U.S. patent application number 09/795025 was filed with the patent office on 2001-08-02 for formulation and devices for monitoring the efficacy of the delivery of aerosols.
Invention is credited to Gonda, Igor.
Application Number | 20010010223 09/795025 |
Document ID | / |
Family ID | 26684093 |
Filed Date | 2001-08-02 |
United States Patent
Application |
20010010223 |
Kind Code |
A1 |
Gonda, Igor |
August 2, 2001 |
Formulation and devices for monitoring the efficacy of the delivery
of aerosols
Abstract
Aerosolizable formulations are disclosed comprised of a
pharmaceutically acceptable carrier, a pharmaceutically active drug
or detectably labeled compound and a compound which is recognized
by its distinct color, taste and/or smell even when present in a
small amount and a low concentration. Examples of such compounds
include menthol, peppermint, cinnamon and vanilla flavors and water
soluble dyes. The compounds can be designed so that they are only
detectable by a specific area of the tongue or seen under a certain
wavelength of light. The degree of detection of the color, taste or
smell of the compound is an indication of the degree of success in
the delivery of an aerosolized formulation to a patient. The
formulation is preferably delivered from a device which monitors
and records information relating to the patient's respiratory
movement and also scans and analyzes the aerosol prior to
inhalation. The device sends the user a visual and/or audible
signal which informs the user about the character of the aerosol
formed. By means of the taste and smell as well as the signal
obtained from the device the user is provided with multiple
indications of the efficacy of the aerosolized dose delivered.
Inventors: |
Gonda, Igor; (San Francisco,
CA) |
Correspondence
Address: |
Karl Bozicevic
BOZICEVIC, FIELD & FRANCIS LLP
200 Middlefield Road, Suite 200
Menlo Park
CA
94025
US
|
Family ID: |
26684093 |
Appl. No.: |
09/795025 |
Filed: |
February 26, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09795025 |
Feb 26, 2001 |
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09012857 |
Jan 22, 1998 |
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6192882 |
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Current U.S.
Class: |
128/200.14 ;
128/200.22 |
Current CPC
Class: |
A61M 2205/6081 20130101;
A61M 15/003 20140204; A61M 15/0043 20140204; A61M 15/00
20130101 |
Class at
Publication: |
128/200.14 ;
128/200.22 |
International
Class: |
A61M 011/00 |
Claims
What is claimed is:
1. An aerosol formulation; comprising: a pharmaceutically
acceptable carrier; an active compound selected from the group
consisting of a pharmaceutically active drug and a detectably
labeled compound; and a sensory compound with a characteristic
selected from the group consisting of a distinctive color, a
distinctive taste and a distinctive smell.
2. The aerosol formulation of claim 1, wherein the sensory compound
has a distinctive taste.
3. The aerosol formulation of claim 1, wherein the sensory compound
is selected from the group consisting of menthol, peppermint,
cinnamon and vanilla.
4. The formulation of claim 1, wherein the active compound is a
pharmaceutically active drug and the carrier is water.
5. The formulation of claim 1, wherein the sensory compound has a
distinctive color.
6. The formulation of claim 1, wherein the active compound is a
pharmaceutically active compound and the sensory compound has a
distinctive taste and color.
7. The formulation of claim 6, wherein the taste is distinctly
sweet, sour, bitter or salty and the color contrasts with the color
of the inside of a human mouth.
8. An aerosolized mist of particles wherein 25% or more of the
particles have a diameter in the range of from about 0.5 micron to
about 10 microns, the particles comprising: a pharmaceutically
acceptable carrier; an active compound selected from the group
consisting of pharmaceutically active drug and a detectably labeled
compound; and a sensory compound with a characteristic selected
from the group consisting of a distinctive color, a distinctive
taste and a distinctive smell.
9. The aerosolized mist of claim 8, wherein 25% or more of the
particles have a diameter in the range of about 1 to about 3
microns.
10. The aerosol formulation of claim 8, wherein the sensory
compound has a distinctive taste.
11. The aerosol formulation of claim 8, wherein the sensory
compound is selected from the group consisting of menthol,
peppermint, cinnamon and vanilla.
12. The aerosol formulation of claim 8, wherein the sensory
compound has a distinctive color.
13. The aerosol formulation of claim 12, wherein the color is from
a water soluble dye which dye has a color selected from the group
consisting of blue, green and purple.
14. A method of monitoring aerosol delivery efficacy, comprising:
creating an aerosolized mist of particles 25% or more of which
having a diameter in the range of from about 1 micron to about 8
microns, the particles comprising: a pharmaceutically acceptable
carrier, an active compound selected from the group consisting of
pharmaceutically active drug and a radioactive labeled compound,
and a sensory compound with a characteristic selected from the
group consisting of a distinctive color, a distinctive taste and a
distinctive smell; inhaling the aerosolized mist through the mouth
and into the lungs; and analyzing delivery efficacy to the lungs
based on detected color, taste or smell.
15. The method of claim 14, further comprising: scanning the
aerosolized mist with light; analyzing the aerosolized mist based
on the scan; and providing a user with results of the analysis.
16. A method of monitoring aerosol delivery efficacy, comprising:
creating an aerosolized mist of particles having a diameter in the
range of 1 micron to 8 microns wherein the particles comprise a
pharmaceutically active drug; scanning the mist with a light source
of a detector; determining a percentage of particles within a given
size range parameter; and signaling; a user when the determined
percentage of particles fall outside of the given size range.
17. The method of claim 16, wherein the given size range is 0.5 to
6.0 microns in diameter.
18. The method of claim 16, wherein the particle are further
comprised of a sensory compound.
19. The method of claim 18, wherein the sensory compound has a
distinctive taste and a distinctive color.
20. The method of claim 16, wherein the particles are further
comprised of a radioactive label.
Description
FIELD OF THE INVENTION
[0001] The invention relates to the field of aerosol formulations,
packaging for dispersing such and devices for the delivery of
aerosols. More specifically, the invention relates to formulations
containing additives with distinct tastes, colors, smells and/or
emmitors of gamma radiation and aerosol devices with sensors
designed to monitor the formation and delivery of such
aerosols.
BACKGROUND OF THE INVENTION
[0002] Aerosolizing formulations for inhalation has been considered
as a convenient alternative to injection for decades. This
alternative to injections is particularly interesting for drugs
which cannot be delivered orally, e.g. insulin. Although most
compounds will effectively move from the lungs into the circulatory
system there is considerable unpredictability in how much
aerosolized formulation reaches the areas of the lungs where the
material can move into the circulatory system. This results in
inefficiency and unpredictability of dosing. A number of devices
have been proposed for improving the efficiency of aerosol
delivery, monitoring patients and teaching patients to correctly
use delivery devices. The present invention makes it easy for the
user to directly monitor aspects of aerosol delivery in a manner
which improves repeatability of dosing.
SUMMARY OF THE INVENTION
[0003] Aerosolizable formulations are disclosed comprising a
pharmaceutically acceptable carrier, a pharmaceutically active drug
or detectably labeled compound and a sensory compound which is
recognized by its distinct taste, color and/or smell even when
present in a small amount and a low concentration. Examples of such
sensory compounds include menthol, peppermint, cinnamon and vanilla
flavors as well as dyes which have colors which contrast with the
color of the inner mouth and throat. The compounds can be designed
so that they are detectable by a specific area of the tongue, i.e.,
the specific area which preferentially detects sweet, salty, sour
or bitter flavors. The degree of detection of the taste or smell of
the compound and the perceived taste or smell is an indication of
the degree of success in the delivery of an aerosolized formulation
to a patient, with little or no taste detection indicating delivery
predominately to the lung. When a color component is included such
as a dark blue or purple dye the lack of any such coloring inside
the mouth or throat after delivery is an indication of a successful
delivery. The formulation is preferably delivered from a device
which monitors and records information relating to the patient's
respiratory movement and also scans and analyzes the aerosol prior
to inhalation. The device sends the user a visual and/or audible
signal which informs the user about the character of the aerosol
formed. By means of the color, taste and smell sensed as well as
the signal obtained from the device the user is provided with
multiple indications of the efficacy of the aerosolized dose
delivered. These indications assist the user in improving delivery
techniques, and in analyzing the effectiveness of a given delivery
procedure after it has been performed thereby improving
repeatability of dosing. The sensory compounds may be used
together, separately or in any combination and may be used with or
without a device which monitors one or more respiratory
parameters.
[0004] An object of the invention is to provide an aerosol
formulation which comprises a sensory compound having a color,
taste and/or smell which provides the user with an indication of
the efficacy of aerosol delivery.
[0005] Another object is to provide formulations which comprise
compounds which emit radiation which is detectable by counters or
cameras which detect the particular radiation emitted e.g. gamma
emissions.
[0006] Another object is to provide a device for aerosolizing
formulations which monitors the physical characteristics of
aerosols created (e.g. particle size) and provides the user with an
audio and/or visual signal which indicates the character of the
aerosol.
[0007] Another object is to provide a formulation with a taste
which is particularly noted on contact with a particular area of
the tongue thereby allowing a user to determine how a particular
aerosolized burst was misdirected.
[0008] Another object is to provide a system of delivery of
aerosols which causes the patient to become accustomed to certain
sensory perceptions during a normal delivery event, such that an
abnormal delivery will be perceived by the patient as
different.
[0009] An advantage of the invention is that it provides a device
with a formulation which uses the electronic sensory components
available in the device along with the users own senses to monitor
the delivery of aerosolized doses.
[0010] A feature of a formulation of the invention is that it has a
distinct detectable color, taste and/or smell.
[0011] Another feature of the invention is that an optical scanner
is used to characterize aerosols formed.
[0012] An advantage of the invention is that the user is quickly
and conveniently provided with information indicative of the
efficacy of delivery of an aerosolized dose.
[0013] These and other objects, advantages and features of the
present invention will become apparent to those skilled in the art
upon reading this disclosure in combination with drawings wherein
like numerals refer to like components throughout.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a schematic, cross-sectional view of an embodiment
of a sample container;
[0015] FIG. 2 is a schematic cross-sectional view of another
embodiment of a sample container;
[0016] FIG. 3 is a schematic view of a delivery device which
includes a particle detection device;
[0017] FIG. 4 is a perspective view of the sample container;
and
[0018] FIG. 5 is a perspective view of a plurality of sample
containers linked together.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0019] Before the present formulation, device and method of
detecting particles is described, it is to be understood that this
invention is not limited to the particular methodology, devices,
containers and formulations described, as such methods, devices,
containers and formulations may, of course, vary. It is also to be
understood that the terminology used herein is for the purpose of
describing particular embodiments only, and is not intended to
limit the scope of the present invention which will be limited only
by the appended claims.
[0020] It must be noted that as used herein and in the appended
claims, the singular forms "a," "an, " and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a sensory compound" includes mixtures of
different sensory compounds, reference to "an assay" includes one
or more assays, and reference to "the method of detection" includes
reference to equivalent steps and methods known to those skilled in
the art, and so forth.
[0021] 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.
[0022] The publications discussed herein are provided solely for
their stated disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the invention is not entitled to antedate such publications by
virtue of prior invention. Further, the actual date of publication
may be different from that stated on the publication and as such
may require independent verification of the actual publication
dates.
Definitions
[0023] The term "sensory compound" is used here to encompass any
compound or group of compounds which provide any or all of a
distinct color, taste or smell to the human eye, tongue or nose.
The sensory compound relating to taste preferably has a distinct
taste which is readily detected by the human tongue and preferable
by taste buds on a particular area of the tongue thereby providing
a distinct sour, sweet, salty or bitter taste even when present in
a small amount and/or in a low concentration. A sensory color
compound preferably has a color which distinctly contrasts with the
color of the inside of the mouth and tongue. The color, taste
and/or smell of the sensory is preferably sufficiently different
from the color, taste or smell of the carrier or active compound
present that human eyes, taste buds and olfactory senses can
readily determine the difference between them. The sensory compound
may be different from the carrier or active compound by having a
distinctly stronger taste, smell or color, e.g., have the same
basic taste, color or smell but have such in a form which is 5 to
10 more time concentrated as compared to the drug and or carrier of
the formulation.
[0024] The term "formulation" is used to describe any mixture,
solution, suspension or the like comprising a sensory compound. The
formulation is preferably further comprised of an active ingredient
and a carrier and more preferably is a liquid that has physical
properties such that when the formulation is moved through a porous
membrane the formulation is aerosolized into particles which are
inhaled into the lungs of a patient and preferably reach the
circulatory system. The active ingredient may be any
pharmaceutically active drug or detectably labeled compound. The
carrier may be any pharmaceutically acceptable material and is
preferably a flowable liquid which is compatible with the sensory
compound and the active agent. Formulations are preferably
solutions, e.g., aqueous solutions, ethanolic solutions,
aqueous/ethanolic solutions, saline solutions, colloidal
suspensions and microcrystalline suspensions. Formulations can be
solutions or suspensions of sensory compounds and/or drugs in the
above mentioned liquids or in the case of a metered dose inhaler a
low boiling point propellant--see U.S. Pat. Nos. 5,404,871; and
5,608,647. Other formulations can be in the form of dry powders of
sensory compounds with or without drugs and carriers see U.S. Pat.
No. 5,458,135.
[0025] The term "carrier" shall mean a pharmaceutically acceptable
excipient material which a sensory compound, an active ingredient
such as a drug, a diagnostic agent or a gene vector is mixed with,
suspended or dissolved in. The carrier is preferably a flowable
liquid. Useful carriers do not adversely interact with the sensory
compound, drug, diagnostic or gene therapy and have properties
which allow for the formation of aerosolized particles preferably
particles having a diameter in the range of 1.0 to 8.0 microns when
a formulation comprising the sensory compound, carrier and active
ingredient is forced through pores having a diameter of 0.5 to 4.0
microns. Carriers include water, ethanol, saline solutions and
mixtures thereof with pure water being preferred. Other carriers
can be used provided that they can be formulated to create a
suitable aerosol and do not adversely effect the particular sensory
compound, active component or human lung tissue. Dry powder
carriers can aid in separation of the particles.
[0026] The term "active compound" means a compound which is either
a pharmaceutically active drug, or a detectably labeled compound.
In turn, a "pharmaceutically active drug" shall be interpreted to
mean any pharmaceutically effective compound used in the treatment
of disease. A "detectably labeled compound" includes compounds
which are radioactively labeled see U.S. Pat. application Ser. No.
08/789,551 Re: detectable labels.
[0027] The terms "electronic particle sensing device" and
"electronic detection system" refer to a device or other means for
measuring and counting particles present in an aerosol mist.
[0028] The term "reporting means" is used herein to indicate a
means by which information obtained from a monitoring device such
as an electronic particle sensing device or a device which monitors
and records information relating to the patient's respiratory
movement, may be provided to the user.
[0029] The terms "aerosol", "aerosol bolus", and the like, are used
interchangeably herein to describe a volume of air greater than 50
ml and less than 4 liters which has suspended within it particles
of a formulation wherein the particles have a diameter in the range
of 0.5 to 8.0 microns, preferably 1 to 3 microns, and preferably
the total volume of formulation is from 5 .mu.l to 10,000 .mu.l.
About 10 .mu.l of particles having a diameter of about 1 to 3
microns are present in a volume of about 50 ml to 2 liters,
preferably 100 ml to 1,000 ml.
[0030] In referring to particle diameter, the diameter measurement
given is the "aerodynamic diameter" measurement which is the
diameter of a sphere of unit density that has the same terminal
sedimentation velocity in air under normal atmospheric conditions
as the particle in question. This is pointed out in that it is
difficult to accurately measure the diameter of small particles
using current technology and the shape may be continually changing.
Thus, the diameter of one particle of material of a given density
will be said to have the same diameter as another particle of the
same material if the two particles have the same terminal
sedimentation velocity in air under the same conditions.
[0031] The terms "air", "particle free air", "aerosol free air,"
and the like, are used interchangeably herein to describe a volume
of air which is substantially free of other material and, in
particular, free of particles intentionally added such as particles
of formulation. The term means that the air does not include
particles of formulation which have been intentionally added but is
not intended to imply that the normal surrounding air has been
filtered or treated to remove all particles although filtering can
take place.
[0032] The term "measuring" describes an event whereby the (1)
total lung capacity, (2) inspiratory flow rate or (3) inspiratory
volume of the patient is measured and/or calculated and the
information used in order to determine an optimal point in the
inspiratory cycle at which to release an aerosol and/or a particle
free volume of air. An actual measurement of both rate and volume
may be made or the rate can be directly measured and the volume
calculated based on the measured rate. The total lung capacity can
be measured or calculated based on the patient's height, sex and
age. It is also preferable to continue measuring inspiratory flow
during and after aerosol delivery and to record inspiratory flow
rate and volume before, during and after the release of
formulation. Such reading makes it possible to determine if
formulation was properly delivered to the patient.
[0033] The term "monitoring" event shall comprise detecting taste
and/or smell and determining the character of an aerosol such as
the size, number and speed of the particles in the aerosol,
further, monitoring may comprise measuring lung functions such as
inspiratory flow, inspiratory flow rate, and/or inspiratory volume
so that a patient's lung function as defined herein, can be
evaluated during before and/or after delivery thereby making it
possible to evaluate the effect of formulation such as respiratory
drug delivery on the patient's lung function.
[0034] The term "inspiratory flow rate" shall mean a value of air
flow rate determined, calculated or measured based on the speed of
the air passing a given point in a measuring device assuming
atmospheric pressure .+-.5% and a temperature in the range of about
10.degree. C. to 40.degree. C.
[0035] 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 that has passed that
point with the volume calculation being based on integration of the
flow rate data and assuming atmospheric pressure, .+-.5% and
temperature in the range of about 10.degree. C. to about 40.degree.
C.
[0036] The term "inspiratory volume" shall mean a determined,
measured or calculated volume of air passing a given point into the
lungs of a patient assuming atmospheric pressure .+-.5% and a
temperature in the range of 10.degree. C. to 40.degree. C.
[0037] 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, i.e., total lung capacity. Methods of quantitatively
determining pulmonary function are used to measure lung function.
Quantitative determination of pulmonary function may be important
when delivering any formulation and in particular respiratory drugs
in order to direct the aerosol to a specific area of the lung and
to determine effectiveness. 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
(FEV.sub.1), 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 FEV.sub.1 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 formulation in a delivery event and monitoring lung
function in a monitoring event. A series of such events may be
carried out and repeated over time to determine if lung (see U.S.
Pat. No. 5,404,871) function is improved.
[0038] 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. FEV.sub.1
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.
[0039] The terms "particles", "aerosolized particles" and
"aerosolized particles of formulation" shall mean particles of
formulation comprised of any sensory compound and preferably an
active ingredient and a carrier, (e.g., a pharmaceutically active
respiratory drug and carrier). Particles of a liquid formulation
are formed upon forcing the formulation through a nozzle which
nozzle is preferably in the form of a flexible porous membrane. The
particles have a size which is sufficiently small such that when
the particles are formed they remain suspended in the air for a
sufficient amount of time such that the patient can inhale the
particles into the patient's lungs. Preferably, the particles have
a size in the range of 0.5 micron to about 8 microns, preferably 1
to 3 microns having been created by being forced through the pores
of a flexible porous membrane which pores have a diameter in the
range of about 0.25 micron to about 6.0 microns (note that a pore
with a diameter of 4.0 microns will produce a particle with a
diameter of about 8.0 microns which particle can be reduced to any
size (e.g., 3.0 or less) via evaporation--the pores being present
on the membrane in a density of about ten to 10,000 pores over an
area in size of from about 1 sq. millimeter to about 1 sq.
centimeter. As indicated above, particle diameter is an aerodynamic
diameter.
General Overview
[0040] A formulation of the invention comprises a sensory compound
and preferably a pharmaceutically acceptable carrier having an
active compound dispersed or dissolved therein. The active compound
is a pharmaceutically active drug or a radioactive labeled
compound. The sensory compound exhibits one or more distinctive
tastes and/or smells which are preferably different from and
stronger than that of the carrier, active drug, or labeled
compound.
[0041] When properly administered, an aerosolized burst of
formulation only contacts certain surfaces in the respiratory
tract. However, if the aerosol is misdirected, e.g., at the tongue,
the formulation (or a portion thereof) does not reach the lungs.
The user may not know that the formulation was not delivered
properly and thereby remain inadequately treated.
[0042] Formulations of the invention are detected by the user due
to a sensory compound which preferably has a distinct taste or
tastes and more preferably has a distinct taste or tastes which are
sensed by a particular area of the tongue. A human tongue detects
different types of tastes, i.e. sweet, bitter, sour, on different
areas of the tongue. Thus, if an aerosolized burst is misdirected
against the tongue the user will be able to detect the mistake via
taste. The user may then correct the error by re-directing the
spray (or moving the tongue) and re-administer the aerosolized
dose.
[0043] In addition to under dosing by misdirecting an aerosolized
burst an error may take place due to a malfunction of the device.
The malfunction could result in (1) no aerosol being released, (2)
inadequate aerosol being released, or (3) aerosol being released
with particles having a size distribution which is incorrect for
the type of pulmonary drug delivery desired. Complete failure to
deliver aerosol may be detected in a number of ways. One way is to
include a sensory compound in the formulation which has a distinct
smell. If the user does not detect the smell after activating the
device then the user can assume no aerosol was released. The user
can then check the electronic reporting system of the device to see
if aerosol was actually released. The reporting system of the
device preferably also detects if and how many particles were
released but whether the particles formed were of the correct
size.
Color, Taste and Smell as a Means of Monitoring Aerosol
Delivery
[0044] Humans are able to perceive and recognize many different
tastes, all of which can be classified into four primary types:
sweet, salty, sour and bitter. Taste is mediated by sensory
receptors,; known as taste buds, which are located in groups on
epithelial structures known as papillae. Most taste buds are on the
tongue, however, some are also present on the palate, pharynx,
larynx, and upper esophagus. The amount of taste buds and their
sensitivity varies somewhat between individuals. Thus, each user of
the present invention may require some learning or adjustment
period to fully utilize the invention.
[0045] In one method of the invention the patient first delivers
doses in a controlled environment to learn how to correctly use the
device and comes to know the type and intensity of taste that is
sensed for a correct delivery. Once a pattern is established the
patient can notice the difference for an incorrect delivery.
[0046] While individual taste buds are not entirely specific for a
particular primary taste, each responds optimally to one kind and
less well to the others. The various types of taste buds are
distributed on the tongue's surface such that different regions are
more highly sensitive to one particular taste then to the others.
Thus, the tip of the tongue is especially sensitive to sweet, the
sides proximate to the tip to salty, the posterior edges to sour,
and the posterior surface to bitter.
[0047] By including a sensory compound that has a distinctive taste
in the aerosol formulation, the user is provided with a means for
indicating the degree of success in delivery of that formulation,
with little or no taste sensation indicating delivery predominantly
to the lungs. Further, the inclusion of a sensory compound which is
sensed by a particular area of the tongue allows a user to
determine whether and how a particular aerosolized burst was
misdirected, (or how the tongue was improperly positioned) and
thereby permits the user to redirect the aerosol flow (or
reposition the tongue) and re-administer an additional dose.
[0048] Similarly, the human olfactory system is capable of
recognizing a myriad of different odors. Although difficult to
classify, there are at least seven primary ones: camphoraceous,
musk, floral, peppermint, ethereal, pungent and putrid.
[0049] Olfactory receptor cells are themselves primary afferent
neurons. Each olfactory receptor cell has an apical process with
cilia that extends into a layer of mucus located at the olfactory
mucosa, a specialized area present in each nasal mucosa. When
chemical substances capable of eliciting an olfactory response are
inhaled, they become dissolved in the mucus layer and bind to
receptor molecules on the cells' cilia. Binding stimulates the
receptor cell and causes a signal to be carried along that cell's
axon to the brain, where it is processed and ultimately perceived
as a particular scent.
[0050] By including a sensory compound that has a distinctive smell
in the aerosol formulation, the user is provided with a means for
indicating whether the device has malfunctioned and failed to
deliver aerosol. If no smell is detected after activating the
device, then the user can assume that the device has malfunctioned
and has failed to release any aerosol. The user can then check the
electronic reporting system of the device to see if aerosol was
actually released, and additionally, to see whether the particles
formed were of the correct size.
[0051] Color can be used alone or in combination with compounds
having a distinct taste or smell. The color can be any color but is
preferably a color easily recognized by human eyes and preferably
sharply distinct from the color of the tongue and the inside of the
mouth. The color is preferably a water soluble dye such as deep
blue or purple such as conventional food coloring The color
component may inherently include a distinct taste and/or smell,
just as a taste component may be designed to have a distinct color
or smell.
Aerosol Formulation
[0052] The aerosol formulations of the present invention are
comprised of a pharmaceutically acceptable carrier, an active
compound selected from the group consisting of pharmaceutically
active drug and a detectably labeled compound, and one or more
sensory compounds having any or all of a distinct color, taste and
smell.
[0053] With respect to sensory compounds having a distinctive
taste, a wide variety of compounds are suitable. Generally, such
compounds, are those with a distinct, sweet, sour, bitter or salty
taste or those with a floral or peppermint smell. Examples include
saline, sucrose, and citrus solutions for taste and peppermint
flavor for smell and taste.
[0054] With respect to sensory compounds having a distinctive
smell, there is also a wide variety of compounds which might be
employed. Generally, compounds suitable for use in the present
invention are those with a pleasant smell. Examples include floral
perfumes, menthol, peppermint, cinnamon, and vanilla. Especially
preferred are the compounds menthol, peppermint, cinnamon and
vanilla.
[0055] With respect of a compound with a distinct color any color
agent can be used but those that are water soluble are preferred.
Bright blues, greens and purples as well as black provide a stark
contrast with the color of the mouth and as such are preferred. It
is also possible to use coloring agents which are fluorescent
including agents which fluoresce when exposed to certain
wavelengths of light.
[0056] With respect to active compounds it is possible to deliver a
wide range of compounds using the present invention. For example,
drugs included within the container could be anti-inflammatory
drugs, insulin, analgesics, bronchodilators, antibiotics, enzymes,
steroids or anticholinergics.
[0057] The active compound can also be variety of detectably
labeled compounds, including those that are radioactively labeled,
such as are described in U.S. application Ser. No. 08/597,084 filed
Feb. 5, 1996.
[0058] Active compounds may be stored in and/or released from a
container of any desired size. In most cases the size of the
container is not directly related to the amount of active compound
being delivered in that most formulations include relatively large
amounts of carrier. Accordingly, a given size container could
include a wide range of different doses by varying the
concentration of the active compound.
[0059] Carriers: A wide variety of pharmaceutically acceptable
carriers are known which are suitable for use in the formulation of
the present invention. Such carriers include alcohol, (e.g.,
ethanol with or without water) water or a saline solution. Pure
water is preferred. If the formulation is a dry powder a carrier
may or may not be used. If the formulation is for use in the
metered dose inhaler (MDI) device the carrier will be a low boiling
point propellant.
[0060] Viscosity of formulation: The drug formulation may be a low
viscosity liquid formulation. Generally, the viscosity of the drug
by itself or in combination with a carrier is not of particular
importance except to note that the formulation must have
characteristics such that the formulation can be aerosolized to
form aerosol mist, the aerosols having a particle size in the range
of about 0.5 to 12 microns, preferably 1-4 microns.
Formulation Containers
[0061] FIG. 1 is a cross-sectional view of a formulation container
1 which is shaped by a collapsible wall 2. The container 1 has an
opening covered by a flexible porous membrane 3 which is covered by
a removable layer 4. The layer 4 may be labeled "sweet", "sour",
"peppermint", "blue", "green", etc. to identify the sensory
compound. The membrane 3 may be rigid and protrude upward in a
convex configuration away from the formulation 5. When the layer 4
is removed the wall 2 can be collapsed thereby forcing the
formulation 5 against the flexible porous membrane 3 which will
then protrude outward in a convex shape. In an alternate
collapsible configuration not shown the bottom wall could be made
to slide like a piston and fit tight against cylindrical walls
thereby forcing the contents out. Although a container is generally
empty after one aerosol burst is created the container can be
designed so that multiple (e.g., 2-10) bursts can be extruded.
However, the burst must be extruded over a short period e.g., less
than one hour to avoid contamination or clogging problems. After
use the container is discarded, see U.S. Pat. No. 5,544,646 issued
Aug. 13, 1996.
[0062] FIG. 2 is a cross-sectional view of a more preferred
embodiment of a formulation container 1. The container is shaped by
a collapsible wall 2. The container 1 includes an opening which
leads to an open channel 6 which channel 6 includes an abutment 7
which is opened upon the application of force created by
formulation 5 being forced from the container. When the abutment 7
is opened the formulation 5 flows to an area adjacent to the
flexible porous membrane 3 and is prevented from flowing further in
the channel 6 by a non-breakable abutment 8.
[0063] FIG. 4 is a perspective view of a preferred embodiment of
the container depicted in FIGS. 1 and 2.
[0064] The disposable package 46 is shown in FIG. 5. The package is
comprised of a plurality of disposable containers 1, shown in
detail in FIGS. 1,2 and 4. Each container 1 includes a formulation
5 and is covered by the porous membrane 3. Formulations comprising
the sensory compound may be stored in and/or released from a
container of any desired size. A number of containers may be
connected together to form a package 46 as shown in FIG. 5. The
package 46 is in the form of an elongated tape but can be in any
configuration, e.g., circular, square, rectangular, etc.
[0065] Formulation containers 1 or packages 46 may include indices
providing information such as the contents of the formulation
(e.g., the taste or smell of the sensory compound) or other
pertinent information. Thus, information as to the particular type
and concentration of sensory compound, drug or detectably labeled
compound present in the formulation may be indicated on the
formulation container. Such indices may be in the form of visually
perceivable symbols such as numbers or letters; alternatively, they
may be in the form of electronically, magnetically or optically
recorded information perceivable by electronic means, which means
may be separate or may be part of the delivery device. The indices
are preferably in the form of a resistor with a set resistance
value specifically set to correspond to a specific formulation with
a given sensory compound, drug, and carrier.
Delivery Device
[0066] It is important to note that a variety of devices can be
used in order to carry out the methodology of the present
invention. However, the device must be capable of aerosolizing
formulation in a container, and preferably includes both a means of
detecting the presence and size of the aerosol particles being
released, and a means for monitoring and recording information
relating to the patient's respiratory movement. An example of such
a device is disclosed in U.S. Pat. No. 5,522,385 and U.S. patent
application Ser. Nos. 08/534,786 filed Sep. 27, 1995, and
08/804,041 filed Feb. 24, 1997.
[0067] A plan view of such a drug delivery device is shown in FIG.
3. The device 40 is loaded and operates with a package 46 of
multiple formulation containers.
[0068] The device 40 pictured in FIG. 3 is a hand-held, portable
delivery deice which is comprised of (a) a device for holding a
disposable package 46 with at least one but preferably a number of
containers 1, and (b) a mechanical mechanism for forcing the
contents of a container (on the package) through a porous membrane.
Preferably, the device further comprises (c) an electronic particle
sensing device 52 for sensing both the presence and size of aerosol
particles, (d) a means 50 for monitoring and recording information
relating to the patient's respiratory movement, and (e) reporting
means 51 for providing the user with the information obtained via
components (c) and (d).
[0069] Electronic Detection System: The electronic detection system
52 can include an energy or light source 53 and a receiver 54 which
detects energy 55 sent from the source 53 and detects interruption
of that energy when deflected, as by a particle in the mouth piece
tube 30.
[0070] Systems and devices which measure, count and analyze
particles in a fluid are known. Such devices are employed, for
example, by semiconductor wafer manufacturers to monitor the extent
of airborne particulate matter in a clean room. Pharmaceutical
manufacturers employ such devices for the detection and control of
foreign particles. To a lesser extent of accuracy, smoke detectors
also measure particle concentration. Such devices and variations
thereof can be used in connection with the present invention to
determine (1) if an aerosol of any sort is created at the desired
point; and (2) the character of the aerosol in terms such as the
number and size of the particles present per unit volume.
[0071] One method of particle detection is the light blockage
particle counting, or light obscuration, method. Light obscuration
sensors work on the principle of the casting of a shadow onto a
photo detector as a flow of particle-laden fluid is directed
through a light beam generated by an incandescent lamp.
[0072] A more sensitive method is the light scattering method. As a
particle passes through a light beam, the particle scatters light.
The amount of scattered light is a function of the particle size,
the wavelength and intensity of the incident light, and the
difference between the light scattering properties of the particle
and the surrounding medium. A laser source may be used to generate
the light beam and the scattered light is sensed by a detector
which provides readable signals indicative of particle size.
[0073] The device is preferably calibrated against a standard which
makes it possible for the device to determine if the reading is
within a satisfactory range for the results being sought. If
readings outside a given range are obtained the device signals the
user of such--indicating an incorrect drug delivery event. The flow
measurement sensor can detect the velocity of the particles in
addition to their size and particle density. All of the parameters
can be measured against a standard and the user can be advised if a
reading is below or above a standard preferred range.
[0074] It is an object of the present invention to provide an
apparatus for detecting particles (their, speed, size velocity
etc.) which is simple, inexpensive and small in size so that it can
be used in a hand-held inhalation device. The devices as described
herein could be equipped with different types of particle detection
and measuring devices such as devices for particle detection
disclosed in U.S. Pat. No. 5,011,286, issued Apr. 30, 1991 to
Petralli (incorporated herein by reference).
[0075] Such devices and method generally require (A) a light
source, (B) a photo detector, (C) a means for interpreting the
photo detector signals and (D) the presence of particles which
absorb or deflect light.
[0076] Device for holding disposable package: The device for
holding the disposable package may be nothing more than a narrow
opening created between two outwardly extending bars 42 and 82 or
may include additional components for moving new packages into
position such as one or more wheels, sprockets or rollers notably
mounted on the end(s) of such bars. The rollers may be spring
mounted so as to provide constant pressure against the surface(s)
of the package. The device may also include a transport mechanism
which may include providing drive power to the roller(s) so that
when they are rotated, they move the package from one container to
the next. After the formulation in a container is aerosolized the
container is discarded and a new full container brought into the
aerosol release position. The power source 43 driving the roller(s)
is programmed via the microprocessor 26 to rotate the rollers only
enough to move the package 39 from one container 1 to the next. The
power source 43 is preferably in the form of standard compact
batteries including rechargeable batteries and alkaline
batteries.
Method of Use
[0077] The formulation preferably includes a sensory compound
having a distinctive color and taste, so as to enable the user to
determine whether the aerosol has been properly generated and
directed to the desired area of the respiratory tract. If the user
detects the colored and flavored compound after administering an
initial dose, he or she may redirect the spray away from the area
of the tongue where the taste was detected, or area where color was
seen, such that the subsequent dose is properly directed.
Additionally or alternatively the light sensor of the device can
produce a signal indicating if the aerosol was formed in the
desired manner e.g. desired particle size and/or number of particle
per cubic unit of space. These indications, which may be combined
with smell, taste and color provide the user with information
useful to obtain repeatable dosing. It is particularly advantageous
to use the present invention when delivering drugs which have a
narrow therapeutic window. For example, the invention can be used
with the aerosolized delivery of insulin (see U.S. Pat. No.
5,672,581 and U.S. application Ser. No. 08/792,616 filed Jan. 31,
1997) and narcotics (see U.S. Pat. No. 5,507,277). The insulin may
be a monomeric insulin e.g. insulin lispro.
[0078] The instant invention is shown and described herein in which
is considered to be the most practical and preferred embodiments.
It is recognized, however, that the 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.
* * * * *