Note: Descriptions are shown in the official language in which they were submitted.
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Title: BREATH ACTIVATED NICOTINE INHALERS
FIELD OF THE INVENTION
The present invention relates to a breath activated inhaler
for dispensing a medicament into the lung. The invention also relates to a
breath activated inhaler for dispensing nicotine into the lung and a method
of assisting withdrawal from tobacco induced nicotine dependency by the
inhalation of nicotine from a breath activated inhaler. The invention
further relates to the use of nicotine inhalers as tobacco substitutes (e.g.
cigarette, cigar, pipe).
BACKGROUND OF THE INVENTION
In industrialized countries about one third of the adult
population smokes cigarettes, resulting in a major avoidable cause of
morbidity and mortality. Smoking is a contributory or causative factor in a
number of diseases including respiratory diseases such as emphysema,
chronic bronchitis, lung infections, and lung cancer; cardiovascular disease;
gastric and duodenal ulcers; and cancer of the lung, oral cavity, larynx and
oesophagus.
Most regular smokers become addicted to, or dependent
upon, the pharmacological effects of nicotine in tobacco smoke. Nicotine is
rapidly absorbed across the blood brain barrier and exerts a direct action on
nicotine receptors in the spinal cord, autonomic ganglia and adrenal
medulla. For more detailed information on the pharmacologic effects of
nicotine see, for example, Oates and Wood, New Eng. J. Med. 319:1318, 1988.
Nicotine itself has been implicated as a contributory factor in coronary heart
diseases, peripheral vascular disease and hypertension.
Although nicotine is responsible for the addictive nature
of cigarette smoking, most of the harmful health effects of smoking are
attributable to other constituents in cigarette smoke (The Lancet, 337:1191,
May 18, 1991). The combustion of tobacco in cigarettes results in the
production of up to 4,000 compounds and the inhalation of such unwanted
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by-products as tar, combustion gases and a range of carcinogens. Nicotine
may be nitrosated to form highly carcinogenic tobacco-specific N-
nitrosamines in tobacco smoke, or in the cured smokeless tobacco for use as
chewing tobacco or snuff. It is an unfortunate feature of cigarette smoking
that the negative consequences of nicotine addiction are largely manifested
by the inhalation of toxic and carcinogenic materials generated by the
combustion of tobacco.
Addiction to smoking is based upon a pharmacological
dependence on nicotine, an addiction comparable to that arising from the
use of heroin. There are a number of acute symptoms of smoking cessation
relating to nicotine withdrawal including irritability, anxiety, insomnia and
a craving for nicotine. The addictive nature of nicotine poses a major
obstacle to those who wish to quit smoking and a number of approaches
have been developed to aid individuals in their efforts to stop smoking.
The more successful of these involve therapy with nicotine substitutes such
as chewing gum, nicotine patches, nicotine nasal sprays, nicotine vapour
and the like. However, as discussed in more detail below, these approaches
have met with limited user acceptance and limited success. In addition,
there are individuals who are unable to stop despite repeated attempts, due
to the addictive nature of nicotine. These individuals could benefit from a
product which fulfilled their craving for nicotine, but did not have the
same detrimental health consequences as cigarettes.
Smoking is a uniquely effective form of systemic drug
administration. As nicotine enters the circulation via the pulmonary
circulation, it is speedily transported to the brain. Smokers achieve a rapid
peak in nicotine levels in the blood within one or two minutes after
finishing a cigarette. Nicotine substitutes generally contain nicotine in
solid
form, in a vapour or in solution. As nicotine is a base, these preparations
are alkaline. The alkalinity of nicotine substitutes is frequently increased,
for example to Ph 10 because at high Ph nicotine is not ionized and
ionization is know to impede the passage of nicotine across biological
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membranes (Burch et al., Am. Rev. Respir. Dis. 1989, 140:955).
With respect to nicotine gum, it is known that nicotine,
even at an alkaline Ph, is absorbed slowly across the mucous membranes of
the oral cavity, so absorption by this route does not produce the very rapid
increase in nicotine levels associated with cigarette smoking. Therefore,
buccal absorption has proved to have limited use in simulating the effects
of cigarette smoking and lessening the adverse symptoms of nicotine
withdrawal. Lower nicotine levels are achieved from chewing nicotine gum
compared to smoking cigarettes and the gum has been associated with
gastro intestinal side effects, hiccups, mouth ulcers and sore throat. The
amount of nicotine absorbed is also highly variable and is dependent upon
the chewing and swallowing actions of the user over a prolonged period of
time.
Nicotine patches are associated with skin irritation at the
application site. Both nicotine gum and dermal patches result in slow
absorption of nicotine which is frequently not effective in satisfying the
patient's craving for cigarettes. This may be one of the reasons for the lack
of
success of these forms of therapy in weaning subjects from smoking.
Self-propelled aerosols (also know as "pressurized
aerosols") which contain nicotine in solution have also been proposed as
cigarette substitutes. An example is the self-propelled aerosol formulation
of Jacobs in U.S. Patent No. 4,635,651. Such formulations are packaged in
pressurized metered dose delivery systems. As shown in Jacobs, these
delivery systems contain a water based aerosol formulation and a propellant
such as pressurized freon which are stored in a pressurized storage
container. When the device is used by an individual, the user aims the
delivery system into their mouth. The user then inhales while causing a
premetered dose of aerosol to be forced from the storage container and
expelled at high speed into the user's mouth.
There are a number of problems with such pressurized
aerosols. Pressurized aerosols require coordination on the part of the user
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who ideally should inhale at exactly the same time as the device is actuated
in order to deliver the drug into the lungs. Frequently pressurized aerosols
are inhaled near the end of respiratory intake resulting in poor delivery to
the distal portions of the lungs. For the foregoing reason, the dose of
nicotine administered by using pressurized aerosols can not be accurately
controlled.
Failure to coordinate actuation of an aerosol inhaler and
inhalation results in deposition of the aerosol in the oral cavities and upper
respiratory tracts. In addition, even if the user properly aims the delivery
device and coordinates the inhalation, the speed with which the aerosol is
expelled from the device and enters the mouth causes much of the aerosol
to impact on the throat and upper airways of the user. For example, Jacobs
in U.S. Patent No. 4,635,651 expelled particles of about 40 m. These
particles would comprise agglomerations of particles and solvents. As the
particles travel from the inhaler into the airway of the user, the particles
would break up into smaller particles and some of the solvent would
operate. However, even these smaller particles would still be at least about
10 m as they travelled through the mouth of the user and would
accordingly impact on the throat and upper airways of the user. Aerosols
utilize nicotine which is in solution. Since nicotine in solution has an
alkaline pH which irritates the throat and upper airways, aerosols have
poor acceptance by smokers (Burch et al., 1989, Am. Rev. Respir. Dis.
140:955).
Further, it is problematic to produce particles of an optimal
size for absorption in the alveoli with a self-propelled aerosol. Jacobs in
U.S.
Patent No. 4,635,651 included a solid particulate component of defined size
into a pressurized aerosol formulation of an inhalable nicotine solution.
SUMMARY OF THE INVENTION
It has been determined that a controlled dose of a
medicament suitable for absorption into the blood stream of a patient
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through alveoli and small airways of the lungs can be delivered to the
alveoli and small airways of the patient's lungs by a breath activated powder
inhaler while causing only minimal noticeable irritation to the throat and
upper airways of the patient and, preferably without causing any noticeable
or significant irritation. It has also been determined that a controlled dose
of
a pharmaceutically acceptable nicotine preparation suitable for absorption
into the bloodstream of the patient through the alveoli and small airways of
the lungs can be delivered into the alveoli and small airways of a patient's
lungs by a breath activated powder inhaler to mimic the pharmacologic
effects of the nicotine administered by a cigarette, cigar, pipe or the like
(hereinafter generally referred to as "cigarette") while minimizing or
preventing the delivery of extraneous irritants or toxins into the oral cavity
and respiratory airways.
The present invention relates to a breath activated nicotine
inhaler for use by a patient to introduce a medicament into the patient's
lungs, comprising a housing, an air conduit within the housing adapted to
conduct air flow to the patient, a non-pressurized, particulate medicament
comprising at least one pharmaceutically acceptable nicotine preparation
suitable for absorption into the bloodstream of the patient through the
alveoli and small airways of the patient's lungs and means for introducing
a predetermined dose of said medicament into said air conduit, whereby on
activation of said inhaler and inhalation by the patient, the medicament is
introduced to the patient's lungs.
The predetermined dose of nicotine may be from about 0.1
to about 10 mg and preferably from about 0.2 to about 2 mg of nicotine. In
order to more closely mimic the pharmacologic effects of the nicotine
administered by a cigarette, the inhaler may be adapted to provide a series of
small doses of the nicotine preparation, such as from about 0.1 mg. to about
0.5 mg., over the period of time in which an individual would smoke a
cigarette.
In an embodiment of the invention, the medicament may
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additionally comprise a pharmaceutically acceptable carrier, binder,
excipient, surface active agent, diluent, or a combination thereof.
In a further embodiment of the invention, the breath
activated nicotine inhaler may have a resistor adapted to impart resistance
to the flow of air in the air conduit.
The nicotine may be a nicotine salt such as a sulphate or a
bitartrate or a nicotine base, such as a nicotine oil formulation or mixtures
thereof. These nicotine formulations may be absorbed, adsorbed or
aggregated onto a suitable carrier or excipient. Alternately, the nicotine oil
formulation may be encapsulated.
The invention also relates to a method of assisting a
person to withdraw from cigarette induced nicotine dependency comprising
introducing a predetermined dose of a non-pressurized, particulate
medicament comprising at least one nicotine formulation suitable for
absorption into the bloodstream of the person through the alveoli and
small airways of the person's lungs into a breath activated inhaler for use by
said person as a cigarette substitute.
The invention further relates to a method of assisting
withdrawal from cigarette induced nicotine dependency comprising
providing a breath activated nicotine inhaler comprising a housing; an air
conduit within the housing adapted to conduct air flow to a patient, a
particulate medicament comprising at least one pharmaceutically acceptable
nicotine formulation suitable for absorption into the bloodstream of the
person through the alveoli and small airways of the person's lungs; and,
means for introducing the medicament into said air conduit. The method
further comprises introducing a predetermined dose of medicament into
the air conduit; applying the patient's mouth to one end of the air conduit
and; inhaling air through the air conduit, thereby drawing medicament
into the lungs, preferably the distal region of the lungs.
In a preferred embodiment the method is repeated at time
intervals sufficient to reduce the negative effects of nicotine withdrawal. In
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a further preferred embodiment, where a patient appears to be unable to
stop smoking, the breath activated inhaler may be used as a cigarette
substitute.
In another aspect, the invention relates to a breath
activated inhaler for use by a patient to introduce a medicament into the
patient's lungs, comprising:
a housing having a first opening and a second opening,
said first opening and said second opening being releasably sealed, one of
said first opening and said second opening being adapted to deliver the
medicament to the mouth of the patient; and,
a non-pressurized, particulate medicament suitable for
absorption into the bloodstream of the patient through the alveoli and
small airways of the patient's lungs positioned in said housing,
whereby, when said seals are removed from said first opening and said
second opening, said housing and said openings define an air conduit
adapted to conduct air flow to the patient; and, on inhalation by the patient,
the medicament is introduced to the patient's lungs.
The breath activated inhaler according to this aspect of the
invention may contain a single dose of a medicament which is intended to
be inhaled by the patient in a single breath. Alternately, if the dosage which
is required by a patient is sufficiently great that it would cause irritation
to
the throat and upper airways of the patient, a full dose may be located in the
inhaler and the inhaler is preferably provided with by-pass air feed means
for supplying air to dilute the air passing through said housing so as to
reduce the concentration of the medicament in the air which is inhaled by
the patient.
Preferably, the by-pass air feed means is located near the
opening which is adapted to deliver the medicament to the mouth of the
patient.
In a further aspect, this invention also relates to a method
of introducing a medicament into the lungs of a patient using a breath
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activated inhaler having a housing having a first opening and a second
opening, said first opening and said second opening being releasably- sealed,
one of said first opening and said second opening being adapted to deliver
the medicament to the mouth of the patient; and, a non-pressurized,
particulate medicament suitable for absorption into the bloodstream of the
patient through the alveoli and small airways of the patient's lungs
positioned in said housing, said method comprising the steps of:
(a) agitating said medicament in said housing to disperse
said medicament throughout said housing;
(b) releasing said seals on said first and second openings;
and
(c) inhaling said medicament.
In these latter two embodiments, the housing is preferably
under sub-atmospheric pressure. The housing has one opening which is
adapted to be received in the mouth of a patient. In use, the medicament in
the housing is agitated so as to disburse the medicament throughout the
housing. This may be achieved by the patient releasing the seal on one
opening of the housing. Since the housing is at sub-atmospheric pressure,
the release of the seal will cause air to rapidly enter the chamber and
disburse the medicament throughout the housing. The patient may then
release the seal on the other opening of the housing and inhale in a slow
and controlled manner so as to draw all of the medicament into the
patient's lungs.
In a further aspect of this invention, a method of
manufacturing a breath activated inhaler is disclosed. The breath activated
inhaler is used by a patient to introduce a medicament into the patient's
lungs. The inhaler has a housing with a first opening and a second opening,
one of said first opening and said second opening being adapted to deliver
the medicament to the mouth of the patient. The method of manufacturing
the inhaler comprises the steps of:
(a) placing said housing between first and second filter
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means;
(b) passing a fluid containing entrained medicament
through said first filter means and said second filter means, to deposit said
medicament in said housing; and
(c) sealing said first and said second openings, said
first filter means being adapted to remove from said fluid particles of the
medicament which are sufficiently large to irritate the throat and upper
airways of the patient, said second filter means being adapted to pass
theretrough said fluid and particles which are sufficiently small that they
would not be absorbed in the lungs of the patient.
BRIEF DESCRIPTION OF THE DRAWINGS
This and other advantages of the instant invention will be
more fully and completely understood by reference to the following
description of the following drawings of an exemplary embodiment of the
invention in which:
Figure 1 is a cross-section of an inhaler according to the
instant invention;
Figure 2 is a top plane view along the line 2-2 in iigure 1;
Figure 3A discloses a cross-section of a further inhaler
according to the instant invention;
Figures 3B and 3C disclose methods of how the inhaler
shown in Figure 3A may be utilized by a patient; and,
Figures 4A - 4D show a method by which a further inhaler
according to the instant invention may be manufactured.
Figures 5A - 5D show a further embodiment of the inhaler
according to the instant invention and the method of use of this further
embodiment of the inhaler.
DETAILED DESCRIPTION OF THE INVENTION
As hereinbefore mentioned the present invention relates
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to a breath activated nicotine inhaler for dispensing a medicament such as a
nicotine formulation to the large airways as well as the distal regions of the
lung, and in particular, the alveoli and the small airways. In the art, "small
airways" is used to refer to the passages in the lungs which are less than
about 2 mm in diameter. The breath activated inhalers of the invention
deliver a predetermined dose of medicament such as nicotine into the
alveoli and small airways, in a particulate form which is sized for rapid
absorption and which simulates the pharmacologic effect of a rapid increase
in nicotine blood levels similar to that achieved by cigarette smoking. The
rapid nicotine absorption is due to deposition of nicotine in the airways and
alveoli of the lung where medicaments are absorbed efficiently across the
large surface area of the highly vascularized alveoli and small airways.
Breath activated inhalers having a housing, an air conduit
adapted to conduct air flow to a patient, and means for introducing a
medicament into the air conduit are generally known in the art, see, for
example, U.S. Patent Serial No. 4,524,769 to Wetterlin; Bell et al., J.
Pharmaceut. Sci. 60:1559, 1971 and; Newman et al., Eur. Res. J. 2:247, 1989.
Examples of suitable inhalers include Spinhaler , Turbuhaler and
Rotahaler . Breath activated inhalers differ from pressurized aerosol
inhalers in that breath activated inhalers are activated by inhalation of the
user so that the medicament is reliably drawn into the distal regions of the
lung.
As shown in Figure 1, breath activated inhalers (10)
generally comprise a hollow housing (12) with an air conduit (14). One end
of the air conduit (16) is adapted for insertion into the mouth of a patient.
Such inhalers have means for introducing the medicament into the air
conduit, for example a rotatable disc (20) having spaced containers (22) of
medicament which can be rotated to introduce a single dose of medicament
into the air conduit (see Figure 2). Referring to Figure 1 in more detail,
housing (12) has a bottom surface (30). Bottom surface (30) is provided with
air inlets (32). Air inlets (32) are sized to provide an appropriate amount of
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air into inhaler (10). As the air enters inhaler (10), it travels past
rotatable
disc (20) and exits through end (16). In use, the patient inserts one end of
the
air conduit into their mouth and inhales. The turbulent airstream created
in the air conduit by the patient's inspiration fluidizes the medicament to
produce a cloud of medicament particles which are carried into the lung
with the inhaled air.
Inhaler (10) also includes means (40) for opening spaced
containers (22) in a controlled fashion. As shown in Figure 1, inhaler (10)
includes actuator button (42). Button (42) is movable between a first position
as shown in Figure 1 and a second position which is shown in dotted
outline in Figure 1. Button (42) is connected to extender arm (44). Attached
to the distal end of extender arm (44) is piercing member (46). Piercing
member (46) has a sharpened edge so that, when actuated, it will pierce
spaced container (22) thus opening the container and allowing the
medicament to be fluidized by the passage of air over the disc. Extender arm
(44) and piercing member (46) are configured such that the sharpened edge
of piercing member (46) is positioned adjacent the circle defined by spaced
containers (22). When actuator button (42) is moved to the position shown
in dotted outline, piercing member (46) is moved so as to open spaced
container (22).
The breath activated nicotine inhaler of the invention
provides a pre-determined dose of a medicament such as nicotine to the
lung. The dose should be physiologically acceptable for administration to
humans by this route of administration. The dose of nicotine delivered to
the lungs may be from about 0.1 to about 10 mg, preferably from about 0.2 to
about 3 mg, more preferably from about 0.2 to about 2 mg, and most
preferably about 1 mg as a total dose in any one treatment. However, one
treatment may consist of multiple inhalations of a smaller dose over a
period of time thus more closely simulating the act of smoking and
minimizing the irritant effect of nicotine impaction in the mouth and
throat. Accordingly, in order to more closely mimic the pharmacologic
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effects of the nicotine administered by a cigarette, the inhaler may be
adapted to provide a series of small doses of the nicotine preparation, such
as from about 0.1 mg. to about 0.5 mg., over the period of time in which an
individual would smoke a cigarette, typically from about 1 to about 10
minutes.
Most inhalers currently in use for the treatment of
respiratory disorders use a low resistance so that sufficient air flow can be
generated by persons having impeded respiratory capacity and obstructed
airways, resulting, for example, from asthmatic attack. However, the high
flow rates generated by users not having obstructed airways could cause the
fine particles of the medicament to impact against the back of the upper
airway. Accordingly, one embodiment of the present invention provides
an inhalation device with a resistor which may serve two functions. First,
to restrict the cross-sectional area of the air conduit so as to reduce the
flow
rate of air thereby decreasing impaction at the back of the throat. Secondly,
to produce turbulence in the air flow to break up any aggregate particles of
the medicament which may be present in the inhaler prior to inhalation.
For example, as shown in Figure 1, inhaler (10) may be provided with
rotating means (50) which is mounted at end (16). Air passing by rotating
means (50) is disrupted so that aggregate particles of the medicament which
might be formed are disrupted.
To avoid the nicotine in the medicament from impacting
on the throat and upper airways of the user during inhalation, the
medicament preferably enters the mouth of the user with a momentum
sufficiently low to cause the medicament to be entrained in the air of the
inhalation so as to follow the curvature in the pathways of the upper
respiratory tract and be carried to the lungs of the user. To achieve this
result, the mass of the particles of the medicament and the velocity of the
medicament must be in a defined range.
The nicotine should be present as a stable powder in a size
range suitable for deposition on and absorption across the small airways and
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the alveolar lining taking into account the amount of water which may be
absorbed by the particles as they pass through the lungs. Larger particles,
over 5 m tend to be deposited in the oral cavity and upper airways,
whereas small particles under 0.5 m tend to be exhaled from the lung
without deposition. The particles grow in size as they are exposed to water
in the atmosphere and in the airways of the user. For example, a 0.1 m
particle may increase to about 0.5 m as it passes through the airways to the
alveoli and smaller airways of a user. In order to have an appropriate mass,
the individual medicament particles, when they exit from the inhaler, may
vary in size from about 0.1 m to about 5, preferably from about 0.1 m to
about 3 m, more preferably from about 0.1 m to about 2 m and most
preferably from about 0.1 m to about 1 m. However, it should be noted
that the individual particles in the medicament introduced into the inhaler
may be aggregated into larger aggregates which are subsequently broken
down in the turbulent air flow on inspiration.
To have an appropriate velocity, the air conduit of the
inhaler is sized to permit an air flow rate therethrough of up to about 1.0
L/s, and preferably up to about 0.5 L/s upon inhalation by the patient.
~
As discussed above, the use of the instant invention allows
a patient to achieve a rapid increase in nicotine blood level which
effectively simulates cigarette smoking. It is recognized that the amount of
nicotine which may be imparted to an individual may reach toxic
proportions if the individual administers doses of the medicament too
frequently. Accordingly, it is preferred to include means to limit the
frequency with which inhaler (10) may be utilized. For example, as shown
in Figure 1, rotatable disc (20) may be mounted on plate (52) which is
attached to axle (54). Axle (54) has one end (56) which is attached to
electric
motor (58) powered by a battery (not shown). Rotation of motor (58) causes
axle (54) to rotate thus rotating rotatable disc (20). Motor (58) is
calibrated so
that each activation of motor (58) causes rotatable disc (20) to move a
sufficient distance to place a new spaced container (22) adjacent piercing
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means (46). Actuator button (42) is connected to timing means (60).
Accordingly, when a patient utilizes inhaler (10), button (42) is moved to
the position shown in dotted outline in Figure 1.
If the amount of nicotine contained in a single dose is
designed to simulate an entire cigarette, then timer (60) may be preset so as
to allow a further dose to be taken only after a reasonable period of time
(e.g.
20 to 30 minutes) has elapsed. Timer (60) is conventional and is connected
to and actuated when button (42) is pushed. Timer (60) cuts off power to
motor (58), for example, two seconds after button (42) is pushed (to allow
the motor enough time to advance disc (20) by one step) and keeps the
power to motor (58) cut off until timer (60) has counted down the desired
time (which can be made adjustable).
If each nicotine dose is made equivalent only to that
obtained by one or two puffs from a cigarette, then timer (60) would
normally not be needed. However, if desired, timer (60) may be preset to
allow a plurality of doses to be taken over a relatively short period of time
to simulate the nicotine levels which are achieved when an individual
smokes a cigarette. For example, timer (60) could be provided and set to
permit a desired number of doses (puffs) within a preset time (for example 5
to 10 doses within, for example, ten to fifteen minutes), and then to cut off
power to motor (58) until a selected time interval (e.g 20 to 30 minutes) has
elapsed. By adjusting the number of doses allowed in each period and the
time intervals between the periods, the total nicotine dosage can be
controlled and, if desired, gradually reduced to wean the patient from
his/her nicotine additions.
Alternatively, timer (60) can be set simply to count the
time between doses even when one dose simply simulates one or two puffs
on a cigarette.
The breath activated nicotine inhalers of the invention are
characterized in that the medicament to be drawn into the lungs may
comprise one or more nicotine formulations. The present invention
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provides a powdered medicament comprising nicotine for use in a breath
activated powder inhaler. The nicotine may be a nicotine salt such as a
sulphate or a bitartrate or a nicotine base, such as a nicotine oil
formulation
or pharmacologically active analogues or derivatives of nicotine or
substances which mimic the effects of nicotine, either alone or in
combination with other active substances. The medicament may be discrete
particles or it may be absorbed, adsorbed or aggregated onto a suitable
carrier
or excipient. Alternately, if the medicament is a liquid, such as a nicotine
oil
formulation, the medicament may be encapsulated.
Nicotine is known to form salts with almost any acid and
double salts with many metals and acids. Nicotine salts vary in their ability
to absorb water. It has been found that the ability of nicotine salts to
penetrate into the distal regions of the lung, such as the peripheral airways
and the alveoli, is based in part upon the size of the particles of the
medicament and the degree of hygroscopicity of the medicament. For
example, some nicotine salts are very hygroscopic. Accordingly, the particles
rapidly increase in size when exposed to an airway of the patient which is
fully water saturated. The absorption of water by the particles favours the
deposition of the nicotine particles in the central airways of the respiratory
system as opposed to the peripheral regions of the lung. By selecting a
nicotine salt which is somewhat hygroscopic, and selecting the particles so
as to be capable of being inhaled and transported to the alveoli and small
airways, a rapid increase in the blood level of nicotine may be obtained in a
patient. This rapid increase in blood level simulates cigarette smoking.
Accordingly, the nicotine may be selected, based upon its
hygroscopicity, to provide nicotine salt particles which are of the sufficient
size to be transported to the distal regions of the lungs and, in particular,
to
the alveoli and small airways. Preferred nicotine salts include sulphate and
tartrate, chloride, bi-chloride, bitartrate, picrates, aipricrates,
salicylates,
picrolonates and dipicrolonates. More preferably, the salt is sulphate,
bitartrate or mixtures thereof.
2146VO54
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A medicament such as nicotine may be mixed with one or
more pharmacologically acceptable binders, excipient or diluents, surface
active agents, colouring or flavouring agents, suitable for inhalation.
Examples of suitable solid diluents or carriers which may be used in the
medicament include mannitol, dextrose and lactose.
In order to facilitate storage, handling and introduction of
the medicament into the air conduit the medicament may be packaged in
powdered form with a desiccant to prevent moisture absorption.
The medicament of the invention, if ionized (e.g. a
nicotine salt), is poorly absorbed across the mucosa of the upper airways and
is relatively non toxic to those surfaces. Surprisingly, the extensive cross-
sectional area of the small airways and the alveolar lining provides a large
stable buffering environment for the ionized nicotine. As the nicotine is
buffered in the lungs, the pH of the nicotine increases and the nicotine
changes to a non-ionized form which may be readily transported across the
biological membranes in the lung. Thus, nicotine, whether acidic or basic,
delivered into the distal regions of the lung is readily buffered and absorbed
by the extensive airway and alveolar surfaces. It is the rapid and efficient
absorption across the expansive buffered alveolar and airway surfaces which
results in the steep rise in nicotine blood levels mimicking the
pharmacological effect of cigarettes. The selective delivery to, and
absorption across, the distal lung regions therefore mimics the
pharmacologic effects of cigarette-derived nicotine while decreasing or
eliminating the undesirable side effects of smoking or other nicotine
substitution therapies.
The medicaments of the present invention are intended
for administration to humans and preferably contain from about 0.1 mg. to
about 10 mg. of nicotine. The medicament can be prepared by known
methods for the preparation of pharmaceutically acceptable compositions
which can be administered to the airways of patients such that an effective
quantity of nicotine is provided, which may be combined in a mixture with
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a pharmaceutically acceptable vehicle as hereinbefore mentioned.
In accordance with one embodiment of the invention a
method of assisting a person withdraw from cigarette induced nicotine
dependency is provided. The method comprises introducing a medicament
comprising one or more nicotine formulations suitable for absorption into
the bloodstream of the person through the alveoli and airways of the
person's lungs into a breath activated powder inhaler for use by a person as
a cigarette substitute.
When smokers attempt to stop smoking the recidivism
rate is high due to the negative symptoms of withdrawal from nicotine
addiction. Replacement therapy with cigarette substitutes is designed to
lessen the impact of nicotine withdrawal and to assist a person in
withdrawing from cigarette induced nicotine dependency. Cigarette
substitutes are suggested as a replacement for cigarettes during the
withdrawal period. The optimal replacement therapy will involve
reproducing the sharp increase in nicotine levels achieved by cigarette
smoking in order to effectively suppress the withdrawal symptoms.
Successful withdrawal from smoking may require the use of the breath
~
activated inhalers of the invention over a period of time during which
inhalers are used to deliver successively smaller nicotine doses until
complete withdrawal may be effected.
In order to effect a controlled withdrawal from nicotine the
present invention provides a breath activated nicotine inhaler to deliver a
predetermined dose into the distal regions of the lung. The predetermined
dose is introduced into the air conduit from where it is efficiently drawn
deep into the lungs. The size of each individual dose may therefore be
accurately controlled.
In a preferred embodiment the minimum time interval
between doses is also controlled to prevent the patient from receiving an
overdose of nicotine. The timer may be set to enforce time periods of from 5
minutes to about 2 hours. If the dosage is set to represent a puff of a
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cigarette, then the timer may have a first setting to permit several dosages
to
be taken over a period of a few minutes and a second setting to prevent a
second plurality of dosages being taken before the expiry of from 5 minutes
to about 2 hours. Accordingly, the present invention provides a highly
controlled yet flexible method of assisting a person to withdraw from
cigarette-induced nicotine dependency by providing controlled doses of
nicotine having a pharmacologic effect similar to that of cigarette smoke
without the adverse side effects. The act of inhaling from a device in the
mouth may also provide patients with a short-term behaviour substitute
for inhaling a cigarette. In some cases where a person is unable to stop
smoking, then the inhaler may be used as a replacement for cigarettes.
An alternate inhaler for delivering a medicament to the
lungs of a user is shown in Figure 3A. Inhaler (70) may comprises a
longitudinally extending housing having a first end (72) and a second end
(74). As will become more apparent below, inhaler (70) may also include
filter (76). A stopper (78) is positioned in each of ends (72) and (74).
Inhaler (70) may be of any particular shape. As shown in
Figure 3A, the inhaler may comprises a longitudinally extending cylinder so
as to simulate the shape of a c garette. One of ends (72) and (74) is adapted
to
deliver a medicament to the mouth of a patient. The other of ends (72) and
(74) may be of any particular shape.
Inhaler (70) is preferably manufactured from an air
impervious or air impregnable material. Preferably, inhaler (70) is also
made from a material which would be effectively electrostatically neutral to
the medicament which is placed in inhaler (70). The material may be
selected from those which will not develop an electrostatic charge which
would attract the medicament particles. For example, inhaler (70) may be
manufactured from nylon. Alternately, an electrostatically neutral liner or
coating may be placed in inhaler (70). In addition, stoppers (78) are also
preferably made of an air impervious or air impregnable material and form
a airtight seal with ends (72) and (74). Accordingly, when manufactured, the
_ 2~4G954
-19-
inhaler has a stable internal environment which is not in air flow
communication with the surrounding air.
A particulate medicament suitable for absorption into the
bloodstream of a patient through the lungs of the patient and, preferably,
through the alveoli and small airway of the patient's lungs, is positioned
within the inhaler (70). The medicament may be a nicotine formulation of
the particle size discussed above. Preferably, the individual medicament
particles may vary in size from about 0.1 m to about 2 .m and, more
preferably, from about 0.1 m to about 1 gm.
Figures 3B and 3C show a method for the use of inhaler
(70). As shown in Figure 3B, mouth end piece (80) may be inserted through
stopper (78) at end (72) of inhaler (70). For example, stopper (78) may be a
thin walled plastic or rubber member which may be punctured by mouth
end piece (80). Accordingly, end (72) of inhaler (70) may itself be sized or
adapted so as to be received in the mouth of a patient or may be adapted to
receive mouth end piece (80). Mouth end piece (80) may include one way
valve (82).
Once mouth end piece (80) is inserted through stopper (78)
Ir at end (72) of inhaler (70), stopper (78) may be removed from end (74).
Accordingly, end (74), inhaler (70) and mouth end piece (80) define an air
conduit. When the patient inhales, the medicament contained in housing
(70) is transported through mouth end piece (80), through one way valve
(82) and into the lungs of the patient. Preferably, the air conduit is sized
so
as to permit an air flow rate therethrough of up to about 1 L/s upon
inhalation by the patient and, preferably, the airflow rate is up to about 0.5
L/s.
The inhaler may be manufactured by the steps shown in
Figures 4A - 4D. As shown in Figure 4A, inhaler (70) commences as an
longitudinally extending member. Filter (76) is positioned at one end of
inhaler (70) and filter (84) is provided at the other end of inhaler (70).
Preferably, the filters and in particular filter (76) is made from an
2146954
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electrostatically neutral material such as nylon. Filter (84) is sized so as
to
prevent large particles which may irritate the throat and upper airways
from entering inhaler (70). Filter (76) is sized so as to allow minute
particles
which would be expelled from the lung of the patient to exit therethrough
while retraining in tube (70) those particles of a sufficient size which would
be capable of being absorbed in the lungs of the patient. Filter (84) may be
sized so as to allow therethrough particles less than 5 m, preferably less
than about 3 g.m, more preferably less than about 2 m and, most preferably
less than about 1 m. Filter (76) may permit particles less than about 0.1 m
from passing therethrough. Accordingly, when air containing a
medicament travels in the direction of the arrow shown in Figure 4A from
end (72) to end (74), the larger particles will not enter inhaler (70) and
particles which are too small to be retained in the lungs of a patient pass
completely through inhaler (70). Thus, the particles which are retained in
inhaler (70) may conform to the dimension of particles contained in
ordinary cigarette smoke (for example 0.1 - 2 m or more preferably 0.1 - 1
m).
A sufficient amount of air is passed through filter (72) and
(74) to insert a predetermined dosage of medicament in inhaler (70). The
dosage inserted into inhaler (70) may be determined based upon the
concentration of medicament in the air flow and the particle size range
contained in the medicament. The medicament will tend to accumulate
around filter (76). Once the predetermined dose of medicament is inserted
into inhaler (70), filter (84) may be removed from inhaler (70) by cutting
inhaler (70) at point (86) as shown in Figure 4B. As shown in Figure 4C, one
way valve (88) may then be inserted at cut end (86) of inhaler (70). Stoppers
(78) may then be inserted in ends (86) and (74).
In an alternate embodiment, the step shown in Figure 4C
may be omitted and a stopper may be placed in end (86) without installing a
one way valve (88). According to this embodiment, the inhaler shown in
Figure 3A may be prepared. In another embodiment (not shown) Filter (84)
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may be part of the machine which injects medicament into inhaler (70).
According to this embodiment, the machine would contain an injector (not
shown) containing filter (84). The injector would be sized so as to prevent
air flowing out end (72) of inhaler (70) thus forcing all of the air and
entrained medicament to enter inhaler (70).
When stoppers (78) are removed, and the patient inhales,
inhalation will cause the medicament to exit the inhaler and enter the
airways of the patient. The medicament may have a tendency to stick to the
inner walls of inhaler (70) and to filter (76). Accordingly, a rapid
inhalation
may be required and this may cause an undesirable amount of medicament
to impact upon the throat and upper airways of the patient. According to a
preferred embodiment of the instant invention, the medicament in inhaler
(70) is agitated prior to inhalation so as to cause the medicament to draw
away from the walls of inhaler (70) and filter (76). This may be achieved by
the patient shaking inhaler (70) prior to removing stopper (78) and
inhaling. Alternately, the medicament in inhaler (70) may be at sub-
atmospheric pressure. When one of stoppers (78) is removed, and preferably
stopper (78) located at end (74), the in rush of air will cause the medicament
r
to fill inhaler (70). Accordingly, when the other stopper (78) is removed, the
patient may inhale in a controlled, slow manner so as to draw all of the
medicament into the lungs of the patient.
Inhaler (70) may be used with any particular medicament,
including a nicotine compound as discussed herein. Inhaler (70) provides a
simple method of providing a controlled dose of a medicament into the
alveoli and small airways of the patient's lung without any significant
deposition of same in the throat and upper airways which may result in
irritation of the throat and upper airways and a reduction in the amount of
medicament which is actually absorbed into the bloodstream of the patient.
Due to the design of inhaler (70) a relatively large dose of
medicament may be placed in inhaler (70). Due to the low momentum
which is imparted to the medicament as it leaves inhaler (70) and enters the
CA 02146954 2006-05-01
-22-
patient's mouth, a large dose of medicament may be inhaled in a single
breath. Depending upon the.medicament and the dosage which may be
required, it is appreciated that it may not be possible, even with the use of
inhaler (70) for a patient to inhale a full dosage without causing some
irritation to the patient's throat and upper airways. If the amount of the
dosage is sufficiently high, then two or more inhalers (70) may be utilized by
the patient to achieve a full dose.
Alternately, inhaler (70) may be designed to contain a full
dose of medicament but, due to the use of dilution air, several breaths may
be required to inhale all of the medicament in inhaler (70). For example,
inhaler (70) which is shown in Figure 5A is similar to the inhaler shown in
Figure 4D. Accordingly, inhaler (70) has a filter (76) located adjacent end
(74)
in addition, one way valve (88), which opens at sub-atmospheric pressure, is
positioned adjacent end (72). End (72) is sealed by stopper (78), which is
preferably waterproof. Medicament (90) is generally represented as being
located near or on filter (76). As discussed above, if inhaler (70) is
manufactured according to the steps set out in Figures 4A-4D, the
medicament will tend to accumulate near or adjacent filter (76).
In order to restrict the amount of air which may be drawn
through inhaler (70) with any inhalation, inhaler (70) is provided with end
member (92) positioned at end (74) of inhaler (70) and one or more by-pass
valve (98). End member (92) seals end (74) of inhaler (70). End member (92)
may be formed as an integral part of inhaler (70). End member (92) has
longitudinally extending member (94) which is sealed by releasable seal (96).
Similarly, by-pass valve (98) is sealed by releasable seal (100).
As discussed above, the medicament in inhaler (70) is
preferably agitated so as to disperse medicament (90) throughout inhaler
(70) prior to inhalation. One way to achieve this is to manufacture inhaler
(78) to be at sub-atmospheric pressure. If this method is utilized, one of the
releaseable seals may be removed thus allowing air to enter inhaler (70) as
shown in Figure 5B. The in rush of air disperses medicament (90)
2146954
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throughout inhaler (70). Subsequently, as shown in Figure 5C, stopper (78)
may be removed. Subsequently, as shown in Figure 5D, releasable seal (100)
may be removed. Thus, when the patient inhales, air is drawn through
member (94), through inhaler (70) and through one way valve (88) into the
airways of the patient. Simultaneously, air enters by-pass valve (98) thus
diluting the concentration of medicament (90) in the air inhaled by the
patient. Thus, more than one inhalation is required to withdraw all of the
medicament from inhaler (70).
By varying the number and size of by-pass valves (98), as
well as the size of member (94), the amount of air which flows through
inhaler (70) as opposed to by-pass valve (98) may be adjusted thereby
controlling the number of inhalations which may be required to withdraw
all of the medicament from inhaler (70). Alternately, other modifications
may be utilized to control the amount of medicament which is withdrawn
from inhaler (70). For example, end member (92) may be replaced by a
variable aperture which controls the amount of air which may pass through
inhaler (70).
If the medicament in inhaler (70) is nicotine, inhaler (70)
may be designed to look like a cigarette. In addition, by appropriately
dimensioning by-pass valves (98) and member (94), inhaler (70) may
contain an amount of nicotine which is contained in a cigarette. Several
inhalations (i.e. puffs) would be required to withdraw all of the medicament
in stages from inhaler (70). Thus, not only would the patient use inhaler
(70) in the same manner as they would smoke a cigarette, but the
transportation of nicotine into the patient and the absorbtion thereof in the
lungs of the patient would more closely simulate smoking.
