Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
.$.~'~'~ENlS FOR TH . r~rrRApt~ONAgY
DELIVE:aY OF AEROSOLIZED AQUEOUS FOR,MLI ~TIONS
Field of the Invention
This invention relates generally to methods of
drug delivery, containers and systems used in the
intrapulmonary delivery of drugs. More specifically, the
invention relates to a disposable package which includes
one or more containers which containers may be loaded
into a cassette which can be included in a device used
for the controlled delivery of aerosolized flowable,
liquid formulations.
~ackaround of the Invention
The intrapulmonary delivery of pharmaceutically
active drugs is accomplished by two distinct
methodologies. In accordance with one method, a
pharmaceutically active drug is dispersed in a low
boiling point propellant (a CFC or HFA) and loaded in a
pressurized canister from which the drug/propellant
formulation may be released by the use of a device
generally known as a metered dose inhaler (MDI). Once
released, the propellant evaporates and particles of the
drug are inhaled by the patient. The other method
involves the use of a nebulizer which creates a mist of
fine particles from a solution or suspension of a drug
which mist is inhaled by the patient. Both methods are
hindered by significant problems relating to patient
compliance and dosing as described further below.
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Metered dose inhalers that are generally manually
operated and some breath actuated devices have been
proposed and produced. Breath actuated inhalers '
typically contain a pressurized propellant and provide a
metered dose automatically when the patient s inspiratory '
effort either moves a mechanical lever or the detected
flow rises above a preset threshold, as detected by a hot
wire anemometer. See, for example, U.S. Patents
3,187,748; 3,565,070; 3,814,297; 3,826,413; 4,592,348;
4,648,393; 4,803,978; 4,896,832; and a product available
from 3M Iiealthcare known as Aerosol Sheathed Actuator and
Cap.
A major problem with manual metered dose inhalers
is that the patient frequently actuates the device at the
incorrect point during the breathing cycle to obtain the
benefits of the intended drug therapy or breathes at the
wrong flow rate. Thus, patients may inspire too little
medication, or take a second dose and receive too much
medication. The problem is, therefore, the inability to
administer precise dosages.
Another problem with metered dose inhalers is that
the devices include low boiling point propellants such as
halohydrocarbons and halocarbons which have adverse
environmental effects. Further, other low boiling point
propellants are not desirable in that they may have
adverse medical effects on patients.
A problem with breath activated drug delivery is
that the dose is triggered on crossing a fixed threshold
inspiratory effort. Thus, an inspiration effort may be
sufficient to release a metered dose, but the inspiratory
flow following the release may not be sufficient to cause
the aerpsol medication to pass into the desired portion
of the patient's airways. Another problem exists with
patients whose inspiratory effort is not sufficient to
rise above the threshold to trigger the release valve at
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all. Yet another problem is that the particle size can
vary greatly and larger particles cannot enter the
smaller lung passages and therefore are not delivered to
the same degree and/or rate as are smaller particles.
Any of these problems can make it difficult or impossible
to monitor the delivery of a precise dosage of medication
to a patient.
Attempts have been made to solve the patient
inspiration synchronization problem. U.S. Patent
4,484,577 refers to using a bidirectional reed whistle to
indicate to the patient the maximum rate of inhalation
for desired delivery of the drug and flow restrictor to
prevent the patient from inhaling too rapidly. U.S.
Patent 3,991,304 refers to using biofeedback techniques
to train the patient to adopt a desired breathing
pattern. U.S. Patent 4,677,975 refers to using audible
signals and preselected time delays gated on the
detection of inspiratory flow to indicate to the patient
when to inhale and exhale, and delivering inhalable
material a selected time after the detected onset of
flow. However, these devices also suffer from improper
operation by patients who are not properly trained or do
not conform their breathing to the instructed breathing
pattern and whose inspiratory flow does not provide
adequate delivery of the medication. Such problems make
reproducible delivery of predetermined dosages virtually
impossible.
Studies in Byron (ed.), Respiratory Drucr Delivery,
CRC Press, Inc. (1990); Newman et al., horax, 1981,
36:52-55; Newman et al., horax, 1980, 35:234; Newman et
al., fur. J. Respir. Dis., 1981, 62:3-21; and Newman et
al., Am. Rev. Respir. Dis , 1981, 124:317-320 indicate
that during a single breath of an aerosol compound, only
about ten percent of the total aerosol material presented
is deposited into the lungs and that the location of
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deposition in the lung depends upon (1) breath parameters
such as volume of inspiration, inspiratory flow rate,
inspiratory pause prior to expiration, the lung volume at '
the time the bolus of medication is administered, and
expiratory flow rate, (2) the size, shape and density of '
the aerosol particles (i.e., the medicinal compound, any
carrier, and propellant), and (3) the physiological
characteristics of the patient. Present devices and
methods cannot eliminate these variables and as such
cannot control dosage administration.
A problem with existing metered dose inhalers,
whether or not breath actuated, is that they are factory
preset to deliver a fixed dose at a given particle size
distribution. Such devices are not capable of reducing
the dose to reflect improvement in the patient's
condition, or selecting a maximum desired respirable
fraction of the aerosol mist that is suitable for a
desired location of delivery of the medication in the
particular patient.
Devices for controlling particle size of an
aerosol are known. U.S. Patent 4,790,305 refers to
controlling the particle size of a metered dose of
aerosol for delivery to the walls of small bronchi and
bronchioles by filling a first chamber with medication
and a second chamber with air such that all of the air is
inhaled prior to the inhaling medication, and using flow
control orifices to control the flow rate. U.S. Patent
4,926,852 refers to metering a dose of medication into a
flow-through chamber that has orifices to limit the flow
rate to control particle size. U.S. Patent 4,677,975
refers to a nebulizer device that uses baffles to remove ,
from any aerosol particles above a selected size. U.S.
Patent 3,658,059 refers to a baffle that changes the size ,
of an aperture in the passage of the suspension being
inhaled to select the quantity and size of suspended
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particles delivered. A problem with these devices is
that they process the aerosol after it is generated and
thus are inefficient and wasteful.
It is well known that pulmonary functions, such as
forced expiratory volume in one second, forced vital
capacity, and peak expiratory flow rate, can be measured
based on measured flow rates and used to (1) diagnose the
existence of medical conditions, (2) prescribe
medication, and (3) ascertain the efficiency of a drug
therapy program. See, for example, U.S. Patents
3,991,304 and 4,852,582 and the publications of Newman et
al. discussed above. Heretofore, these tests have been
performed using available spirometers. U.S. Patent
4,852,582 also refers to using a peak flow rate meter to
measure changes in peak flow rate before and after
administration of a bronchodilator. The results of such
tests before and after administration of several
different medications are used to evaluate the efficiency
of the medications.
A problem with the foregoing pulmonary function
test devices is that they are too complicated for most
patients to use effectively and obtain repeated delivery
of a given amount of drug i.e. user error in
administration causes significant variability in the
amount of drug the patient receives. Another problem is
that the data obtained does not directly effect the
operation of the device, i.e. it must be examined and
interpreted by a trained medical practitioner to be
meaningful. Another problem is that they do not provide
adequately for altering the dosage of the medication
administered in a single patient during the course of
therapy,. or from patient to patient, using the same
delivery device for generating an aerosol of the same or
different medications.
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Attempts have been made to solve many of the
above-referred-to problems. However, inconsistent user
compliance combined with undesirably large particle size
continues to cause problems with obtaining precise
dosing.
Nebulizers utilize various means in order to
create a fog or mist from an aqueous solution or
suspension containing a pharmaceutically active drug.
The mist created by the nebulizer device is directed
towards the face of the patient and inhaled through the
mouth and nose. Nebulizer devices and methodology can be
quite useful when the precise dosing of the drug being
delivered to the patient is not of particular importance.
For example, in some situations the nebulizer creates a
mist from an aqueous solution containing a bronchodilator
which can be inhaled by the patient until the patient
feels some improvement in lung function. When precise
dosing is more important the nebulizer device and
delivery methodology suffers from many of the
disadvantages of metered dose inhaler devices and
methodology as described above. In addition, nebulizers
are large in size and not hand-held, easily transportable
devices like MDIs. Accordingly, a nebulizer can only be
used within a fixed location such as the patient's home,
the doctor's office and/or hospital. However, a portable
nebulizer is taught in published PCT application
W092/11050. Another
nebulizer which uses a high frequency generator to create
an aerosol is described in U.S. Patent 3,812,854 issued
May 28, 19'74. Drug formulations placed in nebulizers are
generally diluted prior to delivery. The entire diluted
formulation must generally be administered at a single
dosing event in order to maintain the desired level of
sterility and the.nebulizer cleaned after use. Yet
another disadvantage of nebulizers is that they produce
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an aerosol wYiich has a distribut ion of particle sizes not
all of which are of appropriate size to reach the targeted
areas of the lung. The present invention endeavors to
address and solve these and other problems .
Summary of the Invention
The present invention includes several aspects as
follows:
According to one aspect of the present invention,
there is provided a disposable package for use in
aerosolized delivery of drugs to the lungs, comprising: a
container having at least one wall which is collapsible by
the application of a force and having ate least one opening,
the container having therein a liquid, flowable formulation
which includes a pharmaceutically active drug; a porous
membrane covering the opening wherein tine membrane pores
have a diameter in the range of from about 0.25 micron to
about 6 microns; wherein the formulation has a viscosity
suf f iciently low such that the formulation is aerosolized to
particles having a diameter of about 0.5 to 12 microns when
force is applied to the collapsible wall and the formulation
is moved out of the pores .
According to another aspect of the present
invention, there is provided a disposable package,
comprising: a container having an opening leading to a
channel, the container having a liquid, flowable formulation
therein which formulation comprises a pharmaceutically
active drug. wherein at least one wall of the container is
collapsible in a manner so as to allow the formulation in
the container to be forced out of the opening into the
channel ; a resonance cavity in fluid connection with the
container by means of the channel, the resonance cavity
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having a surface comprising a porous membrane wherein pores
of the membrane have a diameter in the range of 0.25 to 6
microns; and an interconnecting component connecting the
container and resonance cavity.
(1) A disposable, collapsible package comprised of
porous membrane surface area having pores with a diameter in
the range of 0.25 micron to 6 microns and a pore density in
the range of 1 X 104 to 1 X 108 pores per square centimeter
(alternatively about 10 to about 10,000 pores in an area of
about 1 mm2 to about 1 cm2) and at least one surface which i~
collapsible in a manner so as to force the contents of the
container out of the porous membrane;
(2) A dual package in the form of a compartment
container wherein the first compartment is as described in
(1) and includes a dry powder form of a drug and a second
compartment which is connected to the first compartment by a
rupturable membrane the second compartment being comprised
of such that when pressure is applied liquid within the
second compartment is forced through the rupturable membrane
into the first compartment to dissolve or suspend the dry
powder whereby the contents can be aerosolized;
(3) A package in the form of a cellular array of
containers of the type described in (1) or (2) which
cellular array may be in any configuration and include any
number of containers;
(4) A member preferably in the form of a tape
which includes areas covered by the porous membrane which
member may be loaded into a dispensing device which
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includes a multiple dose container from which doses of
pharmaceutically active drug may be dispersed through
membranes; '
(5) A disposable or reloadable cassette which may '
be loaded with any package of (1), (2), (3) or (4) which
cassette is designed so as to position individual
containers of the package or membranes in a manner such
that the contents of each container or a unit dose of
drug from a multiple dose container can be dispersed to a
patient;
(6) A dispensing device into which the member,
cassette or package of (1), (2), (3) or (4) may be loaded
so that a formulation of any pharmaceutically active drug
can be dispersed to a patient;
(7) Methodology for delivering an aerosolized
mist of a formulation such as therapeutic drugs to a
patient which methodology uses a device for dispersing
formulation from porous membranes thereby providing for
intrapulmonary drug delivery to a patient -- wherein the
device is preferably a hand-held, self-contained,
portable device comprised of a means for removing a
surface cover from individual porous membranes and
automatically dispersing formulation through the
membranes, preferably in response to a signal obtained as
a result of measuring both the inspiratory flow and
inspiratory lung volume of a patient to calculate an
optimal point for release of drug to optimize
repeatability of dosing;.
An important object of the invention is to provide
a disposable container which includes an opening covered
by a porous membrane and which preferably contains a
liquid flowable formulation such as an aqueous
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formulation of a drug used in the treatment of lung
diseases.
Another important object of the invention is to
provide a disposable container comprised of unitary,
surfaces interconnected wherein one of the surfaces
includes an area of having pores therein wherein the
pores are configured as the porous membrane defined
herein and wherein at least surface of the container is
collapsible in a manner so as to force pharmaceutical
formulation contained in the container out thru the
pores.
Another object is to provide a dual compartment
container wherein one compartment includes a dry powder
form of a drug and a second compartment separated from
the first by a rupturable membrane includes a solvent
such as water which when combined with the dry powder
forms a solution or suspension which can be forced
through a porous membrane and delivered to a patient as
an aerosol.
Another object is to provide a cellular array of a
single compartment or dual compartment containers;
Another object is to provide a disposable cassette
which can incorporate a package (e. g., a cellular array
of containers or interconnected membranes) and which
cassette may be loaded into a device which can disperse a
formulation thru a membrane which membrane may cover an
opening in the container or be formed by drilling holes
in an area of the container.
Another object is to provide a dispensing device
which is a hand-held easily portable device that
functions so as to disperse formulation from the
containers, preferably in response to measuring both
inspiratory flow and inspiratory volume of a patient
simultaneously to determine an optimal point for the
release of drug needed to obtain repeatability in dosing.
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An advantage of the invention is that the membrane
is used only once thereby eliminating any problems with
respect to clogging and/or contamination.
Another advantage when disposable containers are
used is that the containers include a single dose thereby
avoiding issues with respect to contamination and
negating the need for the inclusion of bacteriostatic
compounds within the formulation.
Another advantage is that the formulation does not
require the use of low boiling point propellants which
may cause environmental damage.
Another object of the invention is to provide a
dispersing device which is capable of simultaneously
measuring inspiratory flow and inspiratory volume as well
as other parameters and making calculations based on the
measurements to determine an optimal point for the
release of drug which optimal point is calculated so as
to maximize repeatability of the amount of drug delivered
to the patient.
Another object is to provide such a dispersing
device wherein measurements such as inspiratory flow and
inspiratory volume are recorded prior to, during and
after dispensing drug and wherein the measurements are
recorded in order to determine the effectiveness of each
drug release with respect to its ability to effectively
provide drug to the patient via the intrapulmonary route.
Another advantage of the invention is that the
liquid drug solutions contained within the individual
containers need not and preferably do not include
preservatives and/or any type of bacteriostatic compounds
in that the containers are originally packaged in a
sterile. form and preferably consist essentially of liquid
drug alone or in combination with a liquid and excipient
carrier and the contents of the individual containers are
used completely upon opening.
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Another advantage is that the system makes it
possible to disperse aerosolized drug at a relatively low
velocity as compared to the velocity of aerosols
dispersed from conventional metered dose inhalers.
Another advantage is that drugs which are unstable
in a liquid (e.g. aqueous) state can be stored in a dry
state and combined with a liquid immediately prior to
aerosolization.
Another feature of the present invention is that a
wide range of different pharmaceutically active drugs
(with an excipient carrier as needed to form a liquid
formulation) can be packaged within the individual
sterile containers.
Another feature of the invention is that the
individual containers of the package include one or more
openings through which air can be forced, which openings
are in close proximity to a thin membrane having cone
shaped pores of substantially uniform diameter at their
narrowest point in the range of about 0.25 micron to
6 microns.
Another feature of the invention is that the
individual containers of a package and/or the package may
be unitary in configuration and have a surface with pores
positioned therein wherein the pores have a diameter in
the range of 0.25 micron to 6 microns with about l0 to
10,000 pores being present in a surface area in the range
of 1 mm2 to about 1 cm2.
Another feature of the invention is that the
containers have channels leading therefrom to the porous
membranes so that a vibrating mechanism in the cassette
can be positioned directly below the porous membrane.
stet another feature of the present invention is
that the dispensing device or cassette includes a
vibrator or high frequency signal generation device which
vibrates the liquid being forced through the porous
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membrane of the package at different frequencies in a
manner so as to promote regular sizing of the droplets
from the stream forced from an opening and create an
aerosol having uniform (or if desired a range of
different) particle size in the range of 0.5 micron to
12 microns in diameter.
Another feature of the invention is that it may be
used for in the intrapulmonary delivery of all types of
drugs including the systemic drugs, respiratory drugs
and/or any drugs to a patient and obtained a fast acting
effect on the patient.
Another object of the present invention is to
provide a disposable package comprised of a container for
holding a liquid aerosolizable formulation, which
container is connected via one or more channels to a
chamber or resonance cavity positioned directly below a
porous membrane such that when formulation from a
container is forced through the channel into the
resonance cavity and out of the pores of the membrane,
the formulation will be aerosolized into particles having
a diameter in the range of 0.5 micron to 12 microns.
Another advantage of the present invention is that
the system including the device and disposable cassette
is a hand-held, easily portable and usable device.
Another feature of the invention is that the
package may include indices thereon in the form of
visually readable numbers or letters which can be readily
perceived by the user whether a dose has been delivered
for a particular day and/or time of day and/or indicate
the number of doses in the cassette which have been used
and the number which remain for use.
Still another feature of the invention is to
provide, in the cassette, a power source such as a
battery in connection with indices on the package which
are in the form of magnetic, optical and/or electronic
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records which can be read by the drug dispensing device
which in turn presents a visual display to the user
providing information on the amounts and times of doses
released (in total or from a given cassette) and/or to be
released.
Another feature is to provide a battery integral
with the disposable cassette, which battery provides
sufficient energy to power the device, including
providing power to control the microprocessor, vibrating
the device, and piston or bellows to force formulation
through the membranes and thereby create an aerosol from
all of the liquid and/or suspension material contained
within all of the containers present in that cassette.
It is another object of this invention to provide
a pocket-sized, single, integrated device for recording
the date, time and amount of aerosolized drug delivered
at each drug delivery event which device is also capable
of monitoring pulmonary function and maintaining a record
of the date, time and value of each objective lung
function and recording the information on a package.
It is another object of this invention to provide
a device capable of monitoring and recording objective
pulmonary function information and displaying such
information in a manner integrated with drug dosing event
information so as to provide a means of evaluating
quantitative, objective measures of pulmonary function in
the context of actual administered therapy.
It is another object of this invention to show
.that the evaluation of pulmonary function in light of
actual patient compliance only has meaning if drug dosing
events are actually associated with patient inspiration
and firing of the aerosolized drug into the patient s
mouth.
It is another object of this invention to show
that interpretation of pulmonary function data in the
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context of actual drug dosing events allows physicians to
counsel patients accurately with regard to avoidance of
overdosing of potentially toxic inhaled aerosolized drugs
such as bronchodilators and gives physicians a tool for
quantitatively advising patients regarding adjustments to
their long-term, anti-inflammatory, aerosolized drug
treatment program and/or long term enzyme treatment
program.
These and other objects, advantages and features
of the present invention will become apparent to those
persons skilled in the art upon reading the present
disclosure and reviewing the figures forming a part
hereof wherein like numerals refer to like components.
brief Description of the Drawings
Figure 1 is a perspective view of a disposable
package of the present invention;
Figure 2 is a cross-sectional view of a drug
dispensing device of the invention;
Figure 3 is a top plan view of a disposable
package of the invention;
Figure 4 is a top plan view of another embodiment
of a disposable package of the invention;
Figure 5 is a cross-sectional view of a portion of
a disposable package of the present invention;
Figure 6 is a cross-sectional view of a portion of
another embodiment of a disposable package of the present
invention;
Figure 7 is a cross-sectional view of a portion of
a disposable package and air dispersion vents of the
invention;
Figure 8 is a top plan view of a disposable
package of the invention and air dispersion vents;
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Figure 9 is a cross-sectional plan view of a
disposable package of the invention positioned above a
piston of a dispensing device of the invention;
Figure 10 is a cross-sectional plan view of a
disposable package with dual containers;
Figure 11 is a graph of particle size versus
number of particles in three aerosol dispersions;
Figure 12 is a perspective view of a disposable
tape of the present invention;
Figure 13 is a cross-sectional plan view of a
disposable tape of the invention positioned in a
dispensing device of the invention; and
Figure 14 is a cross-sectional plan view of a
simple embodiment of a disposable of package of the
invention;
Figure 15 is a cross-sectional plan view of
another simple embodiment of a disposable package of the
invention;
Figure 16 is a cross-sectional plan view of a duel
compartment disposable package of the invention;
Figure 17 is a cross-sectional plan view of a
disposable member in the form of a tape positioned above
in a dispensing device of the invention; and
Figure 18 is a cross-sectional plan view of a
disposable member in the form of a tape positioned in a
dual drug container dispensing device of the invention.
Detailed Description of Preferred Embodiments
Before the disposable packages, devices, systems
and methodology of the present invention are described,
it is to be understood that this invention is not limited
to the particular packages, devices, systems, components,
formulations and methodology described, as such may, of
course, vary. It is also to be understood that the
terminology used herein is with the purpose of describing
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particular embodiments only, and is not intended to limit
the scope of the present invention which will be limited
only by the appended claims.
It must be noted that as used herein and in the
appended claims, the singular forms "a," '°and," and "the°'
include plural referents unless the context clearly
dictates otherwise. Thus, for example, reference to "a
formulation" includes mixtures of different formulations
and reference to "the method of treatment" includes
reference to equivalent steps and methods known to those
skilled in the art, and so forth. Although the invention
is largely described in connection with respiratory drugs
it may be used to deliver any drug.
Unless defined otherwise, all technical and
scientific terms used herein have the same meaning as
commonly understood by one of ordinary skill in the art
to which this invention belongs. Although any methods
and materials similar or equivalent to those described
herein can be used in the practice or testing of the
invention, the preferred methods and materials are now
described. All publications mentioned herein are
incorporated herein by reference to describe and disclose
specific information for which the reference was cited in
connection with.
Definition
The terms '°package" and "disposable package°' are
used interchangeably herein and shall be interpreted to
mean a container or two or more containers linked
together by an interconnecting means wherein each
container includes a porous membrane (as defined herein)
and is collapsible (as described herein) to force the
contents of the container out through the porous
membrane. A container may include an opening covered by
a porous membrane or an area with pores therein and
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channels which provide for fluid connection from the
container to a porous membrane preferably not positioned
directly over the container. The structural integrity of
each container is designed such that fluid is forced
through the porous membrane (without rupturing the
container) in a manner such that the contents is
aerosolized. The disposable package may include one or
more openings near the porous membrane through which air
can be forced or can be positioned alongside of air
dispersion vents in a cassette or drug dispensing device
described below. There are two variations of the
package, depending on whether the drug can be stably
stored in a liquid form or must be stored dry and
combined with liquid immediately prior to aerosolization.
The contents of each container preferably consists
essentially of a liquid, flowable formulation which
includes a pharmaceutically active drug of any type and
(if the drug is not liquid and of a sufficiently low
viscosity to allow the drug to be aerosolized) an
excipient carrier, i.e. preferably without any additional
material such as preservatives which might affect the
patient. The formulation is a liquid, flowable
formulation with a relatively low viscosity that can be
readily aerosolized (twice the viscosity of water or less
at 25°C) and is more preferably a flowable, liquid
formulation consisting essentially of a pharmaceutically
active drug dissolved or dispersed in an excipient
carrier - the formulation having a viscosity of 1.25
times that of water or less at 25°C. When the contents
must be stored in a dry state, the package further
includes another container which holds the liquid and can
be combined with the dry drug immediately prior to
administration by breaking a rupturable membrane
separating the containers.
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The term "cassette" shall be interpreted to mean a
container which holds, in a protective cover, a package
or a plurality of packages which packages are '
interconnected to each other and held in the cassette in
an organized manner, e.g. interfolding or wound. The
cassette is connectable to a dispensing device and
preferably includes a power source, e.g. one or more
batteries in the cassette which provide power to the
dispensing device. The cassette may include air
dispersion vents through which air can be forced when
formulation is forced through the porous membranes.
The term "dosing event" shall be interpreted to
mean the administration of a pharmaceutically active drug
to a patient in need thereof by the intrapulmonary route
of administration which event may encompass the release
of drug contained within one or more containers.
Accordingly, a dosing event may include the release of
drug contained within one of many containers of the
package held in a cassette or the drug contained within a
plurality of such containers when the containers are
administered at about the same time (e.g., within 10
minutes of each other, preferably within 1-2 minutes of
each other). A dosing event is not interrupted by a
monitoring event which would indicate, if followed by
further drug delivery, the beginning of a new dosing
event.
The terms "monitoring event" and "measuring" are
used interchangeably herein and shall be interpreted to
mean an event taking place prior to a "dosing event"
whereby both the inspiratory flow and cumulative
inspiratory volume of the patient is measured in order to
determine the optimal point in the inspiratory cycle at
which to actuate the firing of a mechanism (such as a
roller or piston) which causes the collapse of a
container wall forcing the drug from the container in a
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manner such that the drug is aerosolized. It is
preferable to carry out a "monitoring event" immediately
prior to (within two minutes or less) each "dosing event"
so as to optimize the ability to repeatedly deliver the
same amount of drug to the patient at each dosing event.
It is also preferable to continue to monitor inspiratory
flow during and after any drug delivery and to record
inspiratory flow and volume before, during and after the
release of drug. Such reading makes it possible to
determine if drug was properly delivered to the patient.
The term "inspiratory flow" shall be interpreted
to mean a value of air flow calculated based on the speed
of the air passing a given point along with the volume of
the air passing that point with the volume calculation
being based on integration of the flow rate data and
assuming atmospheric pressure and temperature in the
range of about 10°C to about 35°C.
The term "inspiratory flow profile" shall be
interpreted to mean data calculated in one or more
monitoring events measuring inspiratory flow and
cumulative volume, which profile can be used to determine
a point within a patient s inspiratory cycle which is
optimal for the release of drug to be delivered to a
patient. It is emphasized that the optimal point within
the inspiratory cycle for the release of drug is not
necessarily calculated based on a point within the
inspiratory cycle likely to result in the maximum
delivery of drug but rather a point in the cycle most
likely to result in the delivery of the reproducible
amount of drug to the patient at each release of drug,
i.e. repeatability of the amount delivered is important,
not maximizing the amount delivered.
The term "respiratory drug" shall be interpreted
to mean any pharmaceutically effective compound used in
the treatment of any respiratory disease and in
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particular the treatment of diseases such as asthma,
bronchitis, emphysema and cystic fibrosis. Useful
"respiratory drugs" include those which are listed within
the Physician's Desk Reference (most recent edition).
Such drugs include beta adrenergics which include
bronchodilators including albuterol, isoproterenol
sulfate, metaproterenol sulfate, terbutaline sulfate,
pirbuterol acetate and salmeterol formotorol; steroids
including beclomethasone dipropionate, flunisolide,
fluticasone, budesonide and triamcinolone acetonide.
Anti-inflammatory drugs used in connection with the
treatment of respiratory diseases include steroids such
as beclomethasone dipropionate, triamcinolone acetonide,
flunisolide and fluticasone. Other anti-inflammatory
drugs include cromoglycates such as cromolyn sodium.
Other respiratory drugs which would qualify as
bronchodilators include anticholenergics including
ipratropium bromide. The present invention is intended
to encompass the free acids, free bases, salts, amines
and various hydrate forms including semi-hydrate forms of
such respiratory drugs and is particularly directed
towards pharmaceutically acceptable formulations of such
drugs which are formulated in combination with
pharmaceutically acceptable excipient materials generally
known to those skilled in the art - preferably without
other additives such as preservatives. Preferred drug
formulations do not include additional components which
have a significant effect on the overall formulation such
as preservatives. Thus preferred formulations consist
essentially of pharmaceutically active drug and a
pharmaceutically acceptable carrier (e. g., water and/or
ethanol,). However, if a drug is liquid without an
excipient the formulation may consist essentially of the
drug which has a sufficiently low viscosity that it can
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be aerosolized using a dispenser of the present
invention.
The term "drug" shall include "respiratory drug"
as well as other types of drugs such as systemically
effective drugs. The term is intended to encompass the
presently available pharmaceutically active drugs used
therapeutically and to further encompass to be developed
therapeutically effective drugs which can be administered
by the intrapulmonary route.
The term "therapeutic index" refers to the
therapeutic index of a drug defined as LDso/EDso. The LDso
(lethal dose, 50%) is defined as the dose of a drug which
kills 50% of the animals, and the EDso is defined as the
effective dose of the drug for 50% of the individuals
treated. Drugs with a therapeutic index near unity (i.e.
LDso/EDso is approximately equal to 1) achieve their
therapeutic effect at doses very close to the toxic level
and as such have a narrow therapeutic window, i.e. a
narrow dose range over which they may be administered.
The terms "formulation" and "liquid formulation"
and the like are used interchangeably herein to describe
any pharmaceutically active drug by itself or with a
pharmaceutically acceptable carrier in flowable liquid
form and preferably having a viscosity of not more than
25% greater than the viscosity of water. Such
formulations are preferably solutions, e.g. aqueous
solutions, ethanoic solutions, aqueous/ethanoic
solutions, saline solutions and colloidal suspensions.
The terms "lung function" and "pulmonary function"
are used interchangeably and shall be interpreted to mean
physically measurable operations of a lung including but
not limited to (1) inspiratory and (2) expiratory flow
rates as well as (3) lung volume. Methods of
quantitatively determining pulmonary function are used to
measure lung function. Quantitative determination of
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pulmonary function is important because lung disease is
typically associated with deteriorating pulmonary
function. Methods of measuring pulmonary function most -
commonly employed in clinical practice involve timed
measurement of inspiratory and expiratory maneuvers to
measure specific parameters. For example, forced vital
capacity (FVC) measures the total volume in liters
exhaled by a patient forcefully from a deep initial
inspiration. This parameter, when evaluated in
conjunction with the forced expired volume in one second
(FEVi), allows bronchoconstriction to be quantitatively
evaluated. A problem with forced vital capacity
determination is that the forced vital capacity maneuver
(i.e. forced exhalation from maximum inspiration to
maximum expiration) is largely technique dependent. In
other words, a given patient may produce different FVC
values during a sequence of consecutive FVC maneuvers.
The FEF 25-75 or forced expiratory flow determined over
the mid-portion of a forced exhalation maneuver tends to
be less technique dependent than the FVC. Similarly, the
FEV1 tends to be less technique dependent than FVC. In
addition to measuring volumes of exhaled air as indices
of pulmonary function, the flow in liters per minute
measured over differing portions of the expiratory cycle
can be useful in determining the status of a patient's
pulmonary function. In particular, the peak expiratory
flow, taken as the highest air flow rate in liters per
minute during a forced maximal exhalation, is well
correlated with overall pulmonary function in a patient
with asthma and other respiratory diseases. The present
invention carries out treatment by administering drug in .
a drug delivery event and monitoring lung function in a
monitoring event. A series of events are carried out
over time to determine if lung function is improved.
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Each of the parameters discussed above is measured
during quantitative spirometry. A patient's individual
performance can be compared against his personal best
data, individual indices can be compared with each other
for an individual patient (e. g. FEVI divided by FVC,
producing a dimensionless index useful in assessing the
severity of acute asthma symptoms), or each of these
indices can be compared against an expected value.
Expected values for indices derived from quantitative
spirometry are calculated as a function of the patient's
sex, height, weight and age. For instance, standards
exist for the calculation of expected indices and these
are frequently reported along with the actual parameters
derived for an individual patient during a monitoring
event such as a quantitative spirometry test.
The term "respiratory disease" shall be
interpreted to mean any pulmonary disease or impairment
of lung function. Such diseases include restrictive and
obstructive disease and diseases such as emphysema which
involve abnormal distension of the lung frequently
accompanied by impairment of heart action. Restrictive
diseases tend to limit the total volume of air that a
patient is able to exchange through inspiration and
expiration. Restrictive disease, such as can be present
in certain types of fibrotic processes, can therefore be
detected by reduced FVC indices. Obstructive disease,
such as is present in patients with asthma, tends not to
affect the total volume of air exchangeable through
inspiration and expiration but rather the amount of time
required for forced exhalation of air. In particular,
the FEV1 is markedly reduced in patients with acute asthma
symptoms. More specifically, the FEVi, when taken as a
ratio of FVC (i.e. FEV1 divided by FVC), is markedly
reduced in patients with acute asthma. In addition to
increasing the amount of time required for a full forced
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expiration, the presence of acute bronchoconstrictive
disease tends to decrease the peak expiratory flow
measured over a typical forced exhalation.
The term "porous membrane" shall be interpreted to
mean a membrane of material in the shape of a sheet
having any given outer perimeter shape, but preferably
covering a package opening which is in the form of an
elongated rectangle, wherein the sheet has a plurality of
openings therein, which openings may be placed in a
regular or irregular pattern, and which openings have a
diameter in the range of 0.25 micron to 6 microns and a
pore density in the range of 1 x 104 to about 1 x 108
pores per square centimeter. Alternatively, the porous
membrane may be merely an area of the package which has
porous position therein wherein the pores have a size and
a density as described above. The configuration and
arrangement of the pore density may be changed so as to
provide pores which are capable of creating an aerosol.
For example, the porous membrane or area of the container
may have some 10 to 10,000 pores therein which pores are
positioned in an area of from about 1 sq. mm. to about 1
sq. cm. The membrane is preferably comprised of a
material having a density in the range of 0.25 to
3.0 mg/cm2, more preferably 1.7 mg/cm2, and a thickness
of about 2 to about 20 microns, more preferably 8 to
12 microns. The membrane material is preferably
hydrophobic and includes materials such as polycarbonates
and polyesters which may have the pores formed therein by
any suitable method including anisotropic etching or by
etching through a thin film of metal or other suitable
material. Pores can be created in the membrane which may
be an area of the container by use of techniques such as
etching, plating or laser drilling. The membrane
materials, may have pores with a conical configuration
and have sufficient structural integrity so that it is
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maintained intact (will not rupture) when subjected to
force in the amount of about 20 to 200 psi while the
formulation is forced through the pores. The membrane
functions to form an aerosolized mist when the
formulation is forced through it. Those skilled in the
art may contemplate other materials which achieve this
function as such materials are intended to be encompassed
by this invention.
The terms "disposable member" and "member" are
used interchangeably herein to describe a structure of
the invention comprised of a two or more porous membranes
interconnected together by an interconnecting body which
has openings therein which openings are covered by the
porous membrane. As with the container, the disposable
member may be structured such that the entire member is a
unitary piece of material such as elongated flexible tape
wherein areas of the tape have pores positioned therein
which pores have a pore size and pore density as
described above. The preferred disposable member of the
invention is in the form of an elongated tape. However,
other configurations of interconnected porous membranes
are encompassed by the invention. For purposes of
simplicity, the disposable member of the invention is
described herein and shown in the figures in the
configuration of a disposable tape.
General Description
The present invention provides a non-invasive
means of delivering any type of drug to a patient by the
intrapulmonary route. The devices and methodology used
do not require the release of low boiling point
propellants in order to aerosolize drug which propellants
are conventionally used in connection with hand-held
metered dose inhalers. However, like conventional hand-
held metered dose inhalers the devices of the present
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invention are hand-held, self-contained, highly portable
devices which provide a convenient means of delivering
drugs to a patient via the intrapulmonary route.
The liquid, flowable formulations of the present
invention may include preservatives or bacteriostatic
type compounds. However, the formulation preferably
consists essentially of pharmaceutically active drug and
pharmaceutically acceptable carrier. The formulation may
consist essentially of the drug (i.e. without carrier) if
the drug is freely flowable and can be aerosolized.
Useful formulations may consist essentially of
formulations currently approved for use with nebulizers.
However, nebulizer formulations must, in general, be
diluted prior to administration. The formulations are
sterilized and placed in individual containers in a
sterile environment. Further. since preferred
embodiments of the devices used in connection with the
present invention include a means of analyzing breath
flow and a microprocessor capable of making calculations
based on the inhalation profile, the present invention
can provide a means for repeatedly (1) dispensing and
(2) delivering the same amount of drug to a patient at
each dosing event.
The present invention will now be described with
reference to the attached figures and in specific
sections which include (1) a disposable package, (2) a
disposable member which is specifically shown in the form
of a tape, (3) a cassette which includes a plurality of
packages or a tape, (4) a drug dispensing device which
can be loaded with a cassette, and (5) a method of drua
delivery.
Referring now to the figures the details of the
structure and operation of the various aspects of the
invention can be described in detail. Figure 1 provides
a prospective view of a disposable package 1 which
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includes a plurality of substantially identical
containers 2 each of which holds a pharmaceutically
active drug by itself or in combination with an excipient
carrier. The containers 2 are each interconnected with
each other by an interconnecting tape 3 and the tape 3 is
covered by a cover 4. The containers 2 are preferably
not positioned vertically directly beneath the porous
membrane 14 through which the contents of the container
will be aerosolized.
Referring to Figure 2 which is a cross-sectional
view of the cassette 5 loaded into a drug delivery device
6 makes it possible to describe the operation of the
disposable package 1 within the cassette 5 and the device
6. In essence, the disposable package 1 is folded or
wound into the cassette in a manner which makes it
possible to move the individual containers 2 into a drug
release position within the device 6. While the
containers 2 are moved into position the cover 4 is
removed. Although it is possible to rewind any used
portion of the package on a sprocket 7 and rewind the
used cover 4 on a sprocket 8 or randomly fold it into a
compartment it is also possible to disperse the used
portion outside of the cassette 5 and device 6 and
immediately dispose of such.
Although the device 6 shown in Figure 2 includes a
mouthpiece 9 shown here as rotatably attached thereon, it
is possible to reconfigure the components so that the
mouthpiece 9 is part of and integral with the cassette 5.
This arrangement of components makes it possible to
dispose of the mouthpiece with the cassette 5 when all
the containers 2 on the package 1 have been emptied.
In essence, the device 6 operates by having the
user patient inhale from the mouthpiece 9. Components of
the device described further below make it possible to
determine an inhalation profile based on the particular
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users lung capacity and function. The microprocessor
within the device calculates a point within the
inhalation profile at which it would be most desirable to
release drug in order to maximize the repeatability of
the amount of drug delivered to the patient. At this
point, a mechanical device such as a piston (described
below) is released and applies force against a container
2. The drug within the container is ultimately
aerosolized and delivered to the patient. The details of
how drug leaves each container 2 and ultimately leaves
the mouthpiece 9 are described in detail below.
Figures 3 and 4 represents both a top view of a
package as shown in Figure 5, and a top view of a
disposable member in the form of a tape as shown in
Figure 12. In Figure 3, openings 17 and 18 shown on
either side of the porous membrane 14 are optional. Air
can pass out of the openings 17 and 18. Figure 4 does
not include any such air vent openings. The tape of
Figure 12 like the package of Figures 3 and 4 optionally
includes the air vent openings, i.e., the package as
shown in Figures 4 and 6 as well as the tape of Figure 12
can operate without air flow. Air dispersion vents 51 as
shown in Figure 7, may optionally be part of the cassette
or the device. The precise procedures for creating an
aerosol using the package are described further below.
The two relatively simple versions of the package
1 of the invention are shown, in cross section, in
figures 14 and 15. In figure 14 is shown the container 2
having formulation 10 therein. The porous membrane 14 is
positioned over at least a portion of the container 2.
In order to aerosolize formulation 10 the cover 4 is
first removed. The cover 4 is positioned over at least
the membrane 14 in order to prevent contamination of the
formulation 10. After the cover 4 is removed the
container 2 can be collapsed forcing formulation 10
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outward through the porous membrane 14 and creating an
aerosol.
Another relatively simple embodiment of the
package 1 is shown, in cross section, in figure 15. The
container 2 also includes a formulation 10. However, the
porous membrane 14 is not positioned as the upper surface
of the container 2. The porous membrane 14 is a part of
a solid cover 150. When the container 2 is collapsed the
formulation 10 is forced against a barrier 61 which is
broken upon the application of a force causing a pressure
of 50 psi or less. The formulation 10 then flows through
the channel 11 until it is stopped by the abutment 152
after which pressure builds within the channel 11 and the
formulation 10 is forced outward through the porous
membrane 14. In accordance with preferred embodiments of
the invention two or more of the containers 2 are
interconnected together in a pattern such as a linear
pattern, rectangular pattern, spiral pattern, and/or any
suitable pattern of interconnecting components which can
be readily loaded into a cassette or device or the
invention so that the patient using the containers can
readily use one container after another at appropriate
times in order to deliver formulation l0 in an
aerosolized form.
Figure 5 is a cross-sectional view of a somewhat
more complex embodiment of the package 1 which is shown
in Figure 1. A drug formulation 10 is contained within
the container 2. When pressure is applied to the
container 2 such as by the force provided from a piston
the container 2 is collapsed and the formulation 10
within the container 2 is forced out through a channel
11. A rupturable barrier 61 is preferably in the channel
11 to prevent bacterial contamination of the drug in the
container 2. In this embodiment the cover 4 prevents
contamination and clogging of the membrane 14. The
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barrier 61 is broken upon the application of force
causing a pressure of 50 psi or less. The channel 11
leads to a cavity which may be a resonance cavity 12.
The cavity 12 is positioned above a vibrating device 13
which may be a piezoelectric vibrating device. Any
mechanism capable of creating vibrations in the range of
from about 800 kilohertz to about 4,000 kilohertz can be
used. The device is preferably capable of varying the
frequency to create different sized particles. Further,
the device is preferably low cost such as a sheet of poly
(vinylidene fluoride) film an example of which is sold as
Kynar~ by Pennwalt Corporation, Valley Forge,
Pennsylvania (U.S.A.). From the cavity 12 formulation is
forced (by pressure created from collapsing the container
2) through pores within a porous membrane 14 which covers
the upper surface of the cavity 12.
Figure 6 is a cross-sectional view of a simpler
embodiment of the package shown in Figure 5.
Specifically, the package of Figure 6 includes the
container 2 which holds the formulation to and provides
for a channel 11 through which the formulation can pass
into the cavity 12 which is positioned below the porous
membrane 14. The cover 4 is held in place by one or more
seals 50 and 50'. The seals may be comprised of glue or
other suitable materials using suitable sealing
techniques which make it possible to place the cover 4
over the porous membrane and thereafter remove the cover
without damaging the porous membrane or other components
of the package.
It is possible to use a package as shown in
Figures 6, 14 or 15 without the use of additional air
flow such as the air flow coming out of the air vents 17
and 18 as shown in Figures 3 and 5. However, any of the
packages may be used in combination with air dispersion
vents 51 and 52 as shown in Figure 7. The vents 51 and
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52 are either part of and integral with the cassette 5 or
the device 6 as shown in Figure 2. The air vents 51 and
52 have openings which are positioned such that, when air
is forced through the vents, it exits in the general
direction of the particles exiting from the porous
membrane 14. Accordingly, the air causes the particles
to move along in the same direction, and aids in
preventing the collision and thereafter aggregation of
particles.
Figure 8 is a top view of an embodiment as shown
in Figure 7. The device 6 includes a system for forcing
compressed air into the air dispersion vents 51 and 52 on
the device or cassette so that it exits in substantially
the same direction as the particles exiting from the
porous membrane 14. The compressed air being forced out
of the vents 51 and 52 can be derived from any suitable
source, including a container of compressed air (not
shown). However, it is preferable to create the
compressed air by using a mechanical device to be
operated by the user. For example, a spring-loaded
piston or bellows within a cylinder can be cocked by
compressing the spring which, upon release, allows the
piston to move through the cylinder and force air outward
into the vents 51 and 52.
The porous membrane 14 in all of the embodiments
includes pores which have a diameter in the range of
about 0.25 micron to about 6 microns and a pore density
in the range of 1 x 104 to about 1 x 108 pores per square
centimeter. The porous membrane 14 is preferably
comprised of a material having a density in the range of
about 0.25 to 3.0 mg/cma, more preferably about
1.7 mg/cma, and a thickness of about 2 to about
20 microns, more preferably 8 to 12 microns.
Alternatively, the porous membrane may be described as an
area of pores having a diameter in the range of 0.25
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micron to about 6 microns which pores are positioned over
the area of about 1 sq. mm. to about 1 sq. cm. which area
contains from 10 to 10,000 pores. What is important is
that the membrane has pores of sufficient size and in
sufficient numbers such that when the formulation is
forced against the membrane the formulation is
aerosolized and particles suitable for inhalation are
created. The membrane 14 is preferably comprised of a
hydrophobic material which includes materials such as
polycarbonates and polyesters which have pores formed
therein by anisatarpic etching or by etching through a
thin film. The membrane material may include
cylindrically shaped pores, pores which have a non-
cylindrical shape and specifically pores which have a
configuration such as an hour glass or conical
configuration. When a conical configuration is used it
is designed with the narrowest point of the conical
configuration having an opening with a diameter in the
range of 0.2 micron to 6 microns. The narrow end is
positioned away form the container 2. The material of
the porous membrane has sufficient structural integrity
so that it is maintained intact (will not rupture) when
the material is subjected to force sufficient to
aerosolize the formulation. That force will generally be
in the amount of about 20 to about 200 psi while
formulation 10 is being forced through the pores of the
membrane 14. As explained above with respect to Figure 1
the protective cover layer 4, if present, must be removed
prior to release of drug.
In Figure 5, the package 1 also includes openings
15 and 16 which may be positioned along either side of
the porous membrane 14 or connected on either side of the
membrane 14 via channels 17 and 18 respectively. One or .
more openings such as openings 15 and 16 are provided so
that air can be forced through these openings and can
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exit the package 1 along with the formulation l0 being
forced through the pores of the membrane 14. The air
flow forced through the openings 15 and 16 is preferably
maintained at a speed approximately equal to the speed of
the formulation being forced through the pores of the
membrane 14. The air flow is provided in order to aid in
preventing particles of formulation 10 from colliding
with each other and aggregating. Thus the object of the
air flow is to keep the particles which escape from the
pores in the membrane 14 separate from each other so that
they maintain their small size and can be inhaled deeply
into smaller channels within the lungs. However, the
speed of the air forced through the openings 15 and 16
can be varied in order to create an aerosol dispersion
wherein the particles have greater variation in size in
that the speed is adjusted to allow some of the particles
to collide with each other and therefore form particles
which are twice, three times or four times etc. the mass
of the smallest particles. Those skilled in the art will
recognize that adjustments in the air flow can be made in
order to obtain particle sizes of the desired size
dispersion depending upon the particular disease being
treated and results desired.
As indicated above the pores within the membrane
14 have a size in the range of about 0.25 to 6 microns.
When the pores have this size the particles which escape
through the pores to create the aerosol will have a
diameter of approximately twice that size i.e. have a
particle diameter in the range of 0.5 to 12 microns. The
air flow for the openings 15 and 16 is intended to keep
the particles within this size range. The creation of
the small particles is greatly facilitated by the use of
the vibration device 13 which is positioned below the
cavity 12. The vibration device 13 provides a vibration
frequency in the range of about 800 to about
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4000 kilohertz. Those skilled in the art will recognize
that some adjustments can be made in the pore size,
vibration frequency, pressure, and other parameters based
on the density and viscosity of the formulation 10
keeping in mind that the object is to provide aerosolized
particles having a diameter in the range of about 0.5 to
12 microns.
The drug formulation is preferably in a low
viscosity liquid formulation (a viscosity within 25% plus
or minus of water) which is most preferably a formulation
which can be aerosolized easily and includes respiratory
drug formulations currently used in nebulizers. The
viscosity of the drug by itself or in combination with a
carrier must be sufficiently low so that the formulation
can be forced through the membrane 14 to form an aerosol,
e.g., using 20 to 200 psi to form an aerosol preferably
having a particle size in the range of about 0.5 to
12 microns.
The container 2 can be in any desired size. In
most cases the size of the container is not directly
related to the amount of drug being delivered in that
most formulations include relatively large amounts of
excipient material e.g. water or a saline solution.
Accordingly, a given size container could include a wide
range of different doses by varying drug concentration.
The amount of drug delivered to the patient will vary
greatly depending on the particular drug being delivered.
In accordance with the present invention it is possible
to deliver a wide range of different drugs. For example,
the drugs included within the container 2 could be drugs
which have a systemic effect such as narcotic drugs, for
example.fentanyl, sufentanil, or anxiolytic drugs such as
diazepam midazolam as well as peptide drugs, e.g. insulin ,
and calcitonin. In addition, mixed agonist/antagonist
drugs such as butorphanol can also be used for the
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management of pain delivered to provide relief from pain
or anxiety. However, in that the drugs are delivered
directly to the lungs, respiratory drugs are included and
include proteins such as DNAse. The preferred
respiratory drugs are albuterol, beclomethasone
dipropionate, triamcinolone acetonide, flunisolide,
cromolyn sodium, and ipratropium bromide, and include,
free acids, bases, salts and various hydrate forms
thereof generally administered to a patient in an amount
in the range of about 50 ug - 10,000 ~Cg. These doses are
based on the assumption that when intrapulmonary delivery
methodology is used the efficiency of the delivery is
approximately 10% and adjustments in the amount released
must be made in order to take into account the efficiency
of the device. The differential between the amount of
respiratory drug actually released from the device and
the amount of respiratory drug actually delivered to the
patient varies due to a number of factors. In general,
the present device is approximately 20% efficient,
however, the efficiency can be as low as 10% and as high
as 90% meaning that as little as 10% of the released
respiratory drug may actually reach the lungs of the
patient and as much as;90% might be delivered. The
efficiency of the delivery will vary somewhat from
patient to patient and must be taken into account when
programming the device for the release of respiratory
drug. In general, a conventional metered dose inhaling
device is about 10% efficient.
Referring to Figure 2, there is shown an elongated
package comprised of linearly connected containers. Such
a package 1 can be readily integrated with and moved
through.the cassette 5 in the drug dispensing device 6.
The package 1 may also include indices which are
positioned on individual containers 2 or material used to
interconnect the containers. The indices may be
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electronic and may be connected to a power source such as
a battery. When the indices are in the form of visually
perceivable numbers, letters or any type of symbol
capable of conveying information to the patient using the
device. Alternatively, the indices may be connected to a
power source such as a battery when the indices are in
the form of magnetically, optically or electronically
recorded information which can be read by the drug
dispensing device 6 which in turn provides visual or
audio information to the user. The indices can be
designed for any desired purpose but in general provides
specific information relating to the day and/or time
which the drug within a container should be administered
to the patient. Such indices may record, store and
transfer information to the dispensing device 6 regarding
the number of containers 2 remaining in the cassette 5,
the number of containers 2 used and/or the specific drug
10, and amount of drug 10 present in each container 2.
If the user is to take the drug once a day then
each container may be labeled with a day of the week.
However, if the user is to take the drug more than once a
day such as four times a day then only one row of
containers is labeled with the days of the week whereas
the other rows within a column of four are labeled with
different times of the day e.g. 6:00 a.m., 12:00 p.m.,
6:00 p.m., 12:00 a.m. The labeling can be in any format
and could include days of the month or other symbols or
numbers in any variation or language.
In addition to disclosing specific information
regarding the day and time for drug delivery the indices
could provide more detailed information such as the
amount of drug dispensed from each container which might
be particularly useful if the containers included
different amounts of drug. Further, magnetic, optical
and/or electronic indices could have new information
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recorded onto them which information could be placed
there by the drug dispensing device. For example, a
magnetic recording means could receive information from
the drug dispensing device indicating the precise time
which the drug was actually administered to the patient.
In addition to recording the time of delivery the device
could monitor the expected efficacy of the delivery based
on factors such as the inspiratory flow rate which
occurred following the initial release of drug. The
information recorded on the array could then be read by a
separate device, interpreted by the care-giver and used
to determine the usefulness of the present treatment
methodology. For example, if the patient did not appear
to be responding well but the recorded information
indicating that the patient had taken the drug at the
wrong time or that the patient had misdelivered drug by
changing inspiratory flow rate after initial release it
might be determined that further education in patient use
of the device was needed but that the present dosing
methodology might well be useful. However, if the
recordings indicated that the patient had delivered the
drug at the proper time using the proper techniques and
still not obtained the correct results a different drug
or dosing methodology might be recommended.
The containers 2 on the package 1 are also
referred to as drug dosage units. Each container 2
includes at least one wall which can be collapsed to
allow liquid contents 10 present in the container to be
forced out of the pores of the membrane 14. In
accordance with one embodiment the container 2 has
cylindrical walls with bellows or accordion-like
undulations so that the bottom of the container 2 can be
forced upward towards the top of the container and allow
liquid 10 present within the container 2 to be forced out
of a plurality of pores in membrane 14.
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Dual Compartment Package
The packages as shown within Figures 5 and 6 can
be used in connection with nearly all drugs in that '
nearly all pharmaceutically active drugs can be dissolved
in an excipient such as water, saline solution, ethanol, '
or combinations thereof in order to provide the desired
formulation which can be expelled out of the membrane 14.
However, some pharmaceutically active drugs must be
maintained in a dry state in that the drugs are subject
to deterioration such as hydrolysis in the presence of
water. Due to the need to have drugs in a form which is
not substantially deteriorated from their original form,
it is necessary to package such drugs in a dual
compartment system.
A dual system package is shown in Figure 10. The
package includes the same components of the package shown
in Figure 5, such as the cover 4 and porous membrane 14.
However, the drug-containing container is the container
55, which includes a powdered or dry form of a drug 56.
The container 55 is positioned below a piston 59 or other
device for collapsing the container 55. A separate
container 57 includes a liquid 58 which can be combined
with the powder 56 in order to form a solution or a
dispersion. In order to use the package, a piston 60 or
other device is used to collapse the container 57 and
force the contents 58 outward through a breakable seal 61
positioned between the containers 55 and 57.
After the liquid 58 enters into the container 55,
it is mixed with the dry powder 56 using mixing
components 62 and 63, which may be vibrating devices,
ultrasonic devices, or other suitable mechanisms allowing
for the. mixing of the liquid and dry components. After
mixing has taken place, the piston 59 collapses the
container 55, forcing the solution or suspension outward
into the chamber 12 and through the porous membrane 14
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after the removal of the cover 4. The mixing of the
solvent with the dry powder may take place by the use of
flow channels and/or with various types of mechanical
devices or any mixing means which would be suitable for
the creation of a suspension or solution which can then
be forced through a porous membrane of the invention.
Another embodiment of the dual compartment system
is shown in Figure 16 wherein a first compartment 160 is
connected to a second compartment 161 by a wall 162 which
includes a weakened portion 163. The compartment 160
includes a liquid 164. When force is applied to the
compartment 160 the liquid 164 present therein is forced
against the weakened portion 163 breaking this portion
open and allowing the liquid to flow into the compartment
161. The liquid 164 suspends or more preferably
dissolves the powder present in the compartment 161. The
suspension or solution is then forced through the porous
membrane 14 after the removal of the cover 4. The
weakened wall portion 163 is generally ruptured upon the
application of additional pressure such as by increasing
the pressure Within the compartment 160 by approximately
50% or more above its original pressure.
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Disposable Take With Remote Container of Druq
As indicated above, the "disposable member" or
"member" of the invention is comprised of interconnected
porous membranes. For purposes of clarity, the
disposable member of the invention is described
specifically with reference to the tape configuration.
However, the invention encompasses any configuration such
as columns and rows of interconnected porous membranes in
the form of a square or rectangle, interconnected
membranes on a card in the form of a circle wherein the
membranes are configured in a spiral configuration or
other configurations suitable for use in the dispensing
of drugs from a dispensing device of the invention.
A perspective view of a tape 120 is shown in
figure 12. The tape 120 is configured in a manner
similar to the disposable package shown in figure 1
except that no drug containers are present. The tape 120
includes openings 121 which are each covered by the
porous membrane 14. In addition, the tape includes
perforations 122 on each edge of the interconnecting body
123 which allows the tape to be moved through a device by
the use of one or more sprockets. The tape is loaded
into a device and the cover 4 is removed prior to forcing
formulation through the porous membranes within the
openings 121.
Referring to figure 13 it can be seen that the
tape 120 can be loaded into a cassette 124 which cassette
can be loaded into a device 125. This is done in a
manner similar to the loading of the package 3 into the
device 6 as shown in figure 2. However, the tape 120
does not include any drug containers. The tape 120 is
wound onto a sprocket 126 after the cover 4 is removed.
The cover 4 may be wound onto a sprocket 127. As the
tape moves to a drug release position an opening 121 is
positioned over an outlet 128 which is connected directly
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to a multiple dose containing container 129. Formulation
within the container 129 is forced through the membrane
14 within each of the individual openings 121 in order to
aerosolize the formulation. The aerosolized mist is then
expelled through the mouthpiece 9. Further details with
respect to the operation of the device 125 are given with
respect to the description of figures 17 and 18.
Particle Accumulation
As pointed out in connection with the description
of the package of Figure 5, air should be forced out of
the package 1 along with the formulation 10 being forced
out of the membrane 14. This can also be efficiently
accomplished using a structural configuration as is shown
in Figure 6. A top view of the package 1 is shown in
Figure 3. The packages of Figures 5 and 6 are shown in
top views, respectively, within Figures 3 and 4. The
containers 2 are positioned below the package and are not
shown in Figures 3 and 4. Thus, the top view of the
package is the same as the top view of the tape.
Figures 3 and 4 do show openings which can accommodate
teeth, thereby providing a means for moving the package
along within the cassette and the device. Although these
openings 19 are shown within both embodiments, it is not
necessary to include the openings, but it is preferable
to include some means for moving the package along within
the cassette and the device so that individual containers
2 can be brought into a firing position within the
cassette and device and then moved out of position once
the formulation within the container 2 has been expelled.
When the drug formulation 10 within a package 2 is
forced out of the porous membrane 14, air is
simultaneously forced out of the elongated openings 17
and 18 positioned on either side of each of the porous
membranes 14. As formulation is forced out of the porous
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membrane 14, vibration is applied by means of the
vibrating device 13 (shown in Figure 4) so that the
stream of formulation exiting each of the pores in the
membrane 14 is broken up to form particles, which
particles will have a diameter in the range of about
0.5 to 12 microns. In that the particles formed are very
small, they can be substantially effected by the
frictional resistance created from static air. If the
air is not moved along in the direction of the flow of
the particles, the particles may slow in speed and
collide with one another and combine with one another,
thereby forming larger particles. This particle
collision followed by particle accumulation is not
desirable in that the larger particles will not enter
deeply into the lung tissue due to the small size of the
channels within the lungs. In order to reduce particle
collision and accumulation, air is forced from the
openings 17 and 18 at a speed which is approximately
equal to the speed of the particles being forced out of
the pores of the membrane 14. When the air speed and
particle speed are substantially equal, the particles do
not undergo frictional resistance from the surrounding
air and are not slowed and do not collide with one
another - at least do not collide to the same extent they
do when the air flow is not present.
Depending upon the end result required the rate
and amount of air flow can be varied so as to allow for
some collisions between some of the particles. When
collisions occur the resulting aerosol is not a
"monodisperse" aerosol wherein all the particles have
substantially the same size. Collisions result in a
"multi-disperse" aerosol wherein the particle sizes vary
over a predetermined range. For example, the initial
particles being dispersed from the porous membrane could
have a size of approximately 2 microns in diameter. Some
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of these particles could be allowed to collide with other
particles by adjusting the air flow so as to create
particles of twice that volume and some of these
particles could be allowed to collide with particles of
the same size and particles of the original two micron
diameter size thereby creating a multi-dispersed aerosol
containing particles of a size of two microns in
diameter, twice that volume, three times that volume and
four times that volume, etc.
In order to obtain the maximum benefit of the air
flow, it is desirable to have the porous membrane 14 in
an elongated rectangular configuration and to have the
openings 17 and 18 positioned close to the membrane
opening 14 on either side of the membrane 14 with a
similar configuration, i.e. elongated rectangle. The
elongated rectangular configuration is desirable in that
it is a configuration wherein a large amount of the
particles being expelled from the membrane 14 are brought
into contact with and thereby influenced by the air flow
exiting from the openings 17 and 18. If the
configuration of the opening of the membrane 14 were, for
example, circular, the particles exiting near the center
of the circular configuration would not be carried along
by the air flow, and would therefore slow down due to
resistance from the air and collide with one another.
Drua Delivery Device - With Disposable Packaae
A plan view of a simple embodiment of a drug
delivery device 6 of the present invention is shown
within Figures 4 and 5. This device operates with the
disposable package and not the disposable member or tape.
Before describing the details of the individual
components of the device 6, a general description of the
device and its operation as distinguished from prior art
devices is in order.
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As indicated in the background of the invention,
conventional metered dose inhalers and nebulizers suffer
from a number of disadvantages. These disadvantages
result in the inability to use these devices to
repeatedly deliver the same amount of drug to a patient.
In part, this results from the fact that users of such
devices actuate the release of the drug by pushing a
button which opens a valve causing drug to be released.
Such methodology is not desirable because the patient
will often actuate drug release at the wrong point within
the inspiratory cycle. The drug dispensing device of the
present invention preferably includes electronic and
mechanical components which eliminate direct user
actuation of drug release. More specifically, the device
preferably includes a means for measuring inspiratory
flow and sending an electrical signal as a result of the
measurement and also preferably includes a microprocessor
which is programmed to receive, process, analyze and
store the electrical signal of the means for measuring
flow and upon receipt of signal values within appropriate
limits sending an actuation signal to the mechanical
means which causes drug to be extruded from the pores of
the porous membrane.
The device 6 shown in Figure 9 is loaded with a
disposable package 1, which package is not included
within a cassette. The package 1 is comprised of a
plurality of containers 2. Each container 2 includes a
drug formulation 10 and is in fluid connection via a
channel 11 with the resonance cavity 12. The cavity 12
is covered by the porous membrane 14. Further, a
vibrating mechanism 13 of the device 6 is positioned such
that it.is located directly below the resonance cavity 12
when that resonance cavity is in the drug delivery
position.
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The device 6 is a hand-held, portable device which
is comprised of (a) a device for holding a disposable
package with at least one but preferably a number of drug
containers, (b) a mechanical mechanism for forcing the
contents of a container (on the package) from a porous
membrane on the container and preferably (c) a monitor
for analyzing the inspiratory flow of a patient and (d) a
switch for automatically releasing or firing the
mechanical means after the inspiratory flow and/or volume
reaches a threshold level. The device for holding the
disposable package may be nothing more than a narrow
opening created between two outwardly extending bars or
may include additional components such as one or more
wheels, sprockets or rollers notably mounted on the
ends) of such bars. The rollers may be spring mounted
so as to provide constant pressure against the surfaces)
of the package. The device may also include a transport
mechanism which may include providing drive power to the
rollers) so that when they are rotated, they move the
package from one container to the next. The power
driving the rollers) is programmed to rotate the rollers
only enough to move the package from one container to the
next. In order to use the device, the device must be
"loaded," i.e. connected to a package (or cassette
holding a package) which includes drug dosage units
having liquid, flowable formulations of pharmaceutically
active drug therein. The entire device is self-
contained, light weight (less than 1 kg preferably less
than 0.5 kg loaded) and portable.
The device may include a mouth piece at the end of
the flow path, and the patient inhales from the mouth
piece which causes an inspiratory flow to be measured
within the flow path which path may be in a non-linear
flow-pressure relationship. This inspiratory flow causes
an air flow transducer to generate a signal. This signal
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is conveyed to a microprocessor which is able to convert,
continuously, the signal from the transducer in the
inspiratory flow path to a flow rate in liters per
minute. The microprocessor can further integrate this
continuous air flow rate signal into a representation of
cumulative inspiratory volume. At an appropriate point
in the inspiratory cycle, the microprocessor can send a
signal to an actuation means and the vibration device
below the resonance cavity. When the actuation means is
signaled, it causes the mechanical means to force drug
from a container on the package into the inspiratory flow
path of the device and ultimately into the patient s
lungs. After being released, the drug and carrier will
pass through a porous membrane which is vibrated to
aerosolize the formulation and thereafter the lungs of
the patient.
It is important to note that the firing threshold
of the device is preferably not based on a single
criterion such as the rate of air flow through the device
or a specific time after the patient begins inhalation.
The firing threshold is based on an analysis of the
patient s inspiratory flow profile. This means that the
microprocessor controlling the device takes into
consideration the instantaneous air flow rate as well as
the cumulative inspiratory flow volume. Both are
simultaneously considered together in order to determine
the optimal point in the patient s inspiratory cycle most
preferable in terms of reproducibly delivering the same
amount of drug to the patient with each release of drug.
The device preferably includes a means for
recording a characterization of the inspiratory flow
profile for the patient which is possible by including a
microprocessor in combination with a read/write memory
means and a flow measurement transducer. By using such
devices, it is possible to change the firing threshold at
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any time in response to an analysis of the patient's
inspiratory flow profile, and it is also possible to
record drug dosing events over time. In a particularly
preferred embodiment the characterization of the
inspiratory flow can be recorded onto a recording means
on the disposable package.
Figure 9 shows a cross-sectional view of a hand
held, self-contained, portable, breath-actuated inhaler
device 6 of the present invention. The device 6 is shown
with a holder 20 having cylindrical side walls and a hand
grip 21. The holder 20 is "loaded" in that it includes a
package 1. The package 1 includes a plurality of
containers 2.
The embodiment shown in Figure 9 is a simple
version of the invention and is not the preferred
embodiment. The device 6 may be manually actuated and
loaded. More specifically, the spring 22 may be
compressed by the user until it is forced down below the
actuation mechanism 23. When the user pushes the
actuation mechanism 23 the spring 22 is released and the
mechanical means in the form of a plate 24 is forced
upward against a container 2. When the container 2 is
compressed its contents are forced out through the
channel il and membrane 14 and aerosolized. Another
container 2 shown to the left is unused. A top cover
sheet 4 has been peeled away from the top of the membrane
14 by a peeling means 25. The embodiment of Figure 9
could provide the same results as a conventional metered
dose inhaler. However, the device of Figure 9 would not
require the use of low boiling point propellants such as
low boiling point fluorocarbons. Numerous additional
features and advantages of the present invention can be
obtained by utilizing the monitoring and electronic
components described below.
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It is important to note that a variety of devices
can ba used in order to carry out the methodology
(including the respiratory disease treatment methodology)
of the present invention. However, the device must ba
capable of aerosolizing drug formulation in a container
and preterably does such based on pre-programmed criteria
which are readable by the microprocessor 26. The details
of the microprocessor 26 and the details of other drug
delivery devices which include a microprocessor and
pressure transducer of the type used in connection with
the present invention are described and disclosed within
U.S. patent 5,404,871, issued on April 11, 1995 entitled
'"Delivery of Aerosol Medications for Inspiration". The use
of such a microprocessor with a drug delivery device is
disclosed in U.S. patent number 5,709,202
issued Jaa. 20, 1998. The pre-programed information is
contained within a nonvolatile memory which can ba
modified via an external device. In another embodiment,
this pre-programmed information is contained within a
"read only" memory which can ba unplugged from the device
and replaced with another memory unit containing
different programming information. In yet another
embodiment, microprocessor 26, containing read only
memory which in turn contains the pre-programmed
information, is plugged into the device. for each of
these three embodiments, changing the programming of the
memory device readable by microprocessor 26 will
radically change the behavior of the device by causing
microprocessor 26 to be programmed in a different manner.
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This is done to accommodate different drugs for different
types of treatment.
Microprocessor 26 sends signals via electrical
connection 27 to electrical actuation device 28 which
actuates the means 23 which fires the mechanical plate 24
forcing drug formulation in a container 2 to be
aerosolized so that an amount of aerosolized drug is
delivered into the inspiratory flow path 29. The device
28 can be a solenoid, motor, or any device for converting
electrical to mechanical energy. Further, microprocessor
26 keeps a record of all drug dosing times and amounts
using a read/write non-volatile memory which is in turn
readable by an external device. Alternatively, the
device records the information onto an electronic or
magnetic strip on the tape 3 of the package 1. The
recorded information can be read later by the care-giver
to determine the effectiveness of the treatment. In
order to allow for ease of use, it is possible to
surround the inspiratory flow path 29 with a mouth piece
30.
The electrical actuation means 28 is in electrical
connection with the flow sensor 31 which is capable of
measuring a flow rate of about 0 to about 800 liters per
minute. It should be noted that inhalation flow rates
are less than exhalation rates, e.g. max for inhalation
200 lpm and 800 lpm for exhalation. The flow sensor 31
includes screens 32, 33 and 34 which are positioned
approximately 4'~ apart from each other. Tubes 35 and 36
open to the area between the screens 32, 33 and 34 with
the tubes 35 and 36 being connected to a conventional
differential pressure transducer 37. Another transducer
designed to measure outflow through the opening 38 is
also preferably included or the flow sensor 31 is
designed so that the same components can measure inflow
and outflow. When the user draws air through inspiratory
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flow path 29, air is passed through the screens 32, 33
and 34 and the air flow can be measured by the
differential air pressure transducer 37. Alternatively,
other means to measure pressure differential related to
air flow, such as a conventional measuring device in the
air way, may be used. The flow sensor 31 is in
connection with the electrical actuation means 28 (via
the connector 39 to the processor 26), and when a
threshold value of air flow is reached (as determined by
the processor 26), the electrical actuation means 28
fires the release of a mechanical means 23 releasing the
plate 24 which forces the release of formulation from a
container 2 so that a controlled amount of respiratory
drug is delivered to the patient. The microprocessor 26
is also connected via connector 40 to the vibrating
device 13 which is activated prior to fluid 10 entering
the vibrator cavity 12.
The vibrator 13 is designed so as to generate
vibrations which affect the particle formation of
formulation being forced out of the pores within the
membrane 14. The frequency of the vibrations can be
varied depending upon the size of the pores in the
membrane 14 and the viscosity of the formulation 10 and
pressure present within the container 2. However, in
general, the vibrations are within the range of about
800 kilohertz to about 4,000 kilohertz.
The device of Figure 9 does not show the cassette
5 of Figure 2, but does show all of the components
present within the single, hand-held, portable breath
actuated device, e.g. the microprocessor 26 and flow
sensor 31 used to provide the electronic breath actuated
release of drug. The device of Figure 9 includes a
holding means and mechanical means and preferably
operates electronically, i.e. the actuation means is
preferably not directly released by the user. The
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patient inhales through inspiratory flow path 29 which
can form a mouth piece 30. Air enters the device via the
opening 38. The inhaling is carried out in order to
obtain a metering event using the differential pressure
transducer 37. Further, when the inspiratory flow meets
a threshold of a pre-programmed criteria, the
microprocessor 26 sends a signal to an actuator release
electrical mechanism 28 which actuates the mechanical
means 23, thereby releasing a spring 22 and plate 24 or
equivalent thereof, forcing aerosolised formulation into
the channel 11, cavity 12 (vibrated by the vibrator 13j
and out of the membrane 14 into the flow path 29.
Further details regarding microprocessors 26 of Figure 9
are described within U.S. patent 5,394,860 entitled "An
Automatic Aerosol Medication Delivery System and Methods",
issued on March 7, 1995.
Microprocessor 26 of Figure 9 includes an external
non-volatile read/write memory subsystem, peripheral
devices to support this memory system, reset circuit, a
clock oscillator, a data acquisition subsystem and a
visual annunciator subsystem. The discrete components
are conventional parts which have input and output pins
configured in a conventional manner with the connections
being made in accordance with instructions provided by
the device manufacturers. The microprocessor used in
connection with the device of the invention is designed
and programmed specifically so as to provide controlled
and repeatable amounts of respiratory drug to a patient
upon actuation. The microprocessor must have sufficient
capacity to make calculations in real time. Adjustments
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can be made in the program so that when the patient's
inspiratory flow profile is changed such is taken into
consideration. This can be done by allowing the patient
to inhale through the device as a test (monitoring event)
in order to measure air flow with preferred drug delivery
points determined based on the results of several
inhalations by each particular patient. This process can
be readily repeated when the inspiratory flow profile is
changed for whatever reason. When the patient°s lung
function has decreased the program will automatically
back down in terms of the threshold levels required for
release of drug. This "back down" function insures drug
delivery to a patient in need but with impaired lung
function. Determination of optimal drug delivery points
in the inspiratory flow can be done at each dosing event,
daily, weekly, or with the replacement of a new cellular
array in the device.
The microprocessor 26 of the present invention,
along with its associated peripheral devices, can be
programmed so as to prevent triggering the actuation
mechanism 28 more than a given number of times within a
given period of time. This feature makes it possible to
prevent overdosing the patient. The overdose prevention
feature can be particularly designed with each individual
patient in mind or designed with particular groups of
patients in mind. For example, the microprocessor can be
programmed so as to prevent the release of more than
approximately 200 ~g of a given respiratory drug per day
when the patient is normally dosed with approximately
100 ~Cg of drug per day. The device can be designed to
switch off this lock-out function so that drug can be
delivered in an emergency situation.
The systems can also be designed so that only a
given amount of a particular drug such as a respiratory
drug is provided at a given dosing event. For example,
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the system can be designed so that only approximately
~g of respiratory drug is given in a given 15-minute
period over which the patient will make approximately 10
inhalations with 1 ~cg of drug being delivered with each
5 inhalation. By providing this feature, greater
assurances are obtained with respect to delivering the
respiratory drug gradually over time and thereby
providing relief from the symptoms of respiratory disease
without overdosing the patient.
10 The microprocessor of the invention can be
connected to external devices permitting external
information to be transferred into the microprocessor of
the invention and stored within the non-volatile read/
write memory available to the microprocessor. The
microprocessor of the invention can then change its drug
delivery behavior based on this information transferred
from external devices. All of the features of tt,e
invention are provided in a portable, programmable,
battery-powered, hand-held device for patient use which
has a size which compares favorably with existing metered
dose inhaler devices.
The microprocessor of the present invention is
programmed so as to allow for monitoring and recording
data from the inspiratory flow monitor without delivering
drug. This is done in order to characterize the
patient s inspiratory flow profile in a given number of
monitoring events, which monitoring events preferably
occur prior to dosing events. After carrying out a
monitoring event, the preferred point within the
inspiratory cycle for drug delivery can be calculated.
This calculated point is a function of measured
inspiratory flow rate as well as calculated cumulative
inspiratory flow volume. This information is stored and
used to allow activation of the electronic actuation
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means when the inhalation cycle is repeated during the
dosing event.
Drug Delivery Device - With Disposable Tape
The device 6 as shown schematically in figure 9
operates in essentially the same manner as the device
shown within figure 17. However, the device of figure 17
includes the tape 120 which does not include a container
2 in the package one shown in figure 9. In that the tape
120 does not include a container of drug the drug is
obtained from a multiple dose container 170 held within a
gripable handle 171. The container 170 includes a valve
172 which, when opened allows the formulation 10 present
within the container 170 to flow into a channel 173 which
leads to a resonance cavity 174. From the cavity 174 the
pressurized formulation can be forced outward through the
porous membrane 14 within the tape 120. The formulation
is forced outward after the cover 4 is removed. In order
to open the valve 172 an electrical actuation device such
as a motor or solenoid 28 or other similar devices
actuated by a means of a signal sent from the central
processing unit 26.
Yet another embodiment of the invention is shown
within figure 18. In accordance with figure 18 all of
the components are identical and operate in the same
manner as with figure 17 except that two containers are
present. The first container 10 includes a dry powder
form of the drug and the second container 180 includes a
liquid solvent such as water, saline solution or ethanol.
When the device 28 is actuated it opens the valves 181
and 182. In that the contents of the containers are held
under pressure the powder and liquid are forced form the
containers into the channel il and into the residence
cavity 12. Thereafter the powder and liquid are
intermixed and forced outward through the membrane 14.
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Creating Aerosols
In order for any aspects of the present invention
to be utilized an aerosol must be created. When
formulation is initially forced through the pores of the
porous membrane the formulation forms streams which are
unstable and will, do to factors such as surface tension,
break up into droplets on their own. The size of the
droplets will be affected by factors such as the pore
size, temperature, viscosity and the surface tension of
the formulation forced through the pores. With some
formulations the size of the particles within the
dispersion may vary over a range and may include a large
number of particles which are too large to be readily
inhaled. If such occurs not all the drug can effectively
enter the lungs for intrapulmonary delivery to have the
desired effects. This problem can be solved by breaking
the streams of liquid into particles having a diameter
which sufficiently small such that the patient can inhale
the particles into the pulmonary tree. Although the
particle size will vary depending on factors such as the
particular type of formulation being aerosolized, in
general, the preferred particle size is in the range of
about 0.5 micron to about 12 microns. In order to obtain
small particle sizes sufficient to aerosolize a
formulation a number of different porous membranes and
vibrating devices can be utilized and the present
invention is intended to encompass such aerosolizing
systems.
The pharmaceutical formulations in the containers
are forced through the tiny openings (pores) in the
polycarbonate or polyester membrane while the liquid,
container and/or openings are simultaneously subjected to
vibration. By vibrating at a particular frequency it is
possible to form extremely small particles and create a
fine mist aerosol. The particle size is determined by
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the size of the openings on the porous structure through
which the liquid formulation is forced, the rate at which
the fluid is forced from the container, and vibration -
frequency. More specifically, the aerosol particle size
is a function of the diameter of the openings or pores
through which the formulation is forced, vibration
frequency, viscosity, liquid surface tension, and
pressure at which liquid is extruded through the
membrane. In essence, the particle size diameter will be
approximately twice the pore size diameter with a margin
of error of approximately ~ 20% or less. For example, if
the membrane used includes pores having a diameter of
2 microns the aerosolized particles formed will have a
size of approximately 3.6 to 4.4 microns in diameter.
This relationship between particle size and pore diameter
appears to hold over a pore sized diameter of
approximately 0.5 micron to about 50 microns.
Accordingly, it is possible to use membranes with pores
therein having pore sizes of sufficient diameter to form
aerosols having a particle sized diameter of about one
micron to about 100 microns - although preferred
particles have a diameter of about 0.5 to 12 microns.
Different types of membrane materials can be used in
connection with the invention. In general, the membrane
will have a density of about 0.25 to about 3.0 mg/cmz,
more preferably about 1.7 mg/cma and a thickness in the
range of from about 2 to about 50 ~Cm, more preferably
about 14 to 16 Vim. The membrane will cover the entire
opening of the tape or container and the opening will
generally be in the form of an elongated rectangle.
However, the size and the shape of the opening can vary
and will generally have an area in the range of about 1.0
mm2 to about 1.0 cm2 but more preferably about
0.05-0.2 cm2.
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The various components of the invention are
generally used to create a "monodisperse" aerosol wherein
all the particles within the aerosol created have
essentially the same particle size. By adjusting
parameters such as the surface tension of the
formulation, pore hole size, and the air flow speed the
size of the monodispersed particles can be adjusted
within a very narrow range of size e.g. the particles
will have a size diameter equal to each other with a
margin of error of approximately ~ 10% or less, more
preferably ~ 5% or less.
Figure 11 shows a graph of particle size versus
the number of particles. The first peak 70 shows that
nearly all the particles are approximately 1 micron in
diameter, whereas the peak 72 shows nearly all of the
particles have a diameter of approximately 3 microns.
The curve 73 shows a more even distribution of particles
from about 0.25 micron to about 4.5 microns. Nebulizer
devices may be capable of creating particle dispersion
curves such as the curve 73. The present invention can
vary the frequency of the vibrating device in order to
create a particle size distribution as per the curve 73.
This is done by changing the frequency during a single
breath while formulation is forced through the membrane
14. Alternatively, the frequency can be set to create
all the particles within a very narrow distribution as
shown within the curves 70 and 72. Depending upon the
type of disease being treated, the vibration frequency
can be set and the desired results obtained.
a ti-disperse aerosol
As indicated above, the formulation is forced
through the pores of the porous membrane to create
streams. Along with the stream of formulation exiting
the pores an air flow is created out of air dispersion
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vents. The speed of the air flow and its volume can be
adjusted in any desired manner so as to allow for the
collision of some but not all of the particles thereby '
causing an aggregation of the colliding particles to
create particles of different sizes.
In accordance with another method the vibration
frequency can be varied. This vibration frequency can be
gradually varied over the time which formulation is
dispersed or can be oscillated between a high and a low
point thereby varying the point at which the streams
exiting the pores are cut to create different size
particles.
Lastly, the particle size can be varied by using a
membrane which has a range of different pore sizes. All
or any of these three techniques can be used in
combination with each other to obtain the desired
particle size dispersion within the aerosol. In addition
to using these features independently or together it is
possible to vary other parameters such as the viscosity
and surface tension of the formulation.
Ory, disposable, porous membranes
The porous membranes of the invention in the
packages or tapes are used only once. Accordingly,
clogging of the pores is avoided or substantially reduced
as compared to situations where a nozzle is used
repeatedly. The membrane is preferably dry prior to use.
Further, a porous membrane or aerosol creating the system
of the type described herein provides relatively small
particle sizes within a narrow particle size
distribution. Accordingly, the smallest particles
produced will not vary greatly in size as compared to the
largest particles produced. More specifically, two-
thirds or more of the particles produced will,
preferably, have a particle size within 20% of the mean
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particle size. In that the preferred mean particle size
is about 5 microns, the system will produce an aerosol
wherein two-thirds or more of the particles within the
aerosol have a particle size in the range of about
4 microns to about 6 microns. The system can aerosolize
from about 50 ~tl to about 300 ~1, more preferably, 200 ~,1
of liquid from a single container. The contents of a
container is generally aerosolized in a relatively short
period of time, e.g., 1 second or less and inhaled by the
l0 patient in a single breath.
The porous membranes used on the packages of the
present invention can be produced wherein the openings or
pores are all uniform in size and are positioned at
uniform distances from each other. However, the openings
can be varied in size and randomly placed on the
membrane. If the size of the openings is varied the size
of the particles formed will also vary. In general, it
is preferable to maintain uniform opening sizes in order
to create uniform particle sizes and it is particularly
preferable to have the opening sizes within the range of
about 0.25 to about 6 microns which will create particle
sizes of about 0.5 to 12 microns which are preferred with
respect to inhalation applications. When the openings
have a pore size in the range of 0.5 to 3 microns they
will produce an aerosol having particle sizes in the
range of 1 to 6 microns which is particularly useful for
treating the bronchioles and alveoli. Pore sizes having
a diameter of about 3 to 5 microns will produce particle
sizes having a diameter of about 6 to 10 microns which
are particularly useful with respect to treating the
bronchi.
Although the pores are generally smaller the
present invention includes a porous membrane with pore
sizes in the range of 0.5 micron to about 50 microns.
Further, the pores are preferably separated, one from the
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other, in a random pattern providing about 1 x 104 to
about 1 x 10g pores/cmz. The membrane (e.g. an area of a
flexible tape) may include from 10 to 10,000 pores over
an area of from 1 sq. mm. to 1 sq. cm. Further, the pore
diameter indicates that at least 75~ of the pores on the
membrane fall within the prescribed range and preferably
indicates that 85% or more of the pores fit within the
prescribed range. Uniformity in pore size is desirable
for creating uniformity in the particle size of the
aerosol being delivered which is important with respect
to maintaining consistency in dosing.
A variety of different types of materials can be
used for forming the pore openings of the drug dosage
units. It is important that the membrane material which
the pores are placed in has sufficient structural
integrity such that when the liquid in the container is
forced against the material the material will not rupture
and the pore size will remain essentially constant under
pressure. It has been found that porous ceramic oxides
may be used as well as porous glasses, and metal frets,
compressed porous plastics, and certain membranes
including polycarbonate membranes including one preferred
membrane referred to as "Nuclepore~" polycarbonate
membranes produced by Costar Corporation and "Isopore~"
by Millipore Corporation which are commercially produced
for use as filters to have a pore diameter in the range
of 0.015 to 12 microns. Such filter materials are not
being used when a porous membrane is intrical with the
container itself. In such a situation, an area of the
container in the range of 1 sq. mm. to 1 sq. cm. is made
porous by the use of technology such as laser drilling.
Lasers may be used to a drill from 10 to 10,000 holes in
a given area (1 mm2 to 1 cm2) and thereby create a porous
membrane and through which formulation can be forced and
aerosolized.
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Although the thickness of the membrane material
may be of any thickness, it is desirable for the material
to be particularly thin e.g, less than one millimeter and
more preferably less than 20~C with particularly preferred
components having a thickness in the range of about 10~
to 15u. As the thickness of this material is increased
the amount of energy necessary to force the liquid
through the membrane material is increased. Since the
device of the present invention is a hand-held device it
is important to produce materials which require the use
of small amounts of energy in order to create the aerosol
in that the energy supply is somewhat limited.
In order to reduce the amount of energy needed to
force the formulation through the pores of the porous
membrane it is possible to produce the pores in different
configurations. Although the pores are generally
cylindrical in shape they can be non-cylindrical (e. g.
hourglass shaped) and are preferably comically shaped.
The comically shaped pores have the wide end of the cone
shape facing towards the resonance cavity where the drug
formulation is dispersed from and the small end of the
cone at the outer edge of the membrane from which the
particles are dispersed from. The small end of the
comically shaped pores has a diameter in the range of
0.25 to 6 microns. The surface of the comically shaped
pores may have a coating thereon of a reduced friction
type of material such as Teflon~-type materials.
Vibrat~~n device
The porous membrane may be vibrated ultrasonically
in order to produce an aerosol having the desired
particle size. Such vibrations can be carried out by
connecting an ultrasonic vibrator to the drug delivery
device. The vibrator may be positioned on different
components of the drug delivery device but is preferably
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positioned directly to a piston or beneath the resonance
cavity.
The ultrasonic vibrations are preferably at right -
angles to the plane of the membrane and can be obtained
by the use of a piezoelectric ceramic crystal or other
suitable vibration device. The piezoelectric crystal is
connected to a piston or the porous membrane by means of
an attenuator horn or acoustic conduction mechanism,
which when correctly matched with the piezoelectric
l0 crystal frequency, efficiently transmits ultrasonic
oscillations of the piezoelectric crystal to the
resonance cavity and the porous polycarbonate membrane
and if sized correctly permits the ultrasonic energy to
be focused in the polycarbonate membrane allowing for
maximum use of the energy towards aerosolizing the liquid
formulation. The size and shape of the attenuator horn
is not of particular importance. It is preferred to
maintain a relatively small size in that the device is
hand held. The components are chosen based on the
particular material used as the porous material, the
particular formulation used and with consideration of the
velocity of ultrasonic waves through the membrane to
achieve a harmonic relationship at the frequency being
used.
A high frequency signal generator drives the
piezoelectric crystal. This generator is capable of
producing a signal having a frequency of from about
800 kilohertz (Khz) to about 4,000 kilohertz. The power
output required depends upon the amount of liquid being
nebulized per unit of time and the area and porosity of
the polycarbonate membrane used for producing the drug
dosage unit and/or the efficiency of the connection.
The vibration is applied while the liquid is being
forced from the pores of the polycarbonate membrane. The
pressure required for forcing the liquid out can be
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varied depending on the liquid, the size of the pores and
the shape of the pores but is generally in the range of
about one to 200 psi, preferably 50 to 125 psi and may be
achieved by using a piston, roller, bellows, a blast of
forced compressed gas, or other suitable device. The
vibration frequency used and the pressure applied can be
varied depending on the viscosity of the liquid being
forced out and the diameter and length of the openings or
pores. In general, the present invention does not create
effective aerosols if the viscosity of the liquid is
greater than about 50 centipoises.
When small aerosolized particles are forced into
the air, the particles encounter substantial frictional
resistance. This causes the particles to slow down
quickly and may result in particles colliding into each
other and combining, which is undesirable with respect to
maintaining the preferred particle size distribution
within the aerosol. In order to aid in avoiding the
particle collision problem, it is preferable to include
one or more openings in the cassette, tape, or package in
close proximity to the porous membrane. Air or any other
gas is forced through these openings as the aerosol is
forced out of the porous membrane. Accordingly, an air
flow is created toward the patient and away from the
nozzle opening which carries the formed particles along
and aids in preventing their collision with each other.
The amount of gas forced from the openings will vary
depending upon the amount of aerosol being formed.
However, the amount of gas is generally five to two
hundred times the volume of the liquid formulation within
the container. Further, the flow velocity of the gas is
generally about equal to the flow velocity of the
. aerosolized particles being forced from the nozzle. The
shape of the container opening, the shape of the membrane
covering that opening, as well as the positioning and
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angling of the gas flow and particle flow can be designed
to aid in preventing particle collision. When the two
flow paths are substantially parallel, it is desirable to -
shape the opening and matching membrane so as to minimize
the distance between any edge of the opening and the
center of the opening. Accordingly, it is not desirable
to form a circular opening which would maximize the
distance between the outer edges of the circle and the
center of the circle, whereas it is desirable to form an
elongated narrow rectangle. Using such a configuration
makes it possible to better utilize the air flow relative
to all of the particles being forced from the container.
When a circular opening is used, particles which are
towards the center of the circle may not be carried along
by the air being forced from the openings and will
collide with each other. The elongated rectangle could
be formed in a circle, thereby providing an annular
opening and air could be forced outward from the outer
and inner edges of the circle formed.
Method of Administration
The method and device of the invention provides a
number of features which make it possible to achieve the
controlled and repeatable dosing procedure required for
the treatment of diseases, particularly respiratory
diseases such as asthma.
The method of the invention involves the release
of a liquid, flowable drug from individual containers
which may be interconnected in a package held in a
cassette. This is desirable in that the liquid, flowable
drug is packaged under a sterile environment and
therefore does not require and preferably does not
include additional materials such as antifungal,
bacteriostatics, and preservatives which would normally
be required in a liquid formulation if the formulation
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was to be opened, exposed to air, closed and later used
again. The present invention does not require the use of
low boiling point propellants such as low boiling point
fluorocarbons. The use of such low boiling point
propellants in conventional metered dose inhaler devices
is desirable because such propellants eliminate the need
for preservatives, antifungal and bacteriostatic
compounds. However, there are potential environmental
risks to using low boiling point fluorocarbons.
Accordingly, the present invention provides potential
environmental benefits and would be particularly useful
if government regulations prevented further use of
devices which dispensed low boiling point fluorocarbons.
In addition to environmental advantages, the
present invention offers advantages due to the relatively
slow speed at which the aerosol dispersion is delivered
to the patient. A conventional metered dose inhaler
device discharges the aerosol outward at a relatively
high rate of speed which causes a large amount of the
aerosol particles to make contact with the inside of the
patient°s mouth and the back of the patient°s throat.
This decreases the amount of drug actually administered
to the patient's lungs as compared with the present
system, wherein the aerosol is delivered at a relatively
slow rate of speed and can be inhaled slowly by the
patient.
The method preferably uses a drug delivery device
which is not directly actuated by the patient in the
sense that no button is pushed nor valve released by the
patient applying physical pressure. On the contrary, the
device of the invention provides that the actuation
mechanism which causes drug to be forced from a container
is fired automatically upon receipt of a signal from a
microprocessor programmed to send a signal based upon
data received from a monitoring device such as an airflow
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rate monitoring device. A patient using the device
withdraws air from a mouthpiece and the inspiratory rate,
and calculated inspiratory volume of the patient is
measured simultaneously one or more times in a monitoring
event which determines an optimal point in an inhalation '
cycle for the release of a dose of any desired drug.
Inspiratory flow is preferably measured and recorded in
one or more monitoring events for a given patient in
order to develop an inspiratory flow profile for the
patient. Recorded information is preferably analyzed by
the microprocessor in order to deduce a preferred point
within the patient's inspiratory cycle for the release of
drug with the preferred point being calculated based on
the most likely point to result in a reproducible
delivery event.
A flow rate monitoring device continually sends
information to the microprocessor, and when the
microprocessor determines that the optimal point in the
respiratory cycle is reached, the microprocessor actuates
a component which fires a mechanical means (and activates
the vibration device) which causes drug to be forced out
of the container and aerosolized. Accordingly, drug is
always delivered at a pre-programmed place in the
inspiratory flow profile of the particular patient which
is selected specifically to maximize reproducibility of
drug delivery and peripheral deposition of the drug. It
is pointed out that the device of the present invention
can be used to, and actually does, improve the efficiency
of drug delivery. However, this is not the most
important feature. A more important feature is the
reproducibility of the release of a tightly controlled ,
amount of drug (with a narrow range of particle size) at
a particular point in the respiratory cycle so as to .
assure the delivery of a controlled and repeatable amount
of drug to the lungs of each individual patient, i.e.
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intrapulmonary drug delivery with tightly controlled
dosing. Further, this is accomplished without the use of
fluorocarbons and/or bacteriostatic compounds.
The combination of automatic control of the drug
release mechanism, combined with frequent monitoring
events in order to calculate the optimal flow rate and
time for the release of respiratory drug, combine to
provide a repeatable means of delivering drug to the
lungs of a patient. Because the drug release mechanism
is fired automatically and not manually, it can be
predictably and repeatedly fired at that same point in
the inspiratory cycle. Because dosing events are
preferably preceded by monitoring events, the point in
the inspiratory cycle of the release can be readjusted
based on the particular condition of the patient. For
example, patients suffering from asthma have a certain
degree of pulmonary insufficiency which may well change
with the administration of drug. These changes will be
taken into account in the monitoring event by the
microprocessor which will readjust the point of release
of the respiratory drug in a manner calculated to provide
for the administration of an amount of respiratory drug
to the patient presently needed by the patient at each
dosing event.
When administering drug using the inhalation
device of the present invention, the entire dosing event
can involve the administration of anywhere from 10 ~Cg to
1,000 mg of drug formulation, but more preferably
involves the administration of approximately 50 dug to
10,000 ~Cg of drug formulation. This amount of drug is in
a liquid form or is dissolved or dispersed within a
pharmaceutically acceptable, liquid, excipient material
to provide a liquid, flowable formulation which can be
readily aerosolized. The container will include the
formulation having drug therein in an amount of about
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~,1 to 300 ~C1, more preferably about 200 ~.C1. The large
variation in the amounts which might be delivered are due
to different drug potencies and different delivery
efficiencies for different devices. The entire dosing
5 event may involve several inhalations by the patient with
each of the inhalations being provided with drug from the
device. For example, the device can be programmed so as
to release the contents of a single container or to move
from one container to the next on a package of
l0 interconnected containers. Delivering smaller amounts
from several containers can have advantages. Since only
small amounts are delivered from each container and with
each inhalation, even a complete failure to deliver drug
with a given inhalation is not of great significance and
will not seriously disturb the reproducibility of the
dosing event. Further, since relatively small amounts
are delivered with each inhalation, the patient can
safely administer a few additional micrograms of drug (or
milligrams for some drugs) without fear of overdosing.
In addition to drug potency and delivery
efficiency, drug sensitivity must be taken into
consideration. The present invention makes it possible
to vary dosing over time if sensitivity changes and/or if
user compliance and/or lung efficiency changes over time.
Based on the above, it will be understood that the
dosing or amount of drug (and in particular respiratory
drug) actually released from the device can be changed
based on the most immediately prior monitoring event
wherein the inspiratory flow of a patient's inhalation is
measured.
Variations in doses are calculated by monitoring
the effect of one or more lung function parameters in
response to known amounts of respiratory drug released
from each container and delivered to the patient. If the
response in changing measured lung function parameters is
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greater than with previous readings, then the dosage
(number of containers released) is decreased or the
minimum dosing interval is increased. If the response in
changing measured lung function parameters is less than
with previous readings, then the dosing amount is
increased or the minimum dosing interval is decreased.
The increases and decreases are gradual and are
preferably based on averages (of 10 or more readings of
lung function parameter after 10 or more dosing events)
and not a single dosing event and monitoring event. The
preferred drug delivery device of the present invention
can record dosing events and lung function parameters
over time, calculate averages and deduce preferred
changes in administration of respiratory drug.
One of the important features and advantages of
the present invention is that the microprocessor can be
programmed to take two different criteria into
consideration with respect to dosing times.
Specifically, the microprocessor can be programmed so as
to include a minimum time interval between doses i.e.
after a given delivery another dose cannot be delivered
until a given period of time has passed. Secondly, the
timing of the device can be programmed so that it is not
possible to exceed the administration of a set maximum
amount of drug within a given time. For example, the
device could be programmed to prevent dispersing more
than 200 ~Cg (or two 100 ~g containers of drug) of a
particular drug within one hour. More importantly, the
device can be programmed to take both criteria into
consideration. Thus, the device can be programmed to
include a minimum time interval between doses and a
maximum. amount of drug to be released within a given time
period. For example, the microprocessor could be
programmed to allow the release of a maximum of 200 ~cg of
a given drug during an hour which could only be released
WO 94/27653 PCTIUS94/05825
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in amounts of 25 ~.cg with each release being separated by
a minimum of five minutes.
The dosing program can be designed with some
flexibility. For example, if the patient normally
requires 250 ,ug per day of respiratory drug, the
microprocessor of the inhalation device can be programmed
to provide a warning after 250 ~g have been administered
within a given day and to continue the warning thereafter
to alert the user of possible overdoses. By providing a
warning and not a lock-out, the device allows for the
patient to administer additional respiratory drug, if
needed, due to a decreased lung function and/or account
for misdelivery of respiratory drug such as due to
coughing or sneezing during an attempted delivery.
The ability to prevent overdosing is a
characteristic of the device due to the ability of the
device to monitor the amount of respiratory drug released
and calculate the approximate amount of respiratory drug
delivered to the patient based on monitoring a variety of
lung function parameters. The ability of the present
device to prevent overdosing is not merely a monitoring
system which prevents further manual actuation of a
button. As indicated above, the device used in
connection with the present invention is not manually
actuated, but is fired in response to an electrical
signal received from a microprocessor (which received
data from a monitoring device such as a device which
monitors inspiratory flow) and allows the actuation of
the device upon achieving an optimal point in a
inspiratory cycle. When using the present invention,
each actuation of the device will administer drug to the
patient in that the device is fired in response to
patient inhalation. More specifically, the preferred
embodiment of the device does not allow for the release
of respiratory drug merely by the manual actuation of a
WO 94127653 PCT/US94/05825
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button to fire a burst of respiratory drug into the air
or a container. A variety of different embodiments of
the dispersion device of the invention are contemplated.
In accordance with one embodiment it is necessary to
carry out manual cocking of the device. This means that
energy is stored such as by retracting a spring so that,
for example, a piston can be positioned below the drug
containing container. In a similar manner a piston
connected to a spring can be withdrawn so that when it is
released it will force air through the air dispersion
vents. Automatic cocking of forced storing systems for
both the drug formulation and the air flow may be
separate or in one unit. Further, one may be manual
whereas the other may be done automatically. In
accordance with one embodiment the device is cocked
manually but fired automatically and electronically based
on monitoring the patients inspiratory flow.
The microprocessor of the present invention
preferably includes a timing device. The timing device
can be electrically connected with visual display signals
as well as audio alarm signals. Using the timing device,
the microprocessor can be programmed so as to allow for a
visual or audio signal to be sent when the patient would
be normally expected to administer respiratory drug. In
addition to indicating the time of administration
(preferably by audio signal), the device can indicate the
amount of respiratory drug which should be administered
by providing a visual display. For example, the audio
alarm could sound alerting the patient that respiratory
drug should be administered. At the same time, the
visual display could indicate "one dosage unit" as the
amount of drug (number of containers) to be administered.
At this point, a monitoring event could take place.
After completion of the monitoring event, administration
would proceed and the visual display would continually
CA 02162399 2004-10-20
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indicate the remaining amount of respiratory drug which
should be administered. After the predetermined dose
(indicated number of containers] had been administered,
the visual display would indicate that the dosing event
had ended. If the patient did not complete the dosing
event by administering the stated amount of drug, the
patient would be reminded o! such by the initiation of
another audio signal, followed by a visual display
instructing the patient to continua administration.
l0 Additional information regarding dosing with drugs
can be found within Harrison~s - Principles of Internal
Medicine (most recent edition) and the Drug Evaluation
Manual, 1993 (AMA-Division of Drugs and Toxicology), both
of which are published by McGraw Hill Book Company, New
York, disclose conventional information regarding dosing of
drugs and in particular respiratory drugs as well as'other
useful drugs and formulations.
sub~lemental Treatment Methodoloav
The present invention can be used to deliver many
types of drugs. Specifically, the disposable packages,
tapes, cassettes and drug delivery devices can be used to
deliver drugs which have a systemic effect (e. g.
narcotics, proteins such as DNAse and antibiotics) as
wall as drugs which have a local effect primarily on the
lungs (e. g, bronchodilators). Because the present
invention allows drug delivery directly to the lungs
there era certain advantages with respect to using the
invention for the delivery of drugs to treat respiratory
dissases. For this reason, much of the operation of the
invention is described in connection with the delivery of
respiratory drugs. However, the invention is not limited
to respiratory drugs and the examples described herein
would apply with respect to the delivery of drugs having
F
t
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a systemic effect. This is true also with respect to the
supplemental treatment methodology described below even
though this methodology is described with specific
reference to respiratory diseases being treated with
respiratory drugs.
Patients suffering from a given disease such as a
respiratory disease may be treated solely with
respiratory drug as indicated above, i.e. by
intrapulmonary delivery. However, it is possible to
treat such patients with a combination of intrapulmonary
delivery and other means of administration such as oral
administration. The oral drug is preferably given in
amount so as to maintain a baseline level of drug within
the circulatory system which is sufficient to maintain
body functions such as lung function at an acceptable
level. However, this baseline level of drug to blood
ratio (or serum blood level) must be raised in order to
improve the body function such as lung function during
periods of stress such as respiratory difficulty such as
an asthma attack and such can be accomplished by the
intrapulmonary administration of a drug such as a
respiratory drug using the present invention.
Based on the above, it will be understood by those
skilled in the art that a plurality of different
treatments and means of administration can be used to
treat a single patient. For example, a patient can be
simultaneously treated with respiratory drug by
transdermal administration, respiratory drug via
intrapulmonary administration in accordance with the
present invention, and drugs which are orally
administered.
The device 6 as shown in Figure 2 and
schematically shown within Figure 9 can be specifically
operated as follows. A cassette 5 as shown in Figure 2
is loaded into the device 6. The device is then armed
WO 94127653 216 2 3 9 9 pCTlUS94/05825
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meaning that the piston such as the spring-loaded piston
24 shown in Figure 9 is cocked. Further, if applicable,
a piston used to force air from the air vents is cocked
and, if necessary, a piston used to compress the liquid
formulation in the dual container system is cocked. '
Further, a container of the package is moved into
position and the cover 4 is stripped off of the porous
membrane. Thereafter, the patient withdraws air from the
mouthpiece 9 shown in Figure 2 and the patient's
inhalation profile is developed using the microprocessor.
After the inhalation profile is determined, the
microprocessor calculates a point within the inhalation
profile at which the drug should be released in order to
maximize repeatability of the dosing, e.g. by plotting a
curve of breath velocity versus time and determining the
point on the curve most likely to provide repeatability
of dosing. Thereafter, the vibrator is actuated and air
is forced through the air vents. 6~Thile vibration is
occurring and air is being released, the device is fired
and the formulation contained within the containers is
forced through the porous membrane creating an aerosol
which is carried into the patient s lungs. The air
velocity measuring components continue to read the
velocity of the air being withdrawn from the device by
the patient while the drug is being delivered.
Accordingly, the adequacy of this patient's particular
drug delivery maneuver can be determined. All of the
events are recorded by the microprocessor. The recorded
information can be provided to the caregiver for
analysis. For example, the caregiver can determine if
the patient correctly carried out the inhalation maneuver
in order to correctly delivery drug and can determine if
the patient s inhalation profile is effected by the drug
(e.g. with respiratory drugs) in order to determine the
effectiveness of the drug in treating the patient s
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2162399
- 75 -
particular condition. If necessary, various adjustments
can be made such as in the type of drug or the particle
size to obtain a particular desired result.
The instant invention is shown herein in what is
considered to be the most practical and preferred
embodiments. It is recognized, however, that departures
may be made therefrom which are within the scope of the
invention and that obvious modifications will occur to
one skilled in the art upon reading this disclosure.
