drug into the chamber will increase the concentration of 
drug delivered to the patient with each breath. Such high concentration 
dosages are preferable since they can reduce the total number of breaths 
necessary to deliver a prescribed amount of drug, thus increasing the 
total amount of time required for the treatment. 
Loss of aerosolized medicament can be reduced by minimizing mixing between 
the aerosolized medicament and the displaced air as the chamber is being 
filled. Minimum mixing between the aerosol transferred from the mixing 
chamber 40 and the displaced air within chamber 42 can be enhanced by 
properly designing the chamber 42 as well as the inlet flow geometry of 
the aerosol into the chamber. Particularly preferred geometries are 
illustrated in FIGS. 2-5 and 8-11, as described in more detail 
hereinbelow. 
A light 50 and/or an audible signal 52 will alert the user that a puff is 
ready to be withdrawn from chamber 42 when the compressor 22 shuts down. 
At this point in time, the aerosolized bolus of medicine is quite visible. 
From the holding chamber 42 the medicament is inhaled by the patient via a 
conduit 45 through a mouthpiece 46 or in the case of small children or 
infants, a face mask 48. A one-way check valve 47 is disposed across 
conduit 45 to prevent exhalation into chamber 42. The signals 50 and 52 
are set to begin immediately after operation of the compressor 22 ceases. 
The cessation of the compressor sound will also alert the patient that 
bolus formation is complete. This sequence is repeated for each bolus and 
the microprocessor 18 will count and record each instance of compressor 
activation so that the prescribed number of aerosolized boluses have been 
administered. The number of boluses, their hour and date and their size 
(time f compressor use), are recorded, stored and recallable at a future 
time for display on LCD 32 by pressing dosage history button 13c. 
One embodiment of the aerosol holding chamber 42 is best seen in 
cross-section in FIG. 2. The chamber 42 is comprised basically of a top 
54, the previously mentioned transparent sidewall 44 and a bottom 58. The 
chamber 42 is equipped with an aerosol intake stub fitting 60 at the lower 
portion thereof. The chamber top is equipped with an inhalation stub 62. 
Also at the bottom 58 is an atmospheric intake stub 64. The stubs are 
formed to accept conventional connector fittings 70, 72 and 74 
respectively. The fittings connect the conduits 45, 96 and 80 to the 
stub-fillings 60, 62 and 64. The fittings permit the ready interchange of 
chambers having different volumetric capacities. 
Disposed in a conduit 39, between unit 40 and chamber 42, is a valve 80 
that is opened before use of the device and closed between uses. The valve 
80 serves as a vapor lock to prevent evaporation of fluid from unit 40 
when the nebulizer is not in use. Valve 80 can be controlled by hand like 
a stopclock, or it may be electronically controlled by the MCU 18 so that 
upon pressing the puff counter/actuator button 13b, valve 80 opens and 
then closes by default if the machine is not used for a set period. 
Disposed across inhale line 45 is a one-way check valve 47. A one-way 
check valve 94 is also disposed across the air intake conduit 96. 
Particularly preferred chamber geometries are illustrated in FIGS. 8-11. 
Chamber 100 in FIG. 8 comprises a cylindrical body 102 with a tangential 
aerosol inlet port 104. The tangential aerosol inlet port 104 will be 
connected to a suitable aerosol dispersing device, usually either a 
nebulizer or a dry powder device (as described above), preferably a 
nebulizer, and the aerosol will enter and assume a vortical flow pattern, 
as indicated by arrows 106. The entry of the aerosol will displace air 
initially present in the chamber 100 through mouthpiece 108. Usually, but 
not necessarily, the chamber 100 will be oriented vertically with the 
mouthpiece at the top. After the entire aerosol bolus has entered the 
chamber 100 (typically only partially filling the chamber leaving a 
"buffer" of air near the mouthpiece 108), the patient will inhale through 
the mouthpiece 108, drawing in ambient air through ambient air inlet 110, 
thus sweeping the chamber of the aerosolized medicament. Ambient air inlet 
110 will usually have a one-way valve, such as a flap or diaphragm valve 
(not illustrated) in order to prevent loss of aerosol as the aerosol is 
introduced through port 104. 
Chamber 120 in FIG. 9 is similar to chamber 100, except that an inlet tube 
122 extends into the chamber interior, forming a vortical baffle. 
Apertures 124 are disposed about the inlet tube 122 to permit entry of air 
as the patient inhales through mouthpiece 126. Ambient air inlet 128 is 
similar to inlet 104 in FIG. 8. 
A horizontally disposed chamber 140 is illustrated in FIG. 10. Chamber 140 
includes both a tangential aerosol inlet 142 and tangential mouthpiece 
144. Thus, aerosolized medicament will enter through the inlet 142 and 
move horizontally across the chamber interior toward the mouthpiece 144. 
An advantage of this design is that the aerosol particles will tend to 
drop below the level of the mouthpiece 144 as they cross the chamber. 
Thus, loss of the medicament through the mouthpiece 144 will be minimized. 
Ambient air inlet 146 is provided to permit air infusion as the patient 
inhales through the mouthpiece 144. 
A preferred chamber 150 for use with dry powder dispersion devices, such as 
venturi nozzle 200 in FIG. 7, is illustrated in FIG. 11A. The chamber 150 
will generally be maintained with its axis oriented vertically, with an 
aerosol inlet 152 at its lower end and a mouthpiece 154 at its upper end. 
The chamber 150 further includes an internal baffle 156 which is suspended 
from a rod 158 attached to the upper end of the chamber. The baffle 156 is 
preferably hemispherical, with its open or concave end oriented downwardly 
toward aerosol inlet 152. The purpose of the baffle 156 is to contain the 
initial plume of aerosol created by the high velocity air or gas stream. 
The hemispherical design is preferred since it will redirect the initial 
flow of aerosol back downward, creating a recirculation as indicated by 
the arrows in FIG. 11B. Other geometries for the baffle, including flat 
plates, perforated plates, cylinders, cones, and the like, might also find 
use, with the primary requirement being that the baffle design be able to 
provide an initial containment zone within the chamber. 
After an aerosolized dose or bolus of medicament has been introduced to the 
chamber 150, the patient will inhale through the mouthpiece 154, drawing 
ambient air in through ambient air inlet 158. The inlet 158 includes a 
one-way flap or diaphragm valve 160 which permits the inflow of air but 
prevents the initial loss of medicament as the aerosolized dose enters 
through the inlet 152. The ambient air inlet 158 is disposed tangentially 
on the chamber 150, and entry of ambient air through the inlet cause a 
vortical (as illustrated in FIG. 11C) which will cause the suspended 
medicament particles to move radically outward (due to the induced cyclone 
effect) and be carried upward by the airflow through the annular region 
162 between the periphery of the baffle 156 and the interior wall of the 
chamber 150. 
Surprisingly, the design of chamber 150 has been found to be able to 
receive a volume of aerosolized medicament greater than the chamber volume 
without substantial loss of medicament through the mouthpiece. It is 
believe that the baffle 156 can act as a "concentrator," which contains 
the medicament particles in the region below the baffle while permitting 
air flow through the annular region 162. Such concentration is achieved 
while still maintaining the aerosolized particles in suspension and with 
the ability to subsequently transfer the medicament particles to the 
mouthpiece by introducing a vortical flow of ambient air through inlet 
158, as described above. 
In operation, the patient or medical attendant will ready the device by 
operating the puff size button 13a. Button 13b is pressed a second time to 
energize compressor 22 and a pre-selected amount of air under a constant 
pressure is delivered to unit 40 for mixing or nebulizing to form the 
first puff. The medicament begins filling the chamber 42 from the bottom 
(FIG. 6A) through valve 80 and stub fitting 60 and a cloudy, observable 
"puff" is formed as seen in FIG. 6B. During this time interval, valve 94 
is closed. 
After the vessel or chamber 42 is filled, the signals 50 and 52 are 
activated for several seconds by the timer function of the microprocessor 
18. The duration of both signals will be preset in the control program 24. 
As a breath is taken, valves 47 and 94 will open to permit the puff to 
enter the lungs and to permit additional atmospheric air to enter the 
chamber from the bottom through conduit 96. 
The volumetric size of chamber 42 is only a fraction of the capacity of the 
patients' lungs usually being from 200 ml to 1000 ml, typically being 
about 500 ml. Inhalation by the patient will thus initially draw the 
entire dose of medicament into the lungs. The volume of aerosol 
transferred to the chamber will typically be about 10 ml to 750 ml, and 
the air that enters through valve 94 can thus act as an air piston to 
drive the smaller volume of aerosol deep into the user's lungs. The bottom 
to top filling and vertical flow pattern result in a minimum of dispersion 
and dilution of the aerosol. Moreover, the sweeping of chamber 50 with air 
after each inhalation helps assure substantially complete delivery of the 
drug to the patient. 
The atmospheric or pure air and the medicament bolus, each moves from the 
chamber 42 through the one-way check valve 47 into the patient's mouth via 
the conduit 45. A mask 48 with a one-way exhalation port is used for 
patients that require same. A one-way valve 47 may be used to prevent the 
patient from accidentally exhaling into the chamber 42. 
FIG. 6A-6D show illustrations of the sequence of bolus generation and 
withdrawal from the aerosol holding chamber 42. 
The following examples are offered by way of illustration, not by way of 
limitation. 
EXPERIMENTAL 
Experimental Equipment 
Air supply--a nitrogen cylinder with a regulator, a needle valve, a 
pressure gauge, and a solenoid valve that is operated with a timer with a 
resolution of 0.01 second. 
Jet Nebulizer--Rapid-Flo.TM., (Allersearch, Vermont Victoria, Australia) 
Powder Disperser--A venturi (as illustrated in FIG. 7) having a 0.013 inch 
diameter jet nozzle. 
Aerosol Holding Chambers--Fabricated from plastic with internal volumes of 
750 ml. Design 1--3-inch cylindrical chamber with spherical top and bottom 
and one 90.degree.-port at the base, one 45.degree.-port at the top and 
one tangential port on the side (as illustrated in FIG. 8). Design 
2--3-inch cylindrical chamber with spherical top and bottom and a 1 inch 
cylindrical spacer located axially along the center of the chamber. Three 
ports--one 90.degree.-port at the base, one 45.degree.-port at the top and 
one tangential port on the side (as illustrated in FIG. 9). Design 
3--3-inch cylindrical chamber with spherical top and bottom; a 21/2 inch 
hemispherical baffle held in the center of the chamber with a rod. The 
baffle was located approximately 2 inches above the base of the chamber. 
Three ports--aerosol intake: 90.degree.-port at the base, mouthpiece: 
45.degree.-port at the top and makeup air intake: tangential port on the 
side (as illustrated in FIG. 11). Design 2--3-inch cylindrical chamber 
with spherical top and bottom; a 21/2 inch hemispherical baffle located 
23/4 inches above the base on a cone (as illustrated in FIG. 11). 
Methods 
The four aerosol chamber designs were tested using either the jet nebulizer 
or the powder dispenser. Design 1 was tested using either the 
90.degree.-port at the base for the aerosol intake or the tangential port 
as the aerosol intake. 
The total airflow through the apparatus, the aerosol generator and the 
holding chamber, was measured with a rotameter connected to the mouthpiece 
of the holding chamber. The flow was set to the desired rate with the 
needle valve. The pressure was maintained above 15 psig to ensure sonic 
velocity in the nozzle of the aerosol generator. 
Once the airflow was set, the sample was loaded into the aerosol generator. 
The operating period was set on the timer. A toggle switch on the timer 
opened the solenoid valve sending air through the aerosol generator and 
producing the aerosol. We observed the distribution of the aerosol in the 
holding chamber and could observe when the aerosol began to flow out of 
the chamber. The maximum length of time that the aerosol generator could 
be operated and still capture all of the aerosol in the holding chamber 
was determined by adjusting the operating period on the timer and 
repeating the steps listed above. The aerosol dose volume was calculated 
from the flow rate and the time the solenoid was open. A vacuum line was 
connected to the holding chamber following an actuation to clear the 
chamber of the aerosol before actuating again. 
A 0.9% saline solution was used in testing the different holding chamber 
configurations with a Rapid-Flo.TM. nebulizer. The nebulizer was operated 
at flow rate of 19 L/min which resulted in 24 psig across the jet of the 
nebulizer. 
The powder disperser was tested at a pressure of 30 psig which resulted in 
a flow rate of 10.4 L/min through the apparatus. Approximately 5 mg of a 
test powder, prepared by spray drying a solution of mannitol and bovine 
serum albumin, was loaded into the venturi intake and the solenoid valve 
was actuated. We checked for powder remaining in the venturi intake to 
determine whether there was an adequate air supply to disperse the powder. 
The particle size distribution measured from the chamber using an 
Aerosizer (API, Hadley, Mass.) particle size analyzer showed that the 
aerosol contained particles between 1 and 4 .mu.m in diameter. 
Results 
Results comparing the different chamber designs for containing the aerosol 
are reported in Table 1. The maximum volume of the aerosol contained by 
the chamber was calculated from the maximum operating time and the total 
airflow. The proportion of the aerosol volume to the volume of the chamber 
given in the % Chamber Volume column is a way of comparing the 
effectiveness of the different chamber designs for containing the aerosol. 
The air volume needed to disperse 5 mg of powder could be efficiently 
captured in all of the chamber configurations tested. The designs that 
induced a vertical airflow patern in the chamber retained a larger volume 
of aerosol. 
TABLE 1 
__________________________________________________________________________ 
Aerosol Capture Efficiency for several 
Holding Chamber Designs 
Nebulizer Powder Disperser 
% of Increase % of Increase 
Aerosol 
Chamber 
over Aerosol 
Chamber 
over 
Chamber 
Volume 
Volume 
base Volume 
Volume 
base 
__________________________________________________________________________ 
Design 1 
348 mL 
45.8% 
-- 69.mL 
9.24% 
-- 
bottom 
fill 
Design 1 
665 mL 
88.7% 
1.94 95.3 mL 
12.7% 
1.38 
tangential 
fill 
Design 2 
728 mL 
97.1% 
2.12 104 mL 
13.9% 
1.50 
center 
baffle 
Design 3 
950 mL 
127% 
2.77 164 mL 
21.9% 
2.37 
hemisphere 
baffle 
Design 4 
855 mL 
114% 
2.49 161 mL 
21.5% 
2.33 
__________________________________________________________________________ 
Conclusions 
An aerosol holding chamber can be designed that efficiently captures a 
measured volume of aerosol. A chamber designed to induce vortical airflow 
pattern in the chamber by a tangential aerosol intake or using baffles 
distributes the aerosol more evenly in the chamber without loss from the 
mouthpiece. For use with a nebulizer, a vortical airflow produces a higher 
concentration of medicament in the chamber so that an effective dose could 
be taken with fewer puffs. The results with the powder disperser show that 
the vortical flow and properly designed baffles are effective in 
containing a powder aerosol produced by a turbulent jet. 
It should be understood that the preferred embodiments of the present 
invention have been disclosed by way of example and that other 
modifications may occur to those skilled in the art without departing from 
the scope and spirit of the appended claims.