U.S. patent application number 15/599095 was filed with the patent office on 2017-09-07 for sealed nebulizer liquid reservoir systems and methods.
This patent application is currently assigned to Nektar Therapeutics. The applicant listed for this patent is Nektar Therapeutics. Invention is credited to David Blakey, Richard Day.
Application Number | 20170252523 15/599095 |
Document ID | / |
Family ID | 43449861 |
Filed Date | 2017-09-07 |
United States Patent
Application |
20170252523 |
Kind Code |
A1 |
Blakey; David ; et
al. |
September 7, 2017 |
SEALED NEBULIZER LIQUID RESERVOIR SYSTEMS AND METHODS
Abstract
Methods, systems, and devices are described for sealing a
nebulizer's liquid reservoir. A nebulizer liquid reservoir may be
provided that is in fluid communication with an aerosol generator.
The nebulizer liquid reservoir may have an open end and a
headspace. A cap may be placed on the open end of the nebulizer
liquid reservoir, wherein the cap partially fills the headspace of
the nebulizer liquid reservoir. The cap can include a plunger that
passes through the cap and allows for air to escape from the
headspace of the nebulizer liquid reservoir through the cap. The
cap can seal the nebulizer liquid reservoir by actuating the
plunger to a locked position. The plunger may create an airtight
seal with the cap when in the locked position. An ambient pressure
may be maintained in the sealed nebulizer liquid reservoir until a
portion of the liquid is dispensed.
Inventors: |
Blakey; David;
(Hertfordshire, GB) ; Day; Richard;
(Cambridgeshire, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nektar Therapeutics |
San Francisco |
CA |
US |
|
|
Assignee: |
Nektar Therapeutics
San Francisco
CA
|
Family ID: |
43449861 |
Appl. No.: |
15/599095 |
Filed: |
May 18, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14742464 |
Jun 17, 2015 |
9682201 |
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15599095 |
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13384575 |
Jan 17, 2012 |
9084862 |
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PCT/US10/42471 |
Jul 19, 2010 |
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14742464 |
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61226567 |
Jul 17, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 11/06 20130101;
A61M 16/0057 20130101; A61M 11/005 20130101; A61M 11/003 20140204;
A61M 16/06 20130101; B05B 17/0646 20130101; A61M 15/0085 20130101;
A61M 2205/582 20130101; A61M 16/0875 20130101; A61M 11/007
20140204; A61M 16/208 20130101; A61M 16/14 20130101 |
International
Class: |
A61M 11/00 20060101
A61M011/00; A61M 11/06 20060101 A61M011/06; A61M 15/00 20060101
A61M015/00; A61M 16/00 20060101 A61M016/00; A61M 16/06 20060101
A61M016/06; A61M 16/08 20060101 A61M016/08; A61M 16/14 20060101
A61M016/14; A61M 16/20 20060101 A61M016/20; B05B 17/00 20060101
B05B017/00 |
Claims
1. A nebulizer system comprising: an aerosol generator comprising
an aperture plate, wherein the aperture plate is vibrated to
aerosolize a liquid; a liquid reservoir having an open end, wherein
the liquid reservoir is configured to store the liquid such that a
headspace is present within the liquid reservoir as the liquid
reservoir discharges the liquid to the aerosol generator; a cap for
sealing the liquid reservoir and decreasing a volume of the
headspace of the liquid reservoir, wherein: the cap comprises a
plunger that passes through the cap; when the plunger is in an
unlocked position, an air escape route is present that allows air
to pass between the headspace and an external environment through
the cap; when the plunger is in a locked position; the air escape
route is sealed such that air cannot pass between the headspace and
the external environment through the cap; following the liquid
reservoir being sealed with the cap, the cap maintains ambient
pressure in the sealed liquid reservoir until a portion of the
liquid is dispensed; and a negative pressure, as compared with an
external environment, develops within the liquid reservoir as
liquid is discharged from the liquid reservoir after the liquid
reservoir has been sealed using the cap.
2. The nebulizer system of claim 1, wherein: the plunger further
comprises a stopper; and when the plunger is in the locked
position, the stopper creates a seal against a surface of the
cap.
3. The nebulizer system of claim 2, wherein: the plunger further
comprises a unidirectional lock, wherein the unidirectional lock
prevents the plunger from being moved from the locked position to
the unlocked position.
4. The nebulizer system of claim 3, wherein: the plunger is
partially pulled through the cap to cause the plunger to enter the
locked position from the unlocked position.
5. The nebulizer system of claim 3, wherein the unidirectional lock
creates a second seal against a second surface of the cap.
6. The nebulizer system of claim 1, wherein the cap further
comprises a flange that creates a seal between the cap and an inner
surface of the liquid reservoir.
7. The nebulizer system of claim 1, wherein the cap further
comprises an O-ring that creates a seal between the cap and an
inner surface of the liquid reservoir.
8. The nebulizer system of claim 1, wherein the cap is shaped to
partially descend within the liquid reservoir such that the cap
eliminates a portion of the headspace within the liquid
reservoir.
9. A liquid storage system for a nebulizer, comprising: a liquid
reservoir having an open end, wherein the liquid reservoir is
configured to store a liquid such that a headspace is present
within the liquid reservoir and to supply the liquid to an aerosol
generator; a cap for sealing the liquid reservoir and decreasing a
volume of the headspace of the liquid reservoir, wherein: the cap
comprises a plunger that passes through the cap; when the plunger
is in an unlocked position, an air escape route is present that
allows air to pass between the headspace and an external
environment; when the plunger is in a locked position; the air
escape route is sealed such that air cannot pass between the
headspace and the external environment; following the liquid
reservoir being sealed with the cap, the cap maintains ambient
pressure in the sealed liquid reservoir until a portion of the
liquid is dispensed; and a negative pressure, as compared with an
external environment, develops within the liquid reservoir as
liquid is discharged from the liquid reservoir after the liquid
reservoir has been sealed using the cap.
10. The liquid storage system of claim 9, wherein: the plunger
further comprises a stopper; and when the plunger is in the locked
position, the stopper creates a seal against a surface of the
cap.
11. The liquid storage system of claim 10, wherein: the plunger
further comprises a unidirectional lock, wherein the unidirectional
lock prevents the plunger from being moved from the locked position
to the unlocked position.
12. The liquid storage system of claim 11, wherein: the plunger is
partially pulled through the cap to cause the plunger to enter the
locked position from the unlocked position.
13. The liquid storage system of claim 12, wherein the
unidirectional lock creates a second seal against a second surface
of the cap.
14. The liquid storage system of claim 9, wherein the cap further
comprises a flange that creates a seal between the cap and an inner
surface of the liquid reservoir.
15. The liquid storage system of claim 9, wherein the cap further
comprises an O-ring that creates a seal between the cap and an
inner surface of the liquid reservoir.
16. The liquid storage system of claim 9, wherein the cap is shaped
to descend within the liquid reservoir such that the cap eliminates
a portion of the headspace within the liquid reservoir.
17. A method for sealing a nebulizer liquid reservoir, the method
comprising: providing a nebulizer liquid reservoir that is in fluid
communication with an aerosol generator, the aerosol generator
comprising an aperture plate; storing a liquid in the nebulizer
liquid reservoir, wherein the nebulizer liquid reservoir has an
open end and a headspace; placing a cap on the open end of the
nebulizer liquid reservoir, wherein the cap partially fills the
headspace of the nebulizer liquid reservoir and the cap comprises:
a plunger that passes through the cap and allows for air to escape
from the headspace of the nebulizer liquid reservoir through the
cap; sealing the nebulizer liquid reservoir by actuating the
plunger to a locked position, wherein: the plunger creates an
airtight seal with the cap when in the locked position; an ambient
pressure is maintained in the sealed nebulizer liquid reservoir
until a portion of the liquid is dispensed; and vibrating the
aperture plate to dispense the portion of the liquid from the
nebulizer liquid reservoir, wherein: dispensing the portion of the
liquid decreases an amount of the liquid in the sealed nebulizer
liquid reservoir; and decreasing the amount of the liquid in the
sealed nebulizer liquid reservoir creates a negative pressure
within the nebulizer liquid reservoir as compared to the ambient
pressure.
18. The method of claim 17, wherein sealing the nebulizer liquid
reservoir by actuating the plunger to the locked position comprises
partially pulling the plunger through the cap such that a
unidirectional lock of the plunger engages with a surface of the
cap.
19. The method of claim 17, wherein sealing the nebulizer liquid
reservoir by actuating the plunger to the locked position comprises
a stopper of the plunger forming a seal with a surface of the
cap.
20. The method of claim 17, further comprising: forming a seal
between an interior surface of the nebulizer liquid reservoir and
the cap prior to sealing the nebulizer liquid reservoir by
actuating the plunger to the locked position.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This Application is a continuation of U.S. patent
application Ser. No. 14/742,464, filed Jun. 17, 2015, entitled
"NEGATIVELY BIASED SEALED NEBULIZER SYSTEMS AND METHODS," Attorney
Docket No. 78816-948317, which is a divisional of U.S. patent
application Ser. No. 13/384,575, filed Jan. 17, 2012, entitled
"NEGATIVELY BIASED SEALED NEBULIZERS SYSTEMS AND METHODS," Attorney
Docket No. 78816-790551, which is a U.S. National Phase of
PCT/US2010/042471 filed on Jul. 19, 2010, entitled "NEGATIVELY
BIASED SEALED NEBULIZER SYSTEMS AND METHODS," Attorney Docket No.
78816-788684, which claims the benefit of U.S. Provisional Patent
Application No. 61/226,567, filed Jul. 17, 2009 entitled
"NEGATIVELY BIASED SEALED NEBULIZERS SYSTEMS AND METHODS," Attorney
Docket No. 78816-772658, and is related to Provisional Patent
Application No. 61/226,591, filed Jul. 17, 2009 entitled "SYSTEMS
AND METHODS FOR DRIVING SEALED NEBULIZERS," Attorney Docket No.
78816-772659, the entire disclosures of which is incorporated by
reference for all purposes.
BACKGROUND OF THE INVENTION
[0002] Embodiments of the present invention relate to nebulizers.
In particular, the present invention relates to use of a nebulizer
with a sealed drug reservoir to build up and maintain an internal
negative bias pressure.
[0003] A wide variety of procedures have been proposed to deliver a
drug to a patient. In some drug delivery procedures the drug is a
liquid and is dispensed in the form of fine liquid droplets for
inhalation by a patient. A patient may inhale the drug for
absorption through lung tissue. Further, the droplets forming the
mist may need to be very small to travel through small airways of
the patient's lungs, and consistent in size to assure proper
absorption. Such a mist may be formed by a nebulizer.
SUMMARY
[0004] Creating a negative bias pressure on the liquid side of an
aperture used for aerosolizing liquid drug may allow for more
efficient and consistent delivery of aerosolized liquid drugs to a
patient. Such a negative bias may be created by reducing the
pressure within the drug reservoir of a nebulizer. This may be
accomplished by sealing the drug reservoir then discharging an
amount of liquid drug from the reservoir. Because neither air, nor
anything else, is able to fill the space vacated by the discharged
liquid drug, the pressure within the drug reservoir decreases,
thereby creating a negative bias pressure within the liquid drug
reservoir and on the liquid side of the aperture aerosolizing the
liquid drug.
[0005] In some embodiments, a method for creating a negative bias
pressure within a sealed reservoir may be present. The method may
include providing a liquid reservoir coupled with an aerosol
generator, the aerosol generator comprising an aperture plate, the
aperture plate having a liquid side and an air side. The method may
also include receiving a liquid in the liquid reservoir. The method
may include sealing the liquid reservoir to create the sealed
reservoir. An ambient pressure may be maintained while the liquid
reservoir is being sealed. The ambient pressure may be maintained
in the sealed liquid reservoir until a portion of the liquid is
dispensed. The method may include vibrating the aperture plate to
dispense liquid. Dispensing liquid may decrease the amount of
liquid in the sealed reservoir. The method may include decreasing
the amount of liquid in the sealed reservoir to create a negative
bias pressure between an air side and a liquid side of the aperture
plate.
[0006] In some embodiments, a cap is provided, wherein the cap
comprises a first portion configured to couple with the liquid
reservoir and a second portion configured to screw into the first
portion of the cap. The method may further comprise screwing the
second portion of the cap into the first portion of the cap,
wherein a passageway allows the ambient pressure to be maintained
in the liquid reservoir as the second portion of the cap is screwed
into the first portion of the cap. In some embodiments, a cap is
provided, wherein the cap comprises a flexible seal and a pivot.
The method may include pivoting the cap against the liquid
reservoir, such that the flexible seal seals the liquid reservoir.
In some embodiments, a cap is provided that comprises a one-way
valve and a seal. The method may further include pressing the cap
onto the liquid reservoir such that the seal couples the cap with
the liquid reservoir, wherein the one-way valve the ambient
pressure to be maintained as the liquid reservoir is sealed. In
some embodiments, the cap is shaped to reduce headspace within the
liquid reservoir. In some embodiments, a cap is provided that
comprises a plunger and a stopper. The method may further include
placing the cap on the liquid reservoir such that the cap covers
the liquid reservoir, wherein the ambient pressure is maintained by
a passageway between the cap and the stopper. The method may
further comprise pulling the plunger of the cap, wherein the
plunger seals the liquid reservoir by moving the stopper to
obstruct the passageway between the stopper and the cap.
[0007] In some embodiments, sealing the liquid reservoir to create
the sealed reservoir uses a reservoir cap. The method may further
comprise, releasing, via the reservoir cap, air as the liquid
reservoir is sealed to create the sealed reservoir. The method may
further comprise unsealing the liquid reservoir using a reservoir
cap; placing additional liquid in the liquid reservoir; and
resealing the liquid reservoir using the reservoir cap. Also, the
method may comprise receiving, by the aerosol generator, a control
signal from a driver unit. The control signal from the driver unit
may be used to vibrate the aperture plate to dispense liquid. The
liquid may be a drug and the liquid reservoir may be a liquid drug
reservoir.
[0008] In some embodiments, a system for creating a negative bias
pressure within a liquid reservoir is present. The system may
include an aerosol generator comprising an aperture plate having a
liquid side and an air side, wherein the aerosol plate is
configured to be vibrated to dispense liquid. The liquid reservoir
may be configured to: receive liquid; store liquid; discharge
liquid to the aerosol generator; and seal, such that a negative
bias pressure develops between the liquid side and the air side of
the aperture plate as liquid is discharged from the liquid
reservoir. The system may include a cap configured to maintain an
ambient pressure while the liquid reservoir is being sealed. The
ambient pressure may be maintained in the sealed liquid reservoir
until a portion of the liquid is dispensed.
[0009] In some embodiments, a system for creating a negative bias
pressure on liquid to be aerosolized is present. The system may
include means for receiving liquid; means for storing liquid; means
for sealing the stored liquid in a sealed environment; means for
maintaining an ambient pressure on the stored liquid while the
stored liquid is being sealed; means for maintaining the ambient
pressure in the sealed environment until a portion of the liquid is
dispensed; means for discharging liquid of the stored liquid to be
aerosolized; means for aerosolizing liquid of the discharged
liquid; and means for allowing a negative bias pressure to develop
on the stored liquid and discharged liquid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] A further understanding of the nature and advantages of the
present invention may be realized by reference to the following
drawings. In the appended figures, similar components or features
may have the same reference label. Further, various components of
the same type may be distinguished by following the reference label
by a second label that distinguishes among the similar components.
If only the first reference label is used in the specification, the
description is applicable to any one of the similar components
having the same first reference label irrespective of the second
reference label.
[0011] FIG. 1A illustrates a simplified embodiment of a
nebulizer.
[0012] FIG. 1B illustrates a simplified embodiment of a nebulizer
with a driver unit.
[0013] FIG. 1C illustrates a simplified embodiment of a handheld
nebulizer with an integrated driver unit.
[0014] FIG. 1D illustrates a nebulizer integrated with a
ventilator.
[0015] FIG. 2 illustrates a simplified embodiment of a cap that may
seal a drug reservoir.
[0016] FIG. 3 illustrates another simplified embodiment of a cap
that may seal a drug reservoir.
[0017] FIG. 4 illustrates yet another simplified embodiment of a
cap that may seal a drug reservoir.
[0018] FIG. 5 illustrates a simplified embodiment of a cap that may
seal a drug reservoir.
[0019] FIGS. 6A and 6B illustrate a simplified embodiment of a cap
that may seal a drug reservoir.
[0020] FIG. 7 illustrates a method for creating a negative bias
pressure in a drug reservoir.
[0021] FIG. 8 illustrates a method for creating a negative bias
pressure in a drug reservoir, adding additional liquid drug, and
then resealing the drug reservoir.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Devices, systems, and methods are described for the
implementation of a novel architecture of nebulizers. The invention
provides various ways of improving the efficiency and consistency
of a liquid mist ejected from the vibrating aperture plate of a
nebulizer. In some nebulizers, also known as aerosol generators,
operating conditions, such as the existence of excess liquid on the
air-side (front face) of the vibrating aperture plate of the
nebulizer, may change over time. Such excess liquid may arise from
over pressure of the liquid reservoir, forcing some liquid to leak
through the aperture. Also, during operation of the nebulizer,
certain features of the droplet ejection process may lead to stray
droplets falling back onto the aperture plate. This excess liquid
may adversely affect the ejection efficiency of the nebulizer,
which is directly related to the flow rate and droplet diameter
properties of the liquid mist ejected from the nebulizer.
[0023] In addition, such excess liquid on the air-side of the
aperture plate may lead to the ejection of larger diameter droplets
from the vibrating aperture. These larger droplet diameters may
result in an improper amount of the drug being administered to the
patient and the drug being deposited in the large airways of the
patient's lungs as opposed to the smaller passageways where the
drug may be absorbed more readily. When the pressure on the
reservoir side of the aperture plate, which may be connected to the
drug reservoir of the nebulizer, is lower than the air-pressure
immediately on the air-side of the aperture plate what is known as
a "negative bias pressure" may be created. Such a negative bias
pressure may cause the efficiency of the nebulizer to be increased,
thus allowing it to achieve higher liquid flow rates, with smaller
and more consistent droplet size, than in comparable conditions
without a bias pressure. The negative bias pressure may be created
by sealing the drug reservoir. As the liquid drug is drained from
the drug reservoir (with little or no air entering to replace the
dispensed liquid drug's volume), a negative bias pressure may be
created.
[0024] FIG. 1 illustrates an embodiment of a possible nebulizer
100. The nebulizer 100 may include a nebulizer element 110 (which
is alternatively referred to as an aperture plate), a drug
reservoir 120, a head space 130, an interface 140, and a cap 150.
The nebulizer element 110 may be comprised of a piezoelectric ring
that may expand and contract when an electric voltage is applied to
the ring. The piezoelectric ring may be attached to a perforated
membrane. Such a perforated membrane may have a number of holes
passing through it. When an electric voltage is applied to the
piezoelectric ring, this may cause the membrane to move and/or
flex. Such movement of the membrane while in contact with a liquid
may cause the atomization of the liquid, generating a mist of
liquid droplets.
[0025] Embodiments of nebulizer 100 may utilize a piezoelectric
ring to vibrate a perforated membrane. Further, other nebulizers,
and the techniques associated with such nebulizers, are described
generally in U.S. Pat. Nos. 5,164,740; 5,938,117; 5,586,550;
5,758,637, 6,014,970, 6,085,740; 6,235,177; 6,615,824, 7,322,349
the complete disclosure of which are incorporated by reference for
all purposes.
[0026] A supply of a liquid, commonly a liquid drug, may be held in
the drug reservoir 120 (also referred to as a liquid reservoir). As
illustrated, a drug reservoir is partially filled with the liquid
drug. As the liquid drug is atomized, the amount remaining in the
drug reservoir 120 may decrease. Depending on the amount of liquid
drug in the drug reservoir 120, only a portion of the reservoir may
be filled with liquid drug. The remaining portion of the drug
reservoir 120 may be filled with gas, such as air. This space is
commonly referred to as head space 130 and dead volume. An
interface 140 may serve to transfer amounts of liquid drug between
the drug reservoir 120 and the nebulizer element 110.
[0027] The nebulizer 100-a may have a cap 150 sealing the drug
reservoir. Such a cap 150 may prevent air from entering the drug
reservoir 120. Cap 150 may be attached and sealed to the drug
reservoir 120 such that the ambient pressure (e.g., the pressure
outside of the drug reservoir 120) is maintained in the drug
reservoir 120 until liquid is drained from the drug reservoir
120.
[0028] Therefore, as the liquid drug is evacuated from the drug
reservoir 120, a negative bias pressure may appear in the drug
reservoir 120 (i.e. a lower pressure in the drug reservoir than the
atmospheric pressure). While the drug reservoir 120 is sealed, air
may still enter the drug reservoir 120 through the nebulizer
element 110. The greater the difference in pressure between the
external environment and the drug reservoir 120, the greater the
rate air may enter the drug reservoir 120 through the nebulizer
element 110. At a certain difference in pressure between the inside
of the drug reservoir 120 and the external environment, the plateau
pressure of the nebulizer 100 will be reached. At this point, air
external to the nebulizer 100 may enter the drug reservoir 120
through openings in the nebulizer element 110 (also referred to as
the "aperture plate") at the same rate that liquid is being
atomized by the nebulizer element 110. At the plateau point, air
entering the reservoir 120 via nebulizer element 110 may serve to
reduce the negative bias pressure or cause it to stabilize and stay
roughly at a certain pressure negative bias pressure.
[0029] A nebulizer with a sealed drug reservoir may be part of a
larger system. The embodiment of FIG. 1B illustrates such a system
100-b. FIG. 1B illustrates a nebulizer 151 with a capped drug
reservoir connected to a driver unit 152. The nebulizer with a cap
illustrated in FIG. 1B may be the nebulizer with a cap of FIG. 1A,
or may represent some other nebulizer. The driver unit 152 may
control the rate and size of vibration of the nebulizer element on
the nebulizer 151. The driver unit 152 may be connected to the
nebulizer element 151 via cable 153. The driver unit may be the
driver unit described in co-pending provisional application number
61/226,591 entitled SYSTEMS AND METHODS FOR DRIVING SEALED
NEBULIZERS filed on Jul. 17, 2009, attorney docket number
015225-012600US, the entire disclosure of which is incorporated by
reference for all purposes. Such a driver unit 152 may regulate the
voltage and frequency of the signal provided to the nebulizer
element of nebulizer 151. The regulation of the voltage and
frequency of the signal may be based on the resonance frequency of
the nebulizer element of nebulizer 151. Such a signal may vary
depending on the magnitude of the negative bias pressure.
[0030] In some other embodiments of nebulizers, the driver unit may
be incorporated into a handheld unit. Nebulizer 100-c of FIG. 1C
illustrates an embodiment of a handheld nebulizer with an
integrated driver. Nebulizer 100-c may include a case 155, a
mouthpiece 160, and trigger button 165, and an electrical plug 170.
Case 155 may contain some or all of the elements found in other
embodiments of nebulizers (such as nebulizer 100-a of FIG. 1A) and
drivers (such as driver unit 152 of FIG. 1B). Therefore, contained
with case 155 may be a sealed drug reservoir and/or a device
capable of generating an electrical signal at a particular voltage
and frequency to vibrate an aperture plate that aerosolizes liquid
stored in the drug reservoir. A person receiving the aerosolized
liquid drug may place her mouth on mouthpiece 160 and breath in.
While the person receiving the aerosolized liquid drug is breathing
in, she may press trigger button 165 to trigger the aperture plate
to begin aerosolizing liquid. In some embodiments, nebulizer 100-c
may contain a sensor that detects when the person is breathing in
and triggers the aperture plate to vibrate without trigger button
165 being necessary.
[0031] Nebulizer 100-c may also include an electrical plug 170.
Electrical plug 170 may be connected to an electrical outlet to
power nebulizer 100-c. Nebulizer 100-c may contain a battery,
thereby allowing electrical plug 170 to be connected to an
electrical outlet when nebulizer 100-c is not in use by a person to
charge the battery. Alternatively, in some embodiments of nebulizer
100-c, electrical plug 170 may need to be connected to an
electrical outlet while nebulizer 100-c is in use by a person. In
some embodiments, nebulizer 100-c may use replaceable batteries as
its power source.
[0032] In some embodiments, a nebulizer may operate in conjunction
with a ventilator. System 100-d illustrates a nebulizer 178 that
supplies aerosolized liquid to a person 176 via a ventilator 170.
Ventilator 170 may supply air suitable for breathing to person 176.
Ventilator 170 may assist person 176 in breathing by forcing air
into the lungs of person 176 and then releasing air to mimic
breathing. While person 176 is using ventilator 170, it may be
necessary to provide person 176 with aerosolized liquid, such as a
liquid drug.
[0033] Nebulizer 178 may be connected to a drug reservoir 186 that
is sealed by a cap 180. Drug reservoir 186 may contain an amount of
liquid drug 182. This liquid drug may be delivered to nebulizer 178
as liquid drug is aerosolized by nebulizer 178. As liquid drug is
aerosolized, liquid drug 182 may drain from drug reservoir 186,
thereby increasing the volume of headspace 184. Headspace 184 may
contain air. Headspace 184 may increase in volume, but also
decrease in pressure as liquid drug 182 drains because liquid
reservoir 186 is airtight.
[0034] Driver 172, which may represent the same driver as driver
unit 152 of FIG. 1B (or may represent some other driver unit) may
deliver a signal to nebulizer 178. This signal may control an
aperture plate of nebulizer 178. Nebulizer 178 may be attached to a
tube 179 used to deliver the air and liquid drug to patient 176.
Tube 179 may terminate in a mask 174 covering the mouth and/or nose
of person 176. The air and aerosolized liquid drug may then enter
the airways of person 176.
[0035] Nebulizers of FIGS. 1A-1D may create a negative bias
pressure with a sealed drug reservoir. The overarching principle
behind the bias in pressure formed in the drug reservoir of the
nebulizers by the evacuated liquid drug may be described by the
ideal gas equation:
pV=constant Eq. 1
In equation 1, p represents pressure and V represents volume.
Accordingly, in a sealed drug reservoir, the pressure p.sub.1
multiplied by the volume V.sub.1 prior to the evacuation of an
amount of the liquid drug may equal the pressure p.sub.2 multiplied
by the volume V.sub.2 after the evacuation of the amount of the
liquid drug. Therefore, the relationship may be expressed as:
p 1 V 1 = p 2 V 2 Eq . 2 .thrfore. p 2 = p 1 V 1 V 2
##EQU00001##
[0036] Further, the volume after the liquid drug has been evacuated
may be the same as the volume prior to the drug being evacuated
plus the change in air volume DV due to the out-flow of the liquid
drug from the drug reservoir. From this, a simplified equation may
be used to represent the pressure inside the reservoir 120
following evacuation of an amount of the liquid drug:
p 2 = p 1 V 1 V 1 + DV Eq . 3 ##EQU00002##
Therefore, to minimize p.sub.2, V.sub.1 may be minimized. This may
be accomplished by minimizing the initial amount of air space (also
referred to as "head space") in the drug reservoir, such as head
space 184 of FIG. 1D or head space 130 of FIG. 1A.
[0037] By way of example only, a drug reservoir may be 9.5 mL. Of
this 9.5 mL, 3.6 mL may be filled with a liquid drug, such as
Amikacin. Therefore, an initial head space of 5.9 mL is present. To
decrease the initial head space while still beginning with the same
amount of liquid drug, the size of the drug reservoir may be
reduced.
[0038] Referring to FIG. 1A, as liquid drug is evacuated from the
drug reservoir 120, the negative bias pressure may increase (in
other words, the pressure inside the drug reservoir 120 may become
lower than the external atmospheric pressure). The bubble point of
a stationary aperture plate may be expressed by the following
equation:
P b = 2 .sigma. r Eq . 4 ##EQU00003##
Here, P.sub.b refers to the bias pressure, .sigma. refers to
surface tension of the liquid drug, and r refers to the radius of
the holes in the membrane on the vibrating aperture plate. By way
of example only, if .sigma. is 0.05, such as for the liquid drug
Amikacin, and the radius of the holes in the aperture plate is 2.25
microns, the bias pressure at which air will begin to "bubble" into
the drug reservoir is 444 mbar bias pressure. By way of example
only, using the liquid drug Amikacin, where the initial head space
in the drug reservoir is 1.9 mL, this bubble point may be reached
when 2.4 mL of the initial 3.6 mL of the liquid drug has been
evacuated from the drug reservoir 120. The bubble point may be
greater than or equal to the plateau pressure where the air
entering the aperture plate balances the liquid being ejected from
the aperture plate.
[0039] While the above example refers to the use of the liquid drug
Amikacin, other liquid drugs or other liquids may also be used.
Further, if a different liquid is used, the value of a may change
based on the surface tension of the particular liquid used.
[0040] To allow the negative bias pressure to exist within the drug
reservoir of the nebulizer, the drug reservoir 120 must be sealed
to prevent air from entering the drug reservoir 120 beside through
the perforated membrane of the nebulizer element 110. Further, it
may be desirable that the drug reservoir 120 of the nebulizer 100
not be permanently sealed. A nebulizer with a resealable drug
reservoir 120 may allow for the drug reservoir 120 to be reused or
accessed, such as to add an additional amount of liquid drug. As
such, the drug reservoir may be either permanently or temporarily
capped to prevent air from filling the space created by the
evacuated liquid drug. Also, a decrease in the initial dead volume
may be desired to minimize V1 as previously described. Therefore, a
cap 150 for a drug reservoir of a nebulizer may serve multiple
purposes: to seal the drug reservoir from the external environment
and to fill at least a portion of the dead volume.
[0041] FIG. 2 illustrates an embodiment of a cap to seal a drug
reservoir of a nebulizer 200. The nebulizer of FIG. 2 may be any of
the nebulizers of FIGS. 1A-1D, or it may be some other nebulizer. A
cap 230 may be made of a rigid or semi-rigid material capable of
maintaining a seal, such as plastic or metal. In such an
embodiment, the cap 230 may be inserted a distance into the drug
reservoir 220. Such an insertion may minimize the head space in the
drug reservoir 220 of the nebulizer. The greater the distance the
cap 230 is inserted into the drug reservoir 220, the greater the
amount of head space that may be removed (thereby reducing V.sub.l,
as previously detailed). In the embodiment of FIG. 2, the cap 230
utilizes o-rings 235 to maintain a seal against the inner edge of
the drug reservoir 220. The cap 230 may contain a screw down insert
210. The screw down insert 210 may have threads to allow screw down
insert 210 to be screwed into threads 260 of an outer portion of
the cap 230. The cap 230 may also use o-rings 270 to maintain a
seal against the screw down insert 210. As the screw down insert
210 is screwed into the outer portion of the cap 230, the head
space within the drug reservoir 220 may be reduced by a mass of
material 240 being inserted into the head space. The farther the
screw down insert 210 is screwed down, the farther the mass of
material 240 may be inserted into the drug reservoir 220. The screw
down insert 210 may be limited from being screwed too far into the
drug reservoir 220 by a block at the end of the threads 260 or the
threads on screw down insert 210.
[0042] When a drug reservoir of a nebulizer is partially filled
with liquid drug and a cap is installed on the drug reservoir, the
attachment of the cap may compress air within the head space of the
drug reservoir, resulting in a positive bias pressure within the
drug reservoir. Such a positive bias pressure may cause liquid drug
to be forced out of the perforated membrane of the nebulizer. It
may be desired that this phenomenon be minimized. In the embodiment
of FIG. 2, the screw down insert 210 and/or the mass of material
240 may contain a passageway 250 to maintain the ambient pressure
upon insertion of the cap 230. The passageway 250 may allow air to
exit the cavity of the drug reservoir 220 as the cap 230 is
inserted and the screw down insert 210 is screwed down. The
passageway 250 may allow air to pass to outside of o-ring 270. Once
the screw down insert 210 is screwed down far enough, the entire
passageway 250 may be below the o-ring 270, creating an airtight
seal between the cap 230 and the drug reservoir 220.
[0043] The screw down insert 210 may later be unscrewed. Unscrewing
the screw down insert 210 may leave the mass of material 240 in
place, maintaining the air tight seal between the cap 230 and drug
reservoir 220 of the nebulizer. Alternatively, unscrewing screw
down insert 210 may remove mass of material 240. This may unseal
drug reservoir 220, allowing liquid drug to be removed and/or added
to drug reservoir 220. The screw down insert 210 may then be used
again to reseal drug reservoir 220.
[0044] It may also be desired to invert the filled and sealed
nebulizer so the air inside the reservoir moves to be adjacent to
the aperture plate. The air may then exit through the holes in the
aperture plate. This action may reduce the positive pressurization
in the nebulizer, and affect the performance of the nebulizer.
[0045] FIG. 3 illustrates another embodiment 300 of a cap for a
drug reservoir of a nebulizer, such as the nebulizers of FIGS.
1A-1D, or some other nebulizer. The embodiment of FIG. 3 utilizes a
pivot-based design. The cap 310 may be inserted at an angle into
the cavity of the drug reservoir 320. A seal 330 attached to the
cap 310 may be made of a flexible material capable of maintaining a
seal, such as plastic or rubber. The cap 310 may be plastic, or
metal, or any other rigid or semi-rigid material. Using a pivot
portion 340 of the cap 310, the cap 310 and seal 330 may be pivoted
into position to form an air-tight seal on the drug reservoir 320.
Such a device to cap the drug reservoir 320 may involve the seal
330 deforming or partially deforming to squeeze between the sides
of the drug reservoir 320, thereby creating an airtight seal. Cap
310 may be manipulated to unseal drug reservoir 320 to remove
and/or add liquid drug to drug reservoir 320. Cap 310 may then be
maneuvered to reseal drug reservoir 320.
[0046] FIG. 4 illustrates another embodiment 400 of cap to seal a
nebulizer, such as the nebulizers of FIGS. 1A-1D, or some other
nebulizer. The embodiment of FIG. 4 may include a one-way valve
such as valve 440. FIG. 4 illustrates an embodiment of a cap 450
with a "burp" valve 440. Such a valve 440 prevents a positive bias
pressure from being generated in the drug reservoir 410 of the
nebulizer to equalize with the external atmospheric pressure and
allows the ambient pressure to be maintained. However, valve 440
does not allow air to move from the external environment to inside
drug reservoir 410. Cap 450 may also include o-rings 420 to
maintain a seal between the cap 450 and the drug reservoir 410.
Further, flanges 430 may also form an additional airtight seal
between cap 450 and the drug reservoir 410. Alternatively, flange
430 may not be airtight. It may be possible to pull cap 450 off of
drug reservoir 410 to add and/or remove liquid drug. Cap 450 may
then be reattached to drug reservoir 410.
[0047] Embodiment 500 of FIG. 5 illustrates an additional way of
sealing a drug reservoir of a nebulizer that may allow for the
creation of a negative bias pressure within drug reservoir 510.
Such a way of sealing a drug reservoir may be used in conjunction
with the nebulizers of FIGS. 1A-1D, or some other nebulizer.
Embodiment 500 may also include a one-way "burp" valve 540 to allow
air to exit and the ambient pressure to be maintained, instead of
creating a positive bias pressure within the drug reservoir 510.
Valve 540 may prevent air from the external environment from
entering drug reservoir 510. O-rings 520 may be used to form the
seal between the cap 530 and the drug reservoir 510. Additional
seals 550 may be present to create a seal between the drug
reservoir 510 and the cap 530. In such an embodiment, the depth of
the cap 530 may be varied to regulate the head space within the
drug reservoir 510. For example, the greater the depth of cap 530,
the smaller the amount of head space that will be present in drug
reservoir 510. Additionally, it may be possible to remove cap 530
to add and/or remove liquid drug from drug reservoir 510. Cap 530
may then be reinserted to seal drug reservoir 510.
[0048] FIGS. 6A and 6B illustrate an embodiment 600 of a cap that
may be used to create a sealed drug reservoir for a nebulizer, such
as the nebulizers of FIGS. 1A-1D, or some other nebulizer. FIG. 6A
illustrates the cap 630 prior to sealing with the drug reservoir
610. In such an embodiment, the cap may be placed on the drug
reservoir 610 without a positive bias pressure developing because
of an escape route for the air (thereby the ambient pressure being
maintained), illustrated by dotted arrow 620. The cap 630 may use
flange 640 to create a seal between the drug reservoir 610 and the
edge of the cap 630. In some embodiments, an o-ring is used in
place of flange 640. Cap 630 may contain plunger 605. The plunger
may be attached to a unidirectional lock 650 and a stopper 660. The
stopper may be capable of creating an airtight seal with the bottom
of the cap 630 when the plunger 605 has been elevated. The
unidirectional lock 650 may prevent the plunger 605 from being
depressed once the unidirectional lock 650 has passed through an
opening in the cap 630. The unidirectional lock 650 may be made of
a flexible or semi-flexible material. The unidirectional lock 650
may also form an airtight seal with the cap 630. The cap 630 may be
shaped to eliminate various amounts of head space within the drug
reservoir 610. For example, the depth of cap 630 may be increased
to eliminate an increased amount of head space from drug reservoir
610. Once cap 630 has been inserted, plunger 605 may be pulled to
seal the cap 630 to the drug reservoir 610.
[0049] FIG. 6B illustrates cap 630 after the plunger 605 has been
raised. A user may raise plunger 605 manually. The stopper 660 may
have formed an airtight seal with the bottom of the cap 630. In
this embodiment, the unidirectional lock 650 has passed though the
cap 630, preventing the plunger 605 from descending and/or breaking
the seal between the cap 630 and the drug reservoir 610.
Additionally, unidirectional lock 650 may form an airtight seal
with the top of cap 630. It may be possible to unseal cap 630 by
pushing plunger 605 such that unidirectional lock 650 is forced
back through the top of cap 630. Cap 630 may be removed to allow
liquid drug to be added and/or removed from drug reservoir 610. In
some embodiments, once unidirectional lock 650 has passed through
cap 630, such as in FIG. 6B, it may not be possible to unseal cap
630 using plunger 605. However, it may still be possible to remove
cap 630, add and/or remove additional liquid drug and reseal drug
reservoir 610 using a new cap 630.
[0050] As those with skill in the art will realize, the embodiments
of FIGS. 2-6 represent examples of possible embodiments of caps to
seal a drug reservoir of a nebulizer. Other embodiments of caps may
also be possible. Further, it may be possible to create a
permanently capped reservoir. Such a permanently sealed reservoir
may be formed from a single piece of material or may include a
distinct cap permanently attached to the drug reservoir of the
nebulizer. Such a permanently sealed drug reservoir may be used
once and then disposed.
[0051] Such embodiments of nebulizers and caps, such as those
described in FIGS. 1A-1D, and FIGS. 2-6 may allow for a drug
reservoir of a nebulizer to be sealed using a method, such as
method 700 of FIG. 7. At stage 710, a drug reservoir of a nebulizer
may receive liquid, such as any of the previously described liquid
drugs into a drug reservoir. At stage 720, this liquid may be
stored in the drug reservoir until the liquid drug is either
removed or aerosolized.
[0052] At stage 730, the liquid reservoir may be sealed. The
process of such sealing may allow for air to escape from the liquid
reservoir to prevent a positive bias pressure within the drug
reservoir from developing, and thus maintain the ambient pressure
within the drug reservoir. Once sealed, if any positive pressure
within the liquid reservoir is present it may still be allowed to
escape, however air from the external environment is not permitted
to enter the drug reservoir. The ambient pressure may then be
maintained within the drug reservoir until liquid drug is dispensed
from the drug reservoir.
[0053] At stage 740, liquid drug may be discharged from the drug
reservoir to the aperture plate of the nebulizer. Because the drug
reservoir is sealed, air may not enter the drug reservoir as the
liquid drug is discharged.
[0054] At stage 750, the liquid drug may be aerosolized by the
aperture plate. The aperture plate may be vibrating. As liquid drug
contacts the aperture plate and moves through openings in the
aperture plate, the liquid drug may become atomized into small
airborne particles. Such airborne particles may be suitable for
inhalation by a person.
[0055] At stage 760, as liquid is discharged from the drug
reservoir and is aerosolized by the aperture plate, a negative bias
pressure may develop within the drug reservoir. The negative bias
pressure may develop because neither air nor anything else is
permitted to enter the drug reservoir to take the place of the
liquid drug as it is being discharged.
[0056] FIG. 8 illustrates another embodiment 800 of a method that
allows for a drug reservoir of a nebulizer to be sealed and a
negative bias pressure to form within the drug reservoir. Further,
embodiment 800 allows for additional liquid drug to be added after
the drug reservoir has been sealed. Such embodiments of nebulizers
and caps, such as those described in FIGS. 1A-1D, and FIGS. 2-6 may
allow for embodiment 800 to be performed.
[0057] At stage 810, a drug reservoir of a nebulizer may receive
liquid, such as any of the previously described liquid drugs into a
drug reservoir. At stage 820, this liquid may be stored in the drug
reservoir until the liquid drug is either removed or
aerosolized.
[0058] At stage 830, the liquid reservoir may be sealed. The
process of such sealing may allow for air to escape from the liquid
reservoir to prevent a positive bias pressure within the drug
reservoir from developing. Once sealed, any positive pressure
within the liquid reservoir may still be allowed to escape, however
air from the external environment is not permitted to enter the
drug reservoir.
[0059] At stage 840, liquid drug may be discharged from the drug
reservoir to the aperture plate of the nebulizer. Because the drug
reservoir is sealed, air may not enter the drug reservoir as the
liquid drug is discharged.
[0060] At stage 845, the nebulizer may receive a control signal
from a control unit, such as control unit 152 of FIG. 1B. The
control signal may be at a frequency and a voltage. The frequency
and magnitude of the voltage may determine the rate and amplitude
of the vibration of the aperture plate of the nebulizer. The rate
and amplitude of the aperture plate's vibration may determine the
amount of liquid drug aerosolized and the size of the liquid drug
droplets that are created by the aperture plate.
[0061] At stage 850, the liquid drug may be aerosolized by the
aperture plate based on the control signal received at stage 845.
As liquid drug contacts the aperture plate and moves through
openings in the aperture plate, the liquid drug may become atomized
into small airborne particles. Such airborne particles may be
suitable for inhalation by a person.
[0062] At stage 860, as liquid is discharged from the drug
reservoir and is aerosolized by the aperture plate, a negative bias
pressure may develop within the drug reservoir. The negative bias
pressure may develop because neither air nor anything else is
permitted to enter the drug reservoir to take the place of the
liquid drug as it is being discharged.
[0063] At stage 865, after some amount of liquid drug has been
aerosolized and a negative bias pressure has been created within
the drug reservoir, it may be determined whether additional liquid
drug is to be added to the drug reservoir. Additionally, it may be
determined whether liquid drug will be removed from the drug
reservoir. If no, the method may end at stage 870. The negative
bias pressure created at stage 860 may remain until some future
time.
[0064] However, if at stage 865 additional liquid drug is to be
added (or removed) from the drug reservoir, the drug reservoir cap
may be removed at stage 875. This may involve removing the entire
cap. For example, referring to FIG. 3, cap 310 may be entirely
removed such that drug reservoir 320 may be accessed. This may
involve manipulating only a portion of the cap. In some
embodiments, only a portion of the cap may be removed. For example,
referring to FIG. 2, screw down insert 210 may be unscrewed (or
otherwise removed) while the remainder of cap 230 remains attached
to drug reservoir 220.
[0065] At stage 880, additional liquid may be received in the drug
reservoir. This may represent the same or different liquid drug
than what was aerosolized at stage 850. Drug reservoir may also be
cleaned, especially if a different liquid drug is to be
aerosolized. This additional liquid drug may be stored by the drug
reservoir at block 890. The method may then return to block 830,
where the drug reservoir may be resealed using the same cap or a
different cap. The method may then continue until no additional
liquid drug is to be aerosolized.
[0066] While a wide variety of drugs, liquids, liquid drugs, and
drugs dissolved in liquid may be aerosolized, the following
provides extensive examples of what may be aerosolized. Additional
examples are provided in U.S. application Ser. No. 12/341,780, the
entire disclosure of which is incorporated herein for all purposes.
Nearly any anti-gram-negative, anti-gram-positive antibiotic, or
combinations thereof may be used. Additionally, antibiotics may
comprise those having broad spectrum effectiveness, or mixed
spectrum effectiveness. Antifungals, such as polyene materials, in
particular, amphotericin B are also suitable for use herein.
Examples of anti-gram-negative antibiotics or salts thereof
include, but are not limited to, aminoglycosides or salts thereof.
Examples of aminoglycosides or salts thereof include gentamicin,
amikacin, kanamycin, streptomycin, neomycin, netilmicin, paramecin,
tobramycin, salts thereof, and combinations thereof. For instance,
gentamicin sulfate is the sulfate salt, or a mixture of such salts,
of the antibiotic substances produced by the growth of
Micromonospora purpurea. Gentamicin sulfate, USP, may be obtained
from Fujian Fukang Pharmaceutical Co., LTD, Fuzhou, China. Amikacin
is typically supplied as a sulfate salt, and can be obtained, for
example, from Bristol-Myers Squibb. Amikacin may include related
substances such as kanamicin.
[0067] Examples of anti-gram-positive antibiotics or salts thereof
include, but are not limited to, macrolides or salts thereof.
Examples of macrolides or salts thereof include, but are not
limited to erythromycin, clarithromycin, azithromycin, salts
thereof, and combinations thereof. For instance, vancomycin
hydrochloride is a hydrochloride salt of vancomycin, an antibiotic
produced by certain strains of Amycolatopsis orientalis, previously
designated Streptomyces orientalis. Vancomycin hydrochloride is a
mixture of related substances consisting principally of the
monohydrochloride of vancomycin B. Like all glycopeptide
antibiotics, vancomycin hydrochloride contains a central core
heptapeptide. Vancomycin hydrochloride, USP, may be obtained from
Alpharma, Copenhagen, Denmark.
[0068] In some embodiments, the composition comprises an antibiotic
and one or more additional active agents. The additional active
agent described herein includes an agent, drug, or compound, which
provides some pharmacologic, often beneficial, effect. This
includes foods, food supplements, nutrients, drugs, vaccines,
vitamins, and other beneficial agents. As used herein, the terms
further include any physiologically or pharmacologically active
substance that produces a localized or systemic effect in a
patient. An active agent for incorporation in the pharmaceutical
formulation described herein may be an inorganic or an organic
compound, including, without limitation, drugs which act on: the
peripheral nerves, adrenergic receptors, cholinergic receptors, the
skeletal muscles, the cardiovascular system, smooth muscles, the
blood circulatory system, synoptic sites, neuroeffector junctional
sites, endocrine and hormone systems, the immunological system, the
reproductive system, the skeletal system, autacoid systems, the
alimentary and excretory systems, the histamine system, and the
central nervous system.
[0069] Examples of additional active agents include, but are not
limited to, anti-inflammatory agents, bronchodilators, and
combinations thereof.
[0070] Examples of bronchodilators include, but are not limited to,
.beta.-agonists, anti-muscarinic agents, steroids, and combinations
thereof. For instance, the bronchodilator may comprise albuterol,
such as albuterol sulfate.
[0071] Active agents may comprise, for example, hypnotics and
sedatives, psychic energizers, tranquilizers, respiratory drugs,
anticonvulsants, muscle relaxants, antiparkinson agents (dopamine
antagnonists), analgesics, anti-inflammatories, antianxiety drugs
(anxiolytics), appetite suppressants, antimigraine agents, muscle
contractants, additional anti-infectives (antivirals, antifungals,
vaccines) antiarthritics, antimalarials, antiemetics, anepileptics,
cytokines, growth factors, anti-cancer agents, antithrombotic
agents, antihypertensives, cardiovascular drugs, antiarrhythmics,
antioxicants, anti-asthma agents, hormonal agents including
contraceptives, sympathomimetics, diuretics, lipid regulating
agents, antiandrogenic agents, antiparasitics, anticoagulants,
neoplastics, antineoplastics, hypoglycemics, nutritional agents and
supplements, growth supplements, antienteritis agents, vaccines,
antibodies, diagnostic agents, and contrasting agents. The active
agent, when administered by inhalation, may act locally or
systemically.
[0072] The active agent may fall into one of a number of structural
classes, including but not limited to small molecules, peptides,
polypeptides, proteins, polysaccharides, steroids, proteins capable
of eliciting physiological effects, nucleotides, oligonucleotides,
polynucleotides, fats, electrolytes, and the like.
[0073] Examples of active agents suitable for use in this invention
include but are not limited to one or more of calcitonin,
amphotericin B, erythropoietin (EPO), Factor VIII, Factor IX,
ceredase, cerezyme, cyclosporin, granulocyte colony stimulating
factor (GCSF), thrombopoietin (TPO), alpha-1 proteinase inhibitor,
elcatonin, granulocyte macrophage colony stimulating factor
(GMCSF), growth hormone, human growth hormone (HGH), growth hormone
releasing hormone (GHRH), heparin, low molecular weight heparin
(LMWH), interferon alpha, interferon beta, interferon gamma,
interleukin-1 receptor, interleukin-2, interleukin-1 receptor
antagonist, interleukin-3, interleukin-4, interleukin-6,
luteinizing hormone releasing hormone (LHRH), factor IX, insulin,
pro-insulin, insulin analogues (e.g., mono-acylated insulin as
described in U.S. Pat. No. 5,922,675, which is incorporated herein
by reference in its entirety), amylin, C-peptide, somatostatin,
somatostatin analogs including octreotide, vasopressin, follicle
stimulating hormone (FSH), insulin-like growth factor (IGF),
insulintropin, macrophage colony stimulating factor (M-CSF), nerve
growth factor (NGF), tissue growth factors, keratinocyte growth
factor (KGF), glial growth factor (GGF), tumor necrosis factor
(TNF), endothelial growth factors, parathyroid hormone (PTH),
glucagon-like peptide thymosin alpha 1, IIb/IIIa inhibitor, alpha-1
antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors,
bisphosphonates, respiratory syncytial virus antibody, cystic
fibrosis transmembrane regulator (CFTR) gene, deoxyreibonuclease
(Dnase), bactericidal/permeability increasing protein (BPI),
anti-CMV antibody, 1 3-cis retinoic acid, oleandomycin,
troleandomycin, roxithromycin, clarithromycin, davercin,
azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin,
midecamycin, leucomycin, miocamycin, rokitamycin, andazithromycin,
and swinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin,
levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin,
norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin,
sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fleroxacin,
tosufloxacin, prulifloxacin, irloxacin, pazufloxacin,
clinafloxacin, and sitafloxacin, teicoplanin, rampolanin,
mideplanin, colistin, daptomycin, gramicidin, colistimethate,
polymixins such as polymixin B, capreomycin, bacitracin, penems;
penicillins including penicllinase-sensitive agents like penicillin
G, penicillin V, penicillinase-resistant agents like methicillin,
oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin; gram
negative microorganism active agents like ampicillin, amoxicillin,
and hetacillin, cillin, and galampicillin; antipseudomonal
penicillins like carbenicillin, ticarcillin, azlocillin,
mezlocillin, and piperacillin; cephalosporins like cefpodoxime,
cefprozil, ceftbuten, ceftizoxime, ceftriaxone, cephalothin,
cephapirin, cephalexin, cephradrine, cefoxitin, cefamandole,
cefazolin, cephaloridine, cefaclor, cefadroxil, cephaloglycin,
cefuroxime, ceforanide, cefotaxime, cefatrizine, cephacetrile,
cefepime, cefixime, cefonicid, cefoperazone, cefotetan,
cefinetazole, ceftazidime, loracarbef, and moxalactam, monobactams
like aztreonam; and carbapenems such as imipenem, meropenem,
pentamidine isethiouate, lidocaine, metaproterenol sulfate,
beclomethasone diprepionate, triamcinolone acetamide, budesonide
acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn
sodium, ergotamine tartrate and where applicable, analogues,
agonists, antagonists, inhibitors, and pharmaceutically acceptable
salt forms of the above. In reference to peptides and proteins, the
invention is intended to encompass synthetic, native, glycosylated,
unglycosylated, pegylated forms, and biologically active fragments,
derivatives, and analogs thereof.
[0074] Active agents for use in the invention further include
nucleic acids, as bare nucleic acid molecules, vectors, associated
viral particles, plasmid DNA or RNA or other nucleic acid
constructions of a type suitable for transfection or transformation
of cells, i.e., suitable for gene therapy including antisense.
Further, an active agent may comprise live attenuated or killed
viruses suitable for use as vaccines. Other useful drugs include
those listed within the Physician's Desk Reference (most recent
edition), which is incorporated herein by reference in its
entirety.
[0075] The amount of antibiotic or other active agent in the
pharmaceutical formulation will be that amount necessary to deliver
a therapeutically or prophylactically effective amount of the
active agent per unit dose to achieve the desired result. In
practice, this will vary widely depending upon the particular
agent, its activity, the severity of the condition to be treated,
the patient population, dosing requirements, and the desired
therapeutic effect. The composition will generally contain anywhere
from about 1 wt % to about 99 wt %, such as from about 2 wt % to
about 95 wt %, or from about 5 wt % to 85 wt %, of the active
agent, and will also depend upon the relative amounts of additives
contained in the composition. The compositions of the invention are
particularly useful for active agents that are delivered in doses
of from 0.001 mg/day to 100 mg/day, such as in doses from 0.01
mg/day to 75 mg/day, or in doses from 0.10 mg/day to 50 mg/day. It
is to be understood that more than one active agent may be
incorporated into the formulations described herein and that the
use of the term "agent" in no way excludes the use of two or more
such agents.
[0076] Generally, the compositions are free of excessive
excipients. In one or more embodiments, the aqueous composition
consists essentially of the anti-gram-negative antibiotic, such as
amikacin, or gentamicin or both, and/or salts thereof and
water.
[0077] Further, in one or more embodiments, the aqueous composition
is preservative-free. In this regard, the aqueous composition may
be methylparaben-free and/or propylparaben-free. Still further, the
aqueous composition may be saline-free.
[0078] In one or more embodiments, the compositions comprise an
anti-infective and an excipient. The compositions may comprise a
pharmaceutically acceptable excipient or carrier which may be taken
into the lungs with no significant adverse toxicological effects to
the subject, and particularly to the lungs of the subject. In
addition to the active agent, a pharmaceutical formulation may
optionally include one or more pharmaceutical excipients which are
suitable for pulmonary administration. These excipients, if
present, are generally present in the composition in amounts
sufficient to perform their intended function, such as stability,
surface modification, enhancing effectiveness or delivery of the
composition or the like. Thus if present, excipient may range from
about 0.01 wt % to about 95 wt %, such as from about 0.5 wt % to
about 80 wt %, from about 1 wt % to about 60 wt %. Preferably, such
excipients will, in part, serve to further improve the features of
the active agent composition, for example by providing more
efficient and reproducible delivery of the active agent and/or
facilitating manufacturing. One or more excipients may also be
provided to serve as bulking agents when it is desired to reduce
the concentration of active agent in the formulation.
[0079] For instance, the compositions may include one or more
osmolality adjuster, such as sodium chloride. For instance, sodium
chloride may be added to solutions of vancomycin hydrochloride to
adjust the osmolality of the solution. In one or more embodiments,
an aqueous composition consists essentially of the
anti-gram-positive antibiotic, such as vancomycin hydrochloride,
the osmolality adjuster, and water.
[0080] Pharmaceutical excipients and additives useful in the
present pharmaceutical formulation include but are not limited to
amino acids, peptides, proteins, non-biological polymers,
biological polymers, carbohydrates, such as sugars, derivatized
sugars such as alditols, aldonic acids, esterified sugars, and
sugar polymers, which may be present singly or in combination.
[0081] Exemplary protein excipients include albumins such as human
serum albumin (HSA), recombinant human albumin (rHA), gelatin,
casein, hemoglobin, and the like. Suitable amino acids (outside of
the dileucyl-peptides of the invention), which may also function in
a buffering capacity, include alanine, glycine, arginine, betaine,
histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine,
isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine,
tryptophan, and the like. Preferred are amino acids and
polypeptides that function as dispersing agents. Amino acids
falling into this category include hydrophobic amino acids such as
leucine, valine, isoleucine, tryptophan, alanine, methionine,
phenylalanine, tyrosine, histidine, and proline.
[0082] Carbohydrate excipients suitable for use in the invention
include, for example, monosaccharides such as fructose, maltose,
galactose, glucose, D-mannose, sorbose, and the like;
disaccharides, such as lactose, sucrose, trehalose, cellobiose, and
the like; polysaccharides, such as raffinose, melezitose,
maltodextrins, dextrans, starches, and the like; and alditols, such
as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol
(glucitol), pyranosyl sorbitol, myoinositol and the like.
[0083] The pharmaceutical formulation may also comprise a buffer or
a pH adjusting agent, typically a salt prepared from an organic
acid or base. Representative buffers comprise organic acid salts of
citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric
acid, succinic acid, acetic acid, or phthalic acid, Tris,
tromethamine hydrochloride, or phosphate buffers.
[0084] The pharmaceutical formulation may also include polymeric
excipients/additives, e.g., polyvinylpyrrolidones, celluloses and
derivatized celluloses such as hydroxymethylcellulose,
hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a
polymeric sugar), hydroxyethyl starch, dextrates (e.g.,
cyclodextrins, such as 2-hydroxypropyl-.beta.-cyclodextrin and
sulfobutylether-.beta.-cyclodextrin), polyethylene glycols, and
pectin.
[0085] The pharmaceutical formulation may further include flavoring
agents, taste-masking agents, inorganic salts (for example sodium
chloride), antimicrobial agents (for example benzalkonium
chloride), sweeteners, antioxidants, antistatic agents, surfactants
(for example polysorbates such as "TWEEN 20" and "TWEEN 80"),
sorbitan esters, lipids (for example phospholipids such as lecithin
and other phosphatidylcholines, phosphatidylethanolamines), fatty
acids and fatty esters, steroids (for example cholesterol), and
chelating agents (for example EDTA, zinc and other such suitable
cations). Other pharmaceutical excipients and/or additives suitable
for use in the compositions according to the invention are listed
in "Remington: The Science & Practice of Pharmacy", 19.sup.th
ed., Williams & Williams, (1995), and in the "Physician's Desk
Reference", 52.sup.nd ed., Medical Economics, Montvale, N.J.
(1998), both of which are incorporated herein by reference in their
entireties.
[0086] It should be noted that the methods, systems, and devices
discussed above are intended merely to be examples. It must be
stressed that various embodiments may omit, substitute, or add
various procedures or components as appropriate. For instance, it
should be appreciated that, in alternative embodiments, the methods
may be performed in an order different from that described, and
that various steps may be added, omitted, or combined. Also,
features described with respect to certain embodiments may be
combined in various other embodiments. Different aspects and
elements of the embodiments may be combined in a similar manner.
Also, it should be emphasized that technology evolves and, thus,
many of the elements are examples and should not be interpreted to
limit the scope of the invention.
[0087] Specific details are given in the description to provide a
thorough understanding of the embodiments. However, it will be
understood by one of ordinary skill in the art that the embodiments
may be practiced without these specific details. For example,
well-known processes, algorithms, structures, and techniques have
been shown without unnecessary detail in order to avoid obscuring
the embodiments. This description provides example embodiments
only, and is not intended to limit the scope, applicability, or
configuration of the invention. Rather, the preceding description
of the embodiments will provide those skilled in the art with an
enabling description for implementing embodiments of the invention.
Various changes may be made in the function and arrangement of
elements without departing from the spirit and scope of the
invention.
[0088] Further, the preceding description generally details
aerosolizing liquid drugs. However, it should be understood that
liquids besides liquid drugs may be aerosolized using similar
devices and methods.
[0089] Also, it is noted that the embodiments may be described as a
process which is depicted as a flow diagram or block diagram.
Although each may describe the operations as a sequential process,
many of the operations can be performed in parallel or
concurrently. In addition, the order of the operations may be
rearranged. A process may have additional steps not included in the
figure.
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