U.S. patent application number 16/399673 was filed with the patent office on 2019-08-22 for dry powder inhalers.
The applicant listed for this patent is Adamis Pharmaceuticals Corporation. Invention is credited to Herbert C. Chiou, Michael K. Domroese, Peter D. Hodson, Thomas S. Robison, Stephen W. Stein, Blake D. Walburg, Zhaolin Wang.
Application Number | 20190255265 16/399673 |
Document ID | / |
Family ID | 43126731 |
Filed Date | 2019-08-22 |
United States Patent
Application |
20190255265 |
Kind Code |
A1 |
Hodson; Peter D. ; et
al. |
August 22, 2019 |
DRY POWDER INHALERS
Abstract
Dry powder inhalers and dry powder inhaler storage cassettes
including a compartment housing an elongate carrier preloaded with
a plurality of doses of finely divided powder comprising a
biologically active substance, the compartment being configured
such that said preloaded doses are sealed within said compartment
and such that the carrier may be advanced from the compartment to
the chamber through an exit provided with a moisture barrier
sealing system, wherein the moisture barrier sealing system is
configured and arranged such that it is relaxable during
advancement of the carrier, said sealing system being in sealing
configuration prior to an advancement of the carrier, relaxed upon
an advancement of the carrier and returned to its sealing
configuration at the latest after release of the powder associated
with said area of the carrier.
Inventors: |
Hodson; Peter D.;
(Bracknell, GB) ; Stein; Stephen W.; (Saint Paul,
MN) ; Chiou; Herbert C.; (Saint Paul, MN) ;
Wang; Zhaolin; (Nanjing, CN) ; Robison; Thomas
S.; (Saint Paul, MN) ; Domroese; Michael K.;
(Saint Paul, MN) ; Walburg; Blake D.;
(Minneapolis, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Adamis Pharmaceuticals Corporation |
San Diego |
CA |
US |
|
|
Family ID: |
43126731 |
Appl. No.: |
16/399673 |
Filed: |
April 30, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15276521 |
Sep 26, 2016 |
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16399673 |
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14622617 |
Feb 13, 2015 |
9474870 |
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15276521 |
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13320762 |
Jan 13, 2012 |
8985102 |
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PCT/US2010/035280 |
May 18, 2010 |
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14622617 |
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61179220 |
May 18, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 15/0055 20140204;
A61M 15/0021 20140204; A61M 2205/0216 20130101; A61M 2205/0238
20130101; A61M 15/0025 20140204; A61M 15/0008 20140204; A61M
15/0045 20130101; A61M 2205/19 20130101; A61M 15/0026 20140204;
A61M 15/0005 20140204; A61M 15/0051 20140204; A61M 15/0065
20130101; A61M 2202/064 20130101; A61M 15/0043 20140204; A61M
15/0091 20130101; A61M 15/0096 20140204 |
International
Class: |
A61M 15/00 20060101
A61M015/00 |
Claims
1. A storage device for storing dry powder for use in a dry powder
inhaler, the device comprising: an elongate carrier preloaded with
a plurality of doses of finely divided powder comprising a
biologically active substance, the powder being releasably retained
on a surface of the carrier; a first clamping system and a second
clamping system, wherein the device is configured and arranged such
that during use in a dry powder inhaler wherein a portion of the
carrier is advanced so that the powder associated with an advanced
area can be released from the carrier for inhalation by the patient
through the patient port of the inhaler, the first and second
clamping systems will be moved into a clamping configuration at
least prior to release of the powder associated with the area of
the carrier, so that the area of the carrier will be clamped
between the first and the second clamping systems during release of
the powder associated with the area of the carrier, and wherein the
device further comprises a moisture barrier sealing system, wherein
the device is configured and arranged such that during use in a dry
powder inhaler, the first and second clamping systems are movable,
the clamping systems being moved into a clamping configuration at
least prior to release of the powder associated with the area of
the carrier and such that the area of the carrier will be clamped
between the first and second clamping systems and the moisture
barrier sealing system during release of the powder associated with
the area of the carrier.
2. The storage device of claim 1, wherein the clamping system is
configured and arranged so that when the carrier is being advanced,
the first and second clamping systems are out of their clamping
configuration.
3. The storage device of claim 2, wherein the moisture barrier
sealing system comprises a seal.
4. The storage device of claim 3, wherein the seal comprises a
material having a Shore A durometer value equal to or less than 75
and equal to or greater than 35; and wherein the seal comprises an
elastomeric material, selected from the group consisting of
silicone rubber, EPDM, polypropylene blends, styrene-isoprene
copolymers, combinations and mixtures thereof.
5. The storage device of claim 4, wherein the moisture barrier
sealing system comprises a seal coupled to a moveable member that
is engages with a spring, the spring urging the moveable member in
a first direction such that the moisture barrier seal seals the
compartment exit, and wherein upon advancement of the carrier under
the tension associated with the advancement of the carrier the
moveable member moves in the opposite direction, so that the
moisture barrier seal disengages, and wherein upon cessation of
advancement of the carrier, the moveable member moves in its
original direction under the force of the spring, so that the
moisture barrier seal creates a seal, in particular wherein the
movement of the moveable member comprises a substantially
rotational or linear movement.
6. The storage device of claim 1, wherein the device is configured
to be inserted into the dry powder inhaler.
7. The storage device of claim 1, wherein the storage device is
removable from the dry powder inhaler.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 15/276,521, filed Sep. 26, 2016, which is a continuation of
U.S. application Ser. No. 14/622,617, filed Feb. 13, 2015, which is
continuation of U.S. application Ser. No. 13/320,762, filed Jan.
13, 2012, which is the U.S. national phase of International
Application No. PCT/US2010/035280, filed May 18, 2010, which claims
the benefit of U.S. Provisional Application No. 61/179,220, filed
May 18, 2009. The disclosures of each of these applications are
hereby incorporated herein by reference.
FIELD
[0002] This invention relates to dry powder inhalers as well as to
cassettes, such as removable and/or re-fill supply cassettes, for
use in dry powder inhalers.
BACKGROUND
[0003] Asthma and other respiratory diseases have long been treated
by the inhalation of appropriate medicaments. For many years the
two most widely used and convenient choices of treatment have been
the inhalation of medicament from a drug solution or suspension in
a pressurised metered dose inhaler (pMDI), or inhalation of
powdered drug, generally admixed with an excipient, from a dry
powder inhaler (DPI). Following strong concern about the link
between depletion of the earth's ozone layer and chlorofluorocarbon
(CFC) emissions, the use of these materials in pressurised inhalers
is being phased out and interest in DPI systems has been
stimulated.
[0004] Quite a number of DPI systems or components for DPI systems
have been described including those described in, for example, GB
2242134 (Davies et al.), U.S. Pat. No. 5,192,548 (Velasquez et
al.), U.S. Pat. No. 5,619,984 (Hodson et al.), U.S. Pat. No.
5,657,748 (Braithwaite), WO 98/41255 (Jennings et al.), WO 01/21238
(Seppala), and US 2006/0081246 (Goede et al.).
[0005] In practice most DPIs use either bulk powder reservoirs or
individual pre-measured doses sealed within individual containers
in the form of capsules or blisters, such as blister packs and
blister strips.
[0006] There are, however, problems associated with accurately
metering a measured small quantity (e.g., 500 micrograms or less)
of powder from a bulk reservoir within an inhaler. With many drugs,
e.g., potent drugs, this introduces the necessity to add
excipients, such as lactose powder, to significantly increase the
quantity of powder to be metered. Such excipients are however
generally undesirable as they can pose subsequent powder
deagglomeration problems and can cause dryness and other unwanted
effects in the patient's mouth.
[0007] Furthermore, ingress of moisture (ambient moisture and/or
moisture from a patient's breath e.g., inadvertently exhaled into
the inhaler) into e.g., the bulk powder reservoir can pose a
serious problem. Many biologically active substances, such as
medicaments, delivered by inhalation are susceptible to physical or
chemical change and/or degradation in the presence of moisture
vapor. For example, the powdered particles may re-crystallize in
the presence of adsorbed moisture vapor, which may lead to an
effective increase in the median particle size of the powdered
material, which in turn may lead to reduced penetration of the
particles into relevant delivery sites in the lung, e.g., the lower
airway passages in the lung.
[0008] DPIs where the powder supply, e.g., powdered medicament, is
provided in the form of capsules or blisters generally have
somewhat better moisture protection, due to the fact that each
individual dose is sealed off, where typically a dose on a carrier
component is covered and sealed with a lid component. The
manufacturing of such capsules, blister packs or blister strips,
including accurately metered, small quantities of powder per
capsule/blister for use in a DPI, can be difficult and/or quite
expensive. Furthermore, DPIs using such a powder supply normally
require complex mechanisms for opening the individually sealed
capsules or blisters (e.g., mechanisms for peeling the lid off,
puncturing the capsule/blister, etc.).
SUMMARY
[0009] According to one aspect of the present invention there is
provided a dry powder inhalation device comprising: a chamber; a
patient port in communication with said chamber; a compartment
housing an elongate carrier preloaded with a plurality of doses of
finely divided powder comprising a biologically active substance,
said powder being releasably retained on a surface of the carrier,
said compartment being configured such that said preloaded doses
are sealed within said compartment and such that the carrier may be
advanced from the compartment to the chamber through an exit
provided with a moisture barrier sealing system; an advancement
mechanism for advancing a portion of the carrier from the
compartment to within the chamber so that the powder associated
with an advanced area of the carrier can be released from the
carrier for inhalation by the patient through the patient port;
wherein the moisture barrier sealing system is configured and
arranged such that it is relaxable during advancement of the
carrier, said sealing system being in sealing configuration prior
to an advancement of the carrier, relaxed upon an advancement of
the carrier and returned to its sealing configuration at the latest
after release of the powder associated with said area of the
carrier.
[0010] Such a dry powder inhalation device is advantageous in that
it provides effective protection against moisture and moisture
ingress, while at the same time allowing the provision of a carrier
preloaded with finely divided powder to provide a plurality of
doses, without the necessity of having to provide individual doses
and to hermetically seal each of these individual doses. In other
words the finely divided powder does not need to be pre-metered
into doses and the carrier need not be covered and sealed with a
lid component, such as a foil lid layer component, since the
moisture barrier sealing system advantageously returns to its
sealing configuration at the latest after release of the powder
associated with the advanced area of the carrier prior to
advancement of the next portion of the carrier.
[0011] Protection against moisture and moisture ingress can be
further facilitated in certain favorable embodiments in which the
moisture barrier sealing system is configured and arranged such
that the sealing system is returned to its sealing configuration at
least prior to release of the powder associated with said area of
the carrier. Protection against moisture and moisture ingress can
be yet further enhanced in certain particularly favorable
embodiments in which the moisture barrier sealing system is
configured and arranged such that the sealing system is returned to
its sealing configuration upon cessation of advancement of the
carrier. The latter mentioned embodiments are particularly
advantageous in that the moisture barrier sealing system may
generally and advantageously work in a "dead man's handle" manner
wherein a seal is applied to the supply compartment exit whenever
the carrier is not being advanced, i.e. the moisture barrier
sealing system generally operates such that it returns
automatically to its sealing configuration as soon as advancement
of the carrier stops. (Under the phrases such as "sealing system
returns" or "sealing system is returned" as used herein it will be
understood that the sealing system may return on its own accord or
through the action of a separate mechanism/element.)
[0012] The compartment may be favorably provided within a cassette
that is reversibly removable from the dry powder inhaler. Such a
cassette can be in itself advantageous in that it can be used as a
powder storage and/or supply unit, e.g., an original supply unit
and/or a re-fill supply unit, for a dry powder inhaler.
[0013] According to a second aspect of the present invention there
is provided a device for storing dry powder for use in a dry powder
inhaler, said device provided in the form of a cassette comprising:
a compartment housing an elongate carrier preloaded with a
plurality of doses of finely divided powder comprising a
biologically active substance, said powder being releasably
retained on a surface of the carrier; said compartment being
configured such that preloaded doses are sealed within said
compartment and such that the carrier may be advanced from the
compartment to the outside of the compartment through an exit
provided with a moisture barrier sealing system, wherein said
device is configured and arranged such that during use in a dry
powder inhaler wherein a portion of the carrier is advanced so that
the powder associated with an advanced area can be released from
the carrier for inhalation by the patient through the patient port
of the inhaler, the moisture barrier sealing system is relaxable
during advancement of the carrier, so that said sealing system is
in sealing configuration prior to an advancement of the carrier,
will relax upon an advancement of the carrier and will be returned
to its sealing configuration at the latest after release of the
powder associated with said area of carrier.
[0014] In certain favorable embodiments of devices in accordance
with aspects described above it has been found particularly
advantageous to have the area of the carrier, which has been
advanced into the chamber so that the powder associated with said
area of the carrier can be released from the carrier for inhalation
by the patient through the patient port (referred to in the
following simply as the "dose-release area") be clamped at its
"ends" during release of the powder associated with said area of
the carrier. This double-clamping has been found to be advantageous
in reducing and/or preventing powder from other areas of the
carrier, either behind or ahead of the dose-release area within the
chamber, from being dislodged from the carrier when the powder in
the dose-release area is released, and thus minimizing and/or
preventing build-up of stray powder within the inhaler and
correspondingly allowing for improved reproducibility of the
emitted dose. Accordingly in certain embodiments, devices may
favorably further comprise a first clamping system and a second
clamping system, wherein the systems are configured and arranged
such that they are moved into a clamping configuration at least
prior to release of the powder associated with the dose-release
area, so that the dose-release area will be clamped between the
first and the second clamping systems during release of the powder
associated with the dose-release area. In other words the
dose-release area is positioned between two clamping systems and
clamped by the two systems prior to release of the powder. In other
embodiments, e.g., where the moisture barrier sealing system is
arranged and configured to return to its sealing configuration at
least prior to release of the powder associated with the
dose-release area, the moisture barrier sealing system may
favorably also act as a clamping system. Such embodiments may thus
favorably include a clamping system in addition to the moisture
barrier sealing system, said clamping system being configured and
arranged such that it is moved into a clamping configuration at
least prior to release of the powder associated with the
dose-release area and wherein said clamping system and said
moisture barrier sealing system are configured and arranged
relative to one another such that said area of the carrier will be
clamped between the clamping system and the moisture barrier
sealing system during release of the powder associated with the
dose-release area. In other words the dose-release area is
positioned between the moisture barrier sealing system and a second
clamping system and clamped by the two systems prior to release of
the powder associated with the dose-release area.
[0015] A double-clamping can also be advantageously used in dry
powder inhalers which do not make use of a moisture-barrier sealing
system in accordance with the aforementioned first and second
aspects. Accordingly there is provided in a third aspect of the
present invention a dry powder inhalation device comprising: a
chamber; a patient port in communication with said chamber; an
elongate carrier preloaded with a plurality of doses of finely
divided powder comprising a biologically active substance, said
powder being releasably retained on a surface of the carrier; an
advancement mechanism for advancing a portion of the carrier to
within the chamber so that the powder associated with an advanced
area of the carrier can be released from the carrier for inhalation
by the patient through the patient port; and a first clamping
system and a second clamping system, wherein the first and second
clamping systems are configured and arranged such that they are
moved into a clamping configuration at least prior to release of
the powder associated with said area of the carrier, so that said
area of the carrier will be clamped between the first and the
second clamping systems during release of the powder associated
with said area of the carrier.
[0016] Devices in accordance with the second aspect described
herein, e.g., cassettes, for storing powder for use in a dry powder
inhaler may also comprise an appropriate clamping system or
clamping systems.
[0017] Clamping systems may also be provided in storage devices
that do not include a moisture-barrier sealing system in accordance
with the aforementioned first and second aspects. Thus in a fourth
aspect of the present invention there is provided a device for
storing dry powder for use in a dry powder inhaler, said device
comprising: an elongate carrier preloaded with a plurality of doses
of finely divided powder comprising a biologically active
substance, said powder being releasably retained on a surface of
the carrier; a first clamping system and a second clamping system,
wherein said device is configured and arranged such that during use
in a dry powder inhaler wherein a portion of the carrier is
advanced so that the powder associated with an advanced area can be
released from the carrier for inhalation by the patient through the
patient port of the inhaler, the first and second clamping systems
will be moved into a clamping configuration at least prior to
release of the powder associated with said area of the carrier, so
that said area of the carrier will be clamped between the first and
the second clamping systems during release of the powder associated
with said area of the carrier.
[0018] Dependent claims define further embodiments of the
invention.
BRIEF DESCRIPTION OF DRAWINGS
[0019] The invention will now be described with reference to the
accompanying drawings in which:
[0020] FIGS. 1 to 3 represent partial cross sectional illustrations
of an exemplary dry powder inhaler in its closed position, a
partially open position and its fully opened position,
respectively.
[0021] FIGS. 4 to 7 represent cross sectional illustrations of a
particular region of the exemplary dry powder inhaler in its closed
position, a partially open position and its fully opened position,
as well as at actuation, respectively.
[0022] FIGS. 8 to 11 represent partial cross-sectional
illustrations of an additional particular region of the exemplary
dry power inhaler in its closed position, a partially open
position, a yet further, but not fully opened position and its
fully opened position, respectively.
[0023] FIG. 12 represents a partial cross-sectional illustration of
an additional particular region of the exemplary dry power inhaler
in its sealed position after stopping opening mid-way.
[0024] FIG. 13 represents an isometric view of part of the
compartment of the exemplary dry powder inhaler, showing the supply
spool and the friction brake.
[0025] FIG. 14 represents a partial cross sectional illustration of
the region of the supply spool with the elongate carrier wound on
it, plus the outer component of the friction brake.
DETAILED DESCRIPTION
[0026] It is to be understood that the present invention covers all
combinations of particular, suitable, desirable, favorable,
advantageous and preferred aspects of the invention described
herein.
[0027] FIGS. 1 to 3 represent partial cross sectional illustrations
of an exemplary dry powder inhaler (10) in its closed position, a
partially open position and its fully opened position,
respectively. The inhaler (10) includes a chamber (200) and a
patient port, in particular in the form of a mouthpiece (300), in
communication with said chamber. The patient port is not visible in
FIG. 1, because in the closed position of the illustrated inhaler
the mouthpiece is covered by a cover (301). Only when the user
opens the inhaler for use, i.e. opens the mouthpiece-cover (301) as
shown in FIGS. 2 and 3, does the patient port (300) become visible.
The inhaler (10) also includes an elongate carrier (100) preloaded
with finely divided powder comprising a biologically active
substance (not visible).
[0028] The elongate carrier can be provided in a variety of forms,
such as a tape, web, belt or cord. Desirably the carrier is
provided in the form of a tape or a web. The elongate carrier may
have any ratio of length to width but said ratio is generally
greater than 5 to 1, usually greater than 10 to 1, more
particularly from about 100:1 to about 1000:1. The elongate carrier
may typically have a width of 5 mm to 20 mm, e.g., 10 mm. Its
thickness may typically be from 75 microns to 500 microns,
particularly from 100 microns to 250 microns, more particularly
from about 120 microns to 175 microns. If desired, the elongate
carrier may be provided with a lid component, for example to cover
and/or seal off individual doses. However, such covering and
sealing is generally not needed in embodiments in accordance with
certain aspects of the invention described herein, and thus
accordingly favorably the carrier does not comprise a lid component
covering and sealing off individual doses.
[0029] The powder comprising a biologically active substance,
typically a medicament, is releasably retained on a surface of the
carrier. The powder may be retained on the carrier by attraction
forces, such as electrostatic attraction, van der Waals forces,
physical attraction; mechanical binding; and/or wedging.
Alternatively powder may be retained on the carrier by covering the
powder using a lid component; however as indicated supra it is not
desirable (nor necessary in accordance with certain aspects of the
invention described herein) to use a lid component. To facilitate
favorable release characteristics, it is desirable not to retain
the powder on the carrier via adhesives or glues. The aforesaid
expression "mechanical binding" generally refers to powder
particles being held onto the carrier by intrinsic mechanical means
of the carrier material, e.g., within the entanglement of fibers of
a nonwoven web. The expression "wedging" generally refers to
loading powder particles within/into particular structures of the
elongate carrier (e.g., micro-depressions provided in a plastic
elongate carrier or porous spaces of a nonwoven elongate carrier).
One or more surfaces of the carrier and optionally the interior of
the carrier may be configured to assist in retaining the particles
of powder.
[0030] A carrier may be constructed from one or more of a wide
range of natural and synthetic materials e.g., polyethylene,
polypropylene, polyester e.g., polyethylene terephthalate,
polytetrafluoroethylene or a co-polymer thereof, ethylene vinyl
alcohol, or cellulose. The materials may be in the form of
non-woven fibrous materials, loose weave materials or fabrics,
materials having a surface pile, films, microporous materials,
microgrooved materials, cords of twisted fibers, or any other
suitable material or composites of more than one material.
Desirably a carrier is constructed of a material or a material
composite where small surface depressions, dimples, grooves,
recesses, interstices, apertures or embossed surface structures
having a typical size of equal to or less than 500 microns in
either depth or height and of greater than 0.1 microns in at least
one other dimension are provided to help to retain the particles of
powder. Various materials for carriers as well as particular forms
of carriers suitable for use herein are disclosed in U.S. Pat. No.
5,619,984 (Hodson et al.), the contents of said patent in its
entirety being incorporated herein by reference.
[0031] The form of the elongate carrier can in part play a role in
the storage format. For example a cord may be conveniently stored
as a coil or wound on a spool, while a tape or web may be for
example folded or wound on a spool. Generally it is favorable for
an elongate carrier to be wound on a spool.
[0032] As shown in the exemplary embodiment illustrated in FIGS. 1
to 3, the carrier (100) may be stored initially on a supply spool
(102) and advanced onto an uptake spool (104) during use of the
inhaler. During use of an inhaler, in general, a portion of the
carrier is advanced to within the chamber so that the powder
associated with an advanced area of the carrier can be and is, upon
actuation, released from the carrier for inhalation by the patient
through the patient port.
[0033] For ease of illustration, as well as of viewing, a total
length of carrier shorter than typical has been shown in FIGS. 1 to
3. The carrier (100), with its preloaded finely divided powder
providing a plurality of doses, is housed within a compartment
(105), with the compartment being configured so that the preloaded
doses are sealed within the compartment and such that the carrier
may be advanced from the compartment to the chamber (200) through
an exit (not quite visible in FIGS. 1 to 3) provided with a
moisture barrier sealing system (110).
[0034] This may be better appreciated in FIGS. 4 to 6, which show a
cross-sectional, detailed view of the region about the compartment
exit and the lower portion of the chamber of the exemplary inhaler,
at positions with the mouthpiece cover closed (prior to an
advancement), partially open (during advancement) and fully open
(prior to powder release) respectively. In the Figures the
compartment (105) is to the left, and the compartment wall (106) is
provided with an exit (107), best seen in FIG. 5, through which the
carrier (100) is advanced. In the closed position shown in FIG. 4,
it can be seen that the moisture barrier sealing system (110) is in
a sealing configuration; in particular a seal (111) is pushing
against the carrier and the outer surface (106a) of the compartment
wall (106), thereby sealing over the exit (107) of the compartment.
As shown in FIG. 5--showing a partially open position--as the user
opens the mouthpiece cover, the sealing system relaxes allowing the
seal (111) to disengage from the compartment outer wall surface
(106a) and the carrier (100) to advance (discussed in more detail
infra). When the user has fully opened the cover, or better said,
when advancement of the carrier has been completed by the user, and
prior to release of powder associated with said advanced area of
the carrier, the sealing system returns to its sealing
configuration where, as can be seen in FIG. 6, the seal (111) is
once again clamped against the carrier (100) and the outer surface
(106a) of the wall (106) of the compartment (105), thereby sealing
over the exit (107) of the compartment.
[0035] In favorable embodiments the moisture barrier sealing system
is configured and arranged such that the sealing system is returned
to its sealing configuration at least prior to release of the
powder associated with the dose-release area of the carrier.
[0036] The moisture barrier sealing system suitably comprises a
seal or seals. The seal(s) typically is that component of the
system which seals over the exit of the compartment when the system
is in its sealing configuration. Suitable materials for a moisture
barrier seal may have a Shore A hardness value equal to or less
than 75, in particular equal to or less than 65 (as determined by
ASTM test number D2249). Suitable materials for a moisture barrier
seal may have a Shore A hardness value equal to or greater than 35,
in particular equal to or greater than 45 (as determined by ASTM
test number D2249). Favorably such a seal is resilient, and thus
most desirably comprises an elastomeric material, such as Silicone
rubber. Preferably a thermoplastic elastomer is used, e.g., EPDM
and polypropylene blends, such as those available under the trade
designation SANTOPRENE, or styrene-isoprene copolymers, such as
those available under the trade designation KRATON. Such elastomers
may be co-molded with another component of the device (such as a
pivoting component discussed infra), and may be selected to have
hardness and compliance to provide for optimal sealing when the
moisture barrier sealing system is in its sealing configuration.
Elastomeric materials or co-molded surface components may be
provided on any or all of the relevant sealing surfaces of the
device (e.g., on all the surfaces that contact the carrier and that
form part of the moisture barrier sealing system). Any or all of
the seal or seals may have a molded profile to allow for the
thickness of the carrier, e.g., the seal may have a slight recess
for the carrier's thickness to sit in. Preferably such a recess
would be slightly shallower than the thickness of the carrier.
[0037] The compliance needed in the seal material is relative, and
will depend on several factors. In particular, the degree of
precision in the (manufactured) parts that determine how precisely
the seal and the compartment exit mate with each other, the
thickness of the seal, the area of the seal that makes contact with
the compartment exit, the resilience of the carrier, the use of
springs and their force, and the degree of moisture protection
required may all influence the selection of an optimal seal
material. In certain instances the seal and compartment may mate
sufficiently well so that a non-elastomeric seal material may
provide satisfactory sealing and protection from moisture ingress.
Suitable non-elastomeric seal materials include plastics, such as
polyethylene, polypropylene, and acrylonitrile-butadiene-styrene
(ABS). In one embodiment the seal and another component of the
device (such as a pivoting component) may be integrally formed from
a single plastic material. In another embodiment, said device
component (e.g., a pivoting component) may be made of any resilient
thermoplastic, such as ABS, and an elastomeric seal may be placed
or molded onto said component.
[0038] The compartment may advantageously house a desiccator. The
desiccator may be favorably provided in the form of a cartridge
containing a water and/or moisture adsorbing material. Such water
and/or moisture adsorbing materials are well known and may include
activated alumina, aerogel, benzophenone, bentonite clay, calcium
chloride, calcium hydride, calcium sulfate, copper (II) sulfate,
lithium chloride, lithium bromide, magnesium nitrate, magnesium
sulfate, magnesium perchlorate, molecular sieve(s), potassium
carbonate, silica gel, sodium chlorate, sodium sulfate, sodium
benzophenone. The use of such a desiccator can be easily seen in
the illustrations of the exemplary embodiment in FIGS. 1 to 3, as
component 108.
[0039] Favorably, the compartment is configured so that the
relative humidity within the compartment is maintained at a level
of about 75% or lower, more favorably 65% or lower, most favorably
60% or lower, over a period of thirty (30) days. Thirty days is a
typical duration of intended patient use of a device described
herein (i.e. after the patient has removed the device from any
secondary packaging, such as a sealed pouch, and up to and
including the last dose taken). For example, for a device
containing 120 doses where two doses would be taken twice a day,
the intended duration of use would be thirty 30 days. In certain
instances, it has been found desirable to maintain the relative
humidity within the compartment at more than a certain minimum
level, in order to minimize and/or prevent unwanted electrostatic
effects. Having regard to the aforesaid ranges, in such instances
it is favorable to maintain a relative humidity (within the
aforesaid ranges) at a level of about 20% or higher, more favorably
25% or higher, most favorably 30% or higher. For certain
embodiments where the compartment may house a desiccator, in some
instances it has been found desirable to pre-condition the
desiccant such that the initial relative humidity in the
compartment is set at a particular desired value. For example it
may be desirable that the set initial relative humidity is near the
low end of the desired and/or necessary relative humidity ranges,
for example in the range of about 20% to about 30%, more favorably
from about 25% to about 35%, still more favorably from about 30% to
about 40%.
[0040] Preferably the compartment includes a single exit, i.e. the
exit through which the elongate carrier will be advanced is the
only opening in the compartment.
[0041] The compartment may be made by injection moulding a
thermoplastic material such as high density polyethylene or a
cyclic olefin copolymer. In one embodiment, the supply spool (102)
with elongate tape (100) and the desiccator (108) may be loaded
into the base of the compartment (105) and the tape threaded so
that it is attached to the uptake spool (104). The compartment may
then be closed by heat sealing a foil laminate lid (not shown) to
the top of the compartment wall (106), thereby completely closing
the compartment apart from at its exit (107). In an alternative
configuration, the lid may be a molded plastic component that is
sealed onto the top of the compartment wall, e.g., by ultrasonic
welding, thermal welding, or adhesive bonding.
[0042] Desirably at least a part of, or most desirably all of, the
walls of the compartment are made of a material and/or are
configured such that said wall(s) provide a water vapor barrier. In
particular it is desirable that said wall(s) have a water vapor
transmission rate (WVTR) less than 12 g/(m.sup.2 day) (38.degree.
C., 90% RH), more desirably a WVTR equal to or less than 6
g/(m.sup.2 day) (38.degree. C., 90% RH), even more desirably a WVTR
equal to or less than 3 g/(m.sup.2 day) (38.degree. C., 90% RH),
and most desirably a WVTR equal to or less than 1 g/(m.sup.2 day)
(38.degree. C., 90% RH).
[0043] WVTR may be measured in accordance with a gravimetric method
such as ASTM E96/E96M-05, procedure E, desiccant method at
38.degree. C./90% relative humidity.
[0044] Favorably, at least a part of, or more favorably all of, the
walls of the compartment are made of a material comprising a low
water vapor (moisture) permeability material, in other words a
vapor barrier material. A vapor barrier material can be described
as a material that, when such material has a thickness of 100
microns, has a water vapor transmission rate (WVTR) less than 12
g/(m.sup.2 day) (38.degree. C., 90% RH), in particular a WVTR equal
to or less than 6 g/(m.sup.2 day) (38.degree. C., 90% RH); more
particularly a WVTR equal to or less than 3 g/(m.sup.2 day)
(38.degree. C., 90% RH); and most desirably a WVTR equal to or less
than 1 g/(m.sup.2 day) (38.degree. C., 90% RH).
[0045] Said compartment wall(s) may be made of a single material
(e.g., a vapor barrier material) or alternatively a combination of
materials (e.g., different vapor barrier materials provided
region-by-region or provided as a combination of layers in a wall,
or alternatively vapor barrier material(s) in combination with
other materials). As an example of the second mentioned
alternative, the back wall and side walls may be made of a
polymeric vapor barrier material (such as high density polyethylene
(HDPE)), and the front wall (lid) may be made of a metal foil (such
as aluminum foil or a laminated foil comprising one or more
metallic layers). In another example the wall(s) of the compartment
may be made of two or more layers, each layer providing different
impermeability characteristics. For example, for medicament that is
sensitive to long-term exposure to oxygen it may be favorable to
use a material that provides desirable oxygen barrier
characteristics (such as ethylene vinyl alcohol, nylon 6, nylon 66,
polyvinylidene chloride, polyvinyl acetate) in conjunction with a
material that provides desirable vapor barrier characteristics but
typically does not provide favorable oxygen barrier characteristics
(such as high density polyethylene (HDPE)). Alternatively, wall(s)
of the compartment may comprise two or more layers e.g., for ease
of manufacturing, and/or for stability. For example, wall(s) of the
compartment may be made of an aluminum foil laminated to a suitable
polymer layer or alternatively sandwiched between two appropriate
polymer layers or alternatively aluminum may be deposited onto an
appropriate polymer layer (e.g., creating a metalized polyethylene
terephthalate layer or metalized nylon layer) or alternatively two
metalized plastic layers (e.g., aluminum deposited on polyethylene
or polypropylene) may be laminated together with the metalized
surfaces facing each other. Another alternative is the lamination
of a polymeric vapor barrier layer onto another polymeric layer
inter alia for strength. In addition, wall(s) of the compartment
may comprise an outer layer made of a vapor barrier material and an
inner layer comprising a desiccant material. This could be done,
for example, using a two-shot molding process where the outer layer
is a polymer with low vapor transmission rate (e.g., HDPE,
polypropylene (PP), or a cyclic olefin copolymer) and the inner
layer is a desiccating polymer (e.g., Nylon), or alternatively the
outer layer could be made of a polymeric vapor barrier material,
whose interior surface is lined with a nonwoven embedded with
desiccant particles. In regard to the latter the material of the
desiccant particles can be selected from the aforesaid list of
materials. Additional examples of combinations include a blending
of a vapor barrier material (e.g., PE) with another material (e.g.,
ethylene-vinyl acetate (EVA))
[0046] Suitable vapor barrier materials may include metal foil, in
particular aluminum foil have a thickness of at least 8 microns,
more particularly at least 10 microns, even more particularly at
least 15 microns, most particularly at least 25 microns. The
desired and/or necessary thickness depends on how the foil is used.
For example aluminum foil laminated between layers of polymeric
vapor barrier layers may only need to be 8 microns thick, while for
plain aluminum foil it may be desirable and/or necessary to use a
foil having a thickness of 25 microns or more. The lid may
desirably be 80 microns thick, including an aluminum foil layer of
8 microns sandwiched between layers of low density polyethylene and
with an outer coating of polyethylene terephthalate. Other suitable
vapor barrier materials may include coatings, such as deposited
aluminum coatings (in particular having a thickness of at least 0.1
microns), deposited silicon oxide coatings (in particular having a
thickness of at least 0.04 microns), deposited diamond-like glass
coatings (such coatings, and methods to produce such coatings, are
described in U.S. Pat. No. 6,696,157 (David et al.) the content of
which is incorporated here in its entirety). Further suitable vapor
barrier materials may include polymeric materials such as
polyvinylchloride (hard or plasticized, in particular hard PVC);
ethylene vinyl alcohol (in particular ethylene vinyl alcohol having
a high ethylene content, more particularly an ethylene content of
at least 30%); polyacrylonitrile; polyethylene terephthalate;
polyethylene naphthalate; polyolefins (in particular polypropylene,
copolymers of polypropylene with polyethylene, biaxially orientated
polypropylene; polyethylene (including low density polyethylene
(density equal to or less than 0.925 g/cm.sup.3)), linear low
density polyethylene, medium density polyethylene (density greater
than 0.925 g/cm.sup.3 and less than or equal to 0.94 g/cm.sup.3),
high density polyethylene (density greater than 0.94 g/cm.sup.3);
cyclic olefin copolymers (e.g., such as those commercially
available under the trade designation TOPAS); poly-vinylidene
chloride; polychlortrifluorethylene; and liquid crystal polymers.
Among polyethylenes, high density polyethylenes are particularly
advantageous as a vapor barrier material. Polymers, in particular
polyolefins (including low density polyethylene, linear low density
polyethylene, medium density polyethylene, high density
polyethylene, polypropylene, biaxially orientated polypropylene)
produced using metallocene catalysts are favorable in that the use
of such catalysts generally allows for the production of polymers
having narrower molecular weight distributions than does the use of
more traditional Zeigler-Natta catalysts, and thus allows for a
better, tighter control over composition and in turn vapor barrier
characteristics.
[0047] As applicable, walls of the compartment or parts of walls
may be produced via injection molding (e.g., single shot or
multi-shot molding) as well as other methods including
co-extrusion, extrusion lamination, vacuum metallization, or a
combination of methods as desired and/or needed.
[0048] It may be desirable, depending on the choice of wall
material(s) and the particular medicament(s), to provide at least a
part of or, more desirably all of, the walls of the compartment
with a greater thickness than commonly used in such devices,
without adding so much material as to make the device unwieldy. In
particular, for wall materials that are not foil-based (e.g., not
metal-foil-based, nor polymer and metal-foil laminate based), it
may be desirable to provide at least a part of, or more desirably
all of, the walls of the compartment with a thickness of greater
than or equal to about 500 microns, more desirably greater than or
equal to about 1000 microns, most desirably greater than or equal
to about 1250 microns. It is also desirable to provide at least a
part of, or more desirably all of, the walls of the compartment
with a thickness of less than or equal to 4 mm, more desirably less
than or equal to 3 mm, most desirably less than or equal to 2
mm.
[0049] As mentioned above the compartment may be favorably provided
within a cassette that is reversibly removable from the dry powder
inhaler. Such a cassette would favorably include also an uptake
spool, so that the user can easily insert the cassette into the dry
powder inhaler and/or easily remove the cassette. For long storage
as an original and/or a re-fill supply unit, the cassette may be
sealed in a container, such as a pouch.
[0050] FIG. 7 is an illustration of the region about the
compartment exit and the lower portion of the chamber of the
exemplary inhaler at the point of actuation, i.e. where powder
associated with the dose-release area is released from the carrier
for inhalation by the patient through the patient port.
[0051] Various means for releasing powder from an area of carrier
independent of the patients' inspiratory effort are known. A number
of such means are disclosed in U.S. Pat. No. 5,619,984 (Hodson et
al.), including systems providing mechanical effort, e.g.,
impaction, vibrations, gas flow etc., or electrostatically. The
means for releasing powder from the carrier during inhalation is
favorably triggered in response to the patient inhaling, in order
to avoid the patient having to synchronise actuation of the release
mechanism with inhalation. Airflow detection may conveniently be
accomplished by means of a movable vane positioned within the
chamber or patient port, motion of the vane causing actuation of
the release mechanism.
[0052] In the exemplary embodiment, the release of powder is
triggered in response to the patient inhaling. In particular, upon
inspiration by the user a movable vane (not visible; an outer
portion of a vane positioning pin (201) can be seen in FIGS. 1 to
3) within the chamber releases a trigger mechanism (not visible)
that in turn releases a hammer (205; visible in FIGS. 4 to 7). The
hammer then strikes the carrier (100), so that the powder (90)
associated with the dose-release area is released into the chamber
(200) (as illustrated in FIG. 7).
[0053] It has been found particularly advantageous to have the
dose-release area of the carrier (i.e. that area of the portion of
the carrier that has been advanced to within the chamber for powder
release) be clamped between a first and a second clamping system.
As mentioned above, by clamping the area of the carrier to be
impacted between two clamping systems, during actuation, it is
possible to reduce and/or prevent powder from other areas of the
carrier (i.e. those areas either behind or ahead of the intended
dose-release area) from being dislodged when the powder associated
with the dose-release area is released. This advantageously allows
for improved reproducibility of the emitted dose.
[0054] The double clamping can be achieved by providing a first
clamping system and a second clamping system, wherein the first and
second clamping systems are configured and arranged such that they
are moved into a clamping configuration at least prior to release
of the powder associated with the dose-release area, so that said
area of the carrier will be clamped between the first and the
second clamping systems during release of the powder associated
with said area of the carrier. As mentioned supra, an aspect of the
present invention includes dry powder inhalers which include such a
double clamping system, but do not make use of a moisture-barrier
sealing system. Also as mentioned supra, certain embodiments in
accordance with certain other aspects of the present invention
include inhalers and/or cassettes including such a double clamping
system in addition to a moisture barrier sealing system.
[0055] For certain embodiments of inhalers and/or cassettes in
accordance with the present invention that include a moisture
barrier sealing system that is configured and arranged such that
the sealing system is returned to its sealing configuration at
least prior to release of the powder associated with the
dose-release area, the double clamping can be achieved in an
alternative way, i.e. where the moisture barrier sealing system
acts as a clamping system. Such embodiments would include a
clamping system in addition to the moisture barrier sealing system,
said clamping system being configured and arranged such that it is
moved into a clamping configuration at least prior to release of
the powder associated with the dose-release area and wherein said
clamping system and said moisture barrier sealing system are
configured and arranged relative to one another such that said
dose-release area will be clamped between the clamping system and
the moisture barrier sealing system during release of the powder
associated with the dose-release area. In other words the
dose-release area is positioned between the moisture barrier
sealing system and a second clamping system and is clamped by the
two systems prior to dose release.
[0056] This latter alternative may be better appreciated by looking
at the exemplary embodiment. As described in conjunction with FIGS.
4 to 6, the moisture barrier sealing system (110), in particular
its seal (111), in its sealing configuration seals the exit (107)
of the compartment (105) and at the same time clamps the carrier
(100) against the wall (106) of the compartment (105), between the
seal (111) and the outer surface (106a) of the compartment wall
(106). See e.g., FIGS. 6 and 7 in comparison to FIG. 5. So in the
exemplary embodiment the moisture barrier sealing system also acts
as a clamping system. The exemplary embodiment includes an
additional clamping system (125), where in its clamping
configuration (see again FIGS. 6, and 7 in comparison to FIG. 5),
the carrier (100) is clamped via a grip (126) of the clamping
system (125) against the outer surface (202a) of the chamber wall
(202). Referring to FIG. 7, it will be appreciated that the area of
carrier (100) that was advanced to within the chamber (200) is
clamped between the two systems. In this embodiment the leading end
of said area is clamped by the grip (126) of the clamping system
and the trailing end by the seal (111) of the moisture barrier
sealing system. When the hammer (205) strikes the carrier (100) to
release the powder (90) associated with the area of the carrier
that is positioned between the clamps, transfer of energy from that
area of the carrier to other areas of the carrier (areas ahead or
behind the area of the carrier within the chamber that is intended
for dose release when impaction by the hammer occurs) is minimized
and/or prevented. In this manner, unwanted release of powder from
areas of the carrier still within the supply compartment (105) may
be minimized and/or prevented, as may unwanted release of any
residual and/or remaining powder from areas of used carrier already
in the uptake area.
[0057] In the exemplary embodiment, the second clamping system
(125) is formed as an extension (118) of a pivoting component (112)
that is used in the moisture barrier sealing system (110).
[0058] Here reference is made to FIGS. 8 to 11 showing a partial
cross-sectional, detailed view (now without the cover) of the
region including the supply and uptake spools, compartment exit and
flow chamber of the exemplary inhaler at closed (FIG. 8), partially
open (FIG. 9), between partially & fully open (FIG. 10) and
fully open (FIG. 11) positions, respectively. (FIGS. 8, 9 and 11
correspond to FIGS. 1, 2, and 3, respectively, as well as to FIGS.
4, 5 and 6, respectively.)
[0059] The pivoting component (112) has a front-plate (113) with a
quasi triangular structure (see e.g., FIGS. 8 to 11) and a
quasi-V-shaped rib back-structure (114) plus a pin-like structure
(115) onto which the seal (111) is affixed (see FIGS. 4 to 7). One
end of the aforementioned quasi-V-shaped rib back-structure (the
one distal to the seal (111)) provides the grip (126) of the
clamping system. The other end is provided in the form of a partial
cylinder (116). The pivoting component (112) is held in place by a
pin (not visible) that protrudes from the back of the partial
cylinder (116), the pin being retained within a suitable
cylindrical hole in the main frame or chassis of the inhalation
device. The partial cylinder (116) is positioned within a "socket"
in the curve of the compartment wall (106). There is clearance
between the partial cylinder (116) and the "socket", and as can be
seen in the Figures the partial cylinder "rotates/pivots" in the
"socket". Moreover, comparing FIGS. 8 to 11 it can be seen that the
pivoting component (112) pivots about an axis (P) generally
perpendicular to the front-plate (113), the axis (P) falling within
the partial cylinder (116) near but spaced apart from the seal
(111). (Relative to the printed illustration the axis (P) is
perpendicular to the page of the illustration and is to the left
and below the seal.)
[0060] As can be best seen in FIGS. 4 to 7 the exemplary embodiment
includes a post (120) and a torsional spring (121). The post (120)
is positioned near the quasi-V-shaped rib back-structure but on the
far side relative to the seal (111). The torsional spring (121)
engages portions of the back-structure (114) of the pivoting
component (112) and provides force onto said pivoting component
such that the seal (111) is biased towards its sealing
configuration, sealing off the exit (107) of the compartment (105).
Comparing for example FIGS. 4 and 5, it can be recognized that the
torsional spring (121) is providing a substantially
counterclockwise force on to the pivoting component. The pivoting
action of the pivoting component is limited by providing a slot
(117) in the front-plate structure and having one end of the post
(120) extending through the slot. With reference to FIG. 8--the
closed position of the exemplary inhaler--the post (120) is located
adjacent to the bottom of the slot (117), the seal (111) is sealing
off the exit (107) and at the same time clamping the carrier (100)
against the outer surface of the compartment, and the portion of
the carrier near and around (100a) the uptake spool (104) is
slack.
[0061] As the user opens the mouthpiece cover (301 in FIGS. 1 to 3)
of the exemplary inhaler, as can be seen in FIG. 9--the partially
open position of the mouthpiece cover--the uptake spool turns in a
clockwise direction and the outer turn of carrier about the uptake
spool is drawn tight. The newly created tension of the carrier
(100), and thus force, against the end of the upper extension/grip
(118; visible in FIG. 9/126; not visible in FIG. 9) of the pivoting
component (112) (in particular against the end of the upper portion
of the back structure, referred to above as the grip (126))
overcomes the force from the torsional spring (121), thus causing
the pivoting component (112) to rotate in a substantially clockwise
direction, and at the same time causing the moisture barrier
sealing system to relax (move out of its sealing configuration)
thereby causing the exit (107) of the compartment (105) to be
unsealed. With reference to FIG. 9, the post (120) is adjacent to
the top of the slot (117), the seal (111) has shifted slightly
clockwise and downward, the carrier is advancing over the seal
(111) and over the grip (126, not visible) and the uptake spool has
rotated clockwise by about 90-100 degrees from its illustrated
position in FIG. 8 to its illustrated position in FIG. 9. The
latter is best seen and understood through reference to the
movement of a quasi-semi-circular cam feature (145) on the forward
ratchet (144) on the uptake spool (104), which indicates that said
uptake spool has rotated clockwise by about 90-100 degrees.
[0062] As the user continues to open the mouthpiece cover (301) of
the exemplary inhaler to a position between partially open and
fully open--as can be seen in FIG. 10--the uptake spool continues
to turn in a clockwise direction and the aforementioned cam (145)
on the forward ratchet (144) begins to engage a heel (119) of the
pivoting component (112), thereby urging the pivoting component to
rotate/pivot counter-clockwise and moving the grip (126) of the
clamping system (125) towards the chamber wall (202). Finally as
the user opens the mouthpiece cover (301) completely (to the fully
open position as illustrated in FIG. 11), the grip (126) of the
clamping system (125) is at last fully engaged with the carrier
(100)/chamber wall (202) (i.e. clamping the carrier (100) against
the outer surface (202a) of the chamber wall (202)) and the seal
(111) of the moisture barrier system is engaged with the carrier
(100)/compartment wall (106) (i.e. clamping the carrier (100)
against the outer surface (106a) of the compartment wall (106)), so
that the dose-release area is clamped between the seal (111) and
the grip (126). The presence of an elastomeric seal (111) in the
moisture barrier sealing system (110) enables this seal (111) to
seal against the surface (106a) of the compartment wall (106)
before the grip (126) of the clamping system (125) fully seals
against the surface (202a) of the chamber wall (202). The use of
cam (145) and its engagement against the heel (119) of the pivoting
component (112) facilitates the sealing of the grip (126) against
the chamber wall (202). The exemplary inhaler is now ready for
release of the powder associated with the dose-release area (said
release already having been described in conjunction with FIG.
7).
[0063] In alternative embodiments, the pivoting component (112) may
be substituted by a component that moves linearly to clamp and
unclamp the carrier, said component being located and arranged in
any suitable manner that will be apparent to one skilled in the art
who has studied the present disclosure and exemplary
embodiment.
[0064] A clamping system may comprise a grip or grips. Desirably
such grip(s) have a form and comprise a material suitable for
appropriately clamping the carrier. Suitable materials for a
clamping system grip may have a Shore A hardness equal to or less
than 85, in particular equal to or less than 75 (as determined by
ASTM test number D2249). Suitable materials for a clamping system
grip may have a Shore A hardness equal to or greater than 35, in
particular equal to or greater than 45 (as determined by ASTM test
number D2249). A grip may be made of the same material as another
(e.g., pivoting) component, so that it is contiguous with that
component. Alternatively, a grip may comprise an elastomeric
material, e.g., an elastomeric grip component affixed to the
pivoting component in much the same way as the moisture barrier
seal is affixed to the pivoting component. As other options, the
grip may be 2-shot molded to the pivoting component. Since it is
believed that one of the functions of the double clamping is to
prevent or reduce vibrations of the carrier, by absorbing some or
all of their energy, which occur during release of powder from the
dose-release area, from being transferred to regions of the carrier
outside the dose-release area, this may be facilitated by using an
elastomeric material (in particular such a material having a lower
Shore A hardness value e.g., around 35 to 55) for both the grip(s)
and the seal of moisture barrier sealing system, as applicable.
Increasing the distance along the area of the carrier that the
clamps operate could be more effective in damping. However such
parameters would need to be optimized with other performance
considerations for the device, e.g., disturbance of powder by
contact with the clamps and/or the need to advance lengths of
carrier much longer than the length of the dose-release area.
[0065] In particularly favorable embodiments of devices in
accordance with certain aspects described herein the moisture
barrier sealing system is configured and arranged such that the
sealing system is returned to its sealing configuration upon
cessation of advancement of the carrier. The general functioning of
such particularly favorable embodiments may be as follows: whenever
the patient is advancing the carrier by exerting force on a
user-operated advancing element (such as by pulling/holding the
mouthpiece-cover open in the exemplary inhaler; alternative
user-operated advancing elements may include buttons or levers),
the carrier is placed under tension (part of said patient-exerted
force is transmitted via appropriate device components into tension
in the carrier), said tension causing the moisture barrier sealing
system to disengage, opening the compartment exit thereby allowing
carrier to pass easily through the exit. Upon cessation of
advancement of the carrier (in other words as soon as the patient
ceases to exert force on the user-operated advancing element), the
tension in the carrier is relieved or reduced and the carrier goes
slack, causing the moisture barrier sealing system to return to its
sealing position (e.g., under its own accord (e.g., due to elastic
resilience) or under the influence of a separate component (such as
a torsional spring (as in the exemplary inhaler)). Such embodiments
are particular advantageous in that the medicament supply
compartment is only un-sealed wherever it is needed to advance the
carrier, and sealed whenever it does not need to be unsealed to
allow tape advance, said sealing and unsealing being "automatic"
and not compromised by forgetfulness nor confusion on the part of
the patient. Additional benefits of such a sealing arrangement are
that whenever tape is not being advanced the medicament supply
compartment is protected against moisture ingress from the exhaled
breath if that is inadvertently exhaled into the inhaler device,
and also that any drug powder that may come loose from the supply
of tape cannot escape from the medicament supply compartment.
[0066] In the exemplary inhaler described herein, the moisture
barrier sealing system, in particular the seal thereof, is
favorably coupled to a pivoting member that is engaging a spring,
said spring urging the pivoting member in a direction such that the
moisture barrier seal seals the compartment exit, and wherein upon
advancement of the carrier under the tension associated with the
advancement of the carrier the pivoting member rotates in the
opposite direction, so that the moisture barrier seal disengages,
opening the compartment exit thereby allowing carrier to advance
through the exit, and upon cessation of advancement of the carrier,
under the tension of the spring the pivoting member rotates in its
original direction, so that the moisture barrier seal seals the
compartment exit.
[0067] FIG. 12 shows a sealed position of the exemplary inhaler
reached by a user who has stopped advancing the carrier (i.e. who
has stopped pulling/holding the mouthpiece-cover (301) open) after
having advanced it partially. Upon letting go of the
mouthpiece-cover, the tension in the carrier (100) has caused the
mouthpiece-cover (301), forward ratchet and uptake spool (104) to
rotate counter-clockwise by about 10 degrees or so. This back
rotation relieves tension in the carrier (100) and creates enough
slack in it for the pivoting component (112) to rotate
counter-clockwise under the force of the torsional spring (121)
until the seal (111) of the moisture barrier sealing system
re-engages with the compartment wall (106) and thus re-seals the
exit slot (107) of the compartment (105).
[0068] As mentioned above, the elongate carrier may be wound on a
spool within the supply compartment. It is desirable that the spool
comprises an anti-unspooling mechanism. An anti-unspooling
mechanism, which could utilize a friction brake, a ratchet system,
or some other mechanism to prevent unspooling of the carrier,
desirably reduces or prevents any rotation of the supply spool not
associated with advancement of the carrier. An anti-unspooling
mechanism also favorably provides resistance to movement of the
elongate carrier while it is being advanced, in particular just
after the moisture barrier sealing system has relaxed. This
resistance to movement facilitates the creation/maintenance of
tension in the carrier during advancement of the carrier.
[0069] Such a mechanism may be best understood by reference to
FIGS. 13 and 14, providing an isometric view of part of the
compartment of the exemplary dry powder inhaler, showing the supply
spool and the anti-unspooling mechanism, in particular a friction
brake, and a partial cross sectional illustration of the region of
the supply spool with elongate carrier wound on it, plus the outer
component of the friction brake, respectively.
[0070] The supply spool (102) has the elongate carrier (100),
preloaded with finely divided powder wound thereon. As can be seen
from FIGS. 13 and 14, the lower part of the supply spool has an
annular flange (151) to retain the carrier and a cylindrical core
(152) around which the elongate carrier is wound. The compartment
(105) has a supply post (153) which provides an axle for the supply
spool (102) to rotate about. The supply post is generally
cylindrical, with a smooth surface. As an alternative, the surface
of the supply post may be splined, with splines arranged uniformly
about the circumference directed parallel to the axis. The interior
(155) of the cylindrical core has an inwardly upwardly directed lip
(156) extending from about half way up and arranged to contact the
supply post to provide an interference with frictional properties
at the contact region (157). The lip has two diametrically opposite
wide slits (158a,b) extending from the contact region (157) part of
the way back to the cylindrical core (152). These slits allow the
lip to pull away from the supply post slightly under the influence
of the interference fit, but be retained by the elastic properties
of the supply spool material. Where the supply post is splined, the
contact region of the lip may also have splines. The two sets of
splines allow the supply spool to rotate on the supply post only
when the post splines push the spool splines back a small amount,
causing the spool to click round in defined small increments during
use. The friction brake is provided by the interference in the
contact region (157) and ensures that the elongate carrier remains
tightly wound on the supply spool during use.
[0071] Finely divided powders used in the devices described herein
generally have a mass median particle diameter typically 10 microns
or less. More suitably, said mass median diameter is 7 microns or
less, even more suitably 5 microns or less, and most suitably said
mass median diameter is in the range 1 to 3 microns, with at least
90% by mass of the particles having diameters below 5 microns.
[0072] The powders may be micronized, e.g., by using a fluid energy
mill driven by compressed air, such as shown in `Drug Delivery to
the Respiratory Tract` ed. D. Ganderton and T. Jones, publ. Ellis
Horwood, Chichester (1987) pages 89-90, or by repeated stepwise
millings or by use of a closed loop milling system.
[0073] As indicated supra, desirably finely divided powder is
filled into a plurality of microdepressions in the surface of an
elongate carrier, in particular a flexible elongate carrier, such
as a web or a tape. Depressions may be suitably spaced at an
interval of about 20 to 2000 microns, more suitably at an interval
of about 300 to 2000 microns. Depressions may suitably number from
about 25 to 1000 per cm.sup.2 of the carrier. The volume of each
depression and the spacing or number of the depressions will depend
upon the particular desired application of the resulting filled
elongate carrier, and in the case of biologically active substances
(e.g., medicaments) the potency of the particular substance and the
area of the carrier material intended to provide a single dose of
the substance. Typically it is desirable that the carrier material
has a substantially uniform depression volume per unit area when
considered on a scale of the area of a single dose or other
functional unit. For example, such a dose area might have 200 to
2000 discrete microdepressions, each of about 45 microns depth and
about 150 microns diameter. Advantageously, the rows of
microdepressions along the longitudinal axis of the elongate
carrier do not lie exactly parallel with the axis, but instead lie
skewed at a small angle (e.g., 0.5.degree. to 2.degree.) to it, in
order to avoid "quantization effects" caused by lateral variability
in the slitting positions. (The skew angle can be chosen
appropriate to the microdepression spacing distance and the desired
slit width, such that an exact total microdepression volume is
present on each (e.g., 20 mm.times.10 mm) dose area, no matter
where slitting occurs, laterally.) Preferably, the microdepressions
are provided by cast embossing of a low density polyethylene (LDPE)
layer using a photolitho-graphically patterned and etched, or a
diamond machined, patterning roller. Suitably the aforesaid LDPE
layer is provided on a paper backing or a paper/LDPE laminate
backing (with the paper between the two LDPE layers).
[0074] Such filled elongate carriers are particularly conveniently
be used in the administration of biologically active substances, in
particular medicaments by inhalation. Moreover, elongate carriers
having microdepressions can be substantially accurately and
uniformly filled with such finely divided powders e.g., through
methods disclosed in WO 2007/112267 (Hodson and Wilby) (the content
of which is incorporated in its entirety by reference), thus
allowing for accurate and uniform release of doses of biologically
active substances.
[0075] For delivery by inhalation, suitable medicaments include any
drug or drug combination that may be administered by inhalation,
that is a solid or that may be incorporated in a solid carrier.
Suitable drugs include those for the treatment of respiratory
disorders, e.g., bronchodilators, anti-inflammatories (e.g.,
corticosteroids) anti-allergics, anti-asthmatics, anti-histamines,
and anti-cholinergic agents. Other drugs such as anorectics,
anti-depressants, anti-hypertensive agents, anti-neoplastic agents,
anti-tussives, anti-anginals, anti-infectives (e.g.,
antibacterials, antibiotics, anti-virals), anti-migraine drugs,
anti-peptics, dopaminergic agents, analgesics, beta-adrenergic
blocking agents, cardiovascular drugs, hypoglaecemics,
immunomodulators, lung surfactants, prostaglandins,
sympathomimetics, tranquilizers, steroids, vitamins and sex
hormones, vaccines and other therapeutic proteins and peptides may
be employed for delivery by inhalation.
[0076] It is preferred for delivery by inhalation that the
medicament employed exhibits a potency which permits a single dose
to be loaded onto the elongate carrier in an area of less than
about 25 cm.sup.2 and preferably less than about 5 cm.sup.2. More
preferred is an elongate carrier containing a drug in such a manner
and of such a type that between 0.25 and 2.5 cm.sup.2, most
preferably between 1.5 and 2.25 cm.sup.2, of the elongate carrier
will contain a single dose when used in a device such as those
described in U.S. Pat. No. 5,408,994 or 5,619,984. Stated
differently, given that a filled elongate carrier may conveniently
carry between about 25 and 500 .mu.g of powder per cm.sup.2, the
potency of the medicament will preferably be such that a single
dose may be carried on the above-stated 0.25 to 2.5 cm.sup.2 of
elongate carrier.
[0077] Exemplary drugs which may be employed for delivery by
inhalation include but are not limited to: albuterol, levalbuterol,
terbutaline, fenoterol, metaproterenol, isoproterenol, isoetharine,
bitolterol, epinephrine, tulobuterol, bambuterol, reproterol,
adrenaline, ipratropium, oxitropium, tiotropium, daratropium,
aclidinium, glycopyrronium, beclomethasone, butixocort,
betamethasone, flunisolide, budesonide, mometasone, ciclesonide,
rofleponide, aminophylline, dyphylline, theophylline, cromolyn
sodium, nedocromil sodium, ketotifen, azelastine, ergotamine,
cyclosporine, salmeterol, fluticasone, formoterol, arformoterol,
procaterol, indacaterol, TA2005 (carmoterol), omalizumab,
montelukast, zafirlukast, betamethasone sodium phosphate,
dexamethasone, dexamethasone sodium phosphate, dexamethasone
acetate, prednisone, methylprednisolone acetate, oglemilast,
zileuton, insulin, atropine, prednisolone, benzphetamine,
chlorphentermine, amitriptyline, imipramine, clonidine, actinomycin
c, bromocriptine, fentanyl, buprenorphine, pentamidine, calcitonin,
leuprolide, alpha-1-antitrypsin, interferons, human growth
hormones, propranolol, lacicortone, triamcinolone, dinoprost,
xylometazoline, diazepam, lorazepam, folic acid, nicotinamide,
clenbuterol, ethinyloestradiol, levonorgestrel, and
pharmaceutically acceptable salts and esters thereof such as
albuterol sulfate, formoterol fumarate, salmeterol xinafoate,
aclidinium bromide, glycopyrronium bromide, beclomethasone
dipropionate, triamcinolone acetonide, fluticasone propionate,
fluticasone furoate, tiotropium bromide, leuprolide acetate and
mometasone furoate.
[0078] Further drugs that may also be delivered by inhalation
include but are not limited to aspirin, acetaminophen, ibuprofen,
naproxen sodium, buprenorphine hydrochloride, propoxyphene
hydrochloride, propoxyphene napsylate, meperidine hydrochloride,
hydromorphone hydrochloride, morphine sulfate, fentanyl citrate,
oxycodone hydrochloride, codeine phosphate, dihydrocodeine
bitartrate, pentazocine hydrochloride, hydrocodone bitartrate,
levorphanol tartrate, diflunisal, naltrexone, oxycodone,
sufentanil, remifentanil, diamorphine, trolamine salicylate,
methadone hydrochloride, nalbuphine hydrochloride, nalorphine,
tetrahydrocannabinol, mefenamic acid, butorphanol tartrate, choline
salicylate, butalbital, phenyltoloxamine citrate, diphenhydramine
citrate, methotrimeprazine, cinnamedrine hydrochloride,
meprobamate, ergotamine tartrate, propanolol hydrochloride,
isometheptene mucate, dichloralphenazone, sumatriptan, rizatriptan,
zolmitriptan, naratriptan, eletriptan, barbiturates (e.g.,
pentobarbital, pentobarbital sodium, secobarbital sodium),
benzodiazapines (e.g., flurazepam hydrochloride, triazolam,
tomazeparm, midazolam hydrochloride, lorazepam, buspirone
hydrochloride, prazepam, chlordiazepoxide hydrochloride, oxazepam,
clorazepate dipotassium, diazepam, temazepam), lidocaine,
prilocaine, xylocaine, beta-adrenergic blockers, calcium channel
blockers (e.g., nifedipine, diltiazem hydrochloride, and the like),
diuretics (e.g., amiloride, furosemide), nitrates (e.g.,
nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate,
erythrityl tetranitrate), hydroxyzine pamoate, hydroxyzine
hydrochloride, alprazolam, droperidol, halazepam, chlormezanone,
haloperidol, loxapine succinate, loxapine hydrochloride,
thioridazine, thioridazine hydrochloride, thiothixene, fluphenazine
hydrochloride, fluphenazine decanoate, fluphenazine enanthate,
trifluoperazine hydrochloride, chlorpromazine hydrochloride,
perphenazine, lithium citrate, prochlorperazine, lithium carbonate,
bretylium tosylate, esmolol hydrochloride, verapamil hydrochloride,
amiodarone, encainide hydrochloride, digoxin, digitoxin, mexiletine
hydrochloride, disopyramide phosphate, procainamide hydrochloride,
quinidine sulfate, quinidine gluconate, quinidine
polygalacturonate, flecainide acetate, tocainide hydrochloride,
lidocaine hydrochloride, phenylbutazone, sulindac, penicillamine,
salsalate, piroxicam, azathioprine, indomethacin, meclofenamate
sodium, gold sodium thiomalate, ketoprofen, auranofin,
aurothioglucose, tolmetin sodium, colchicine, allopurinol, heparin,
heparin sodium, warfarin sodium, urokinase, streptokinase,
altoplase, aminocaproic acid, pentoxifylline, empirin, ascriptin,
valproic acid, divalproate sodium, phenytoin, phenytoin sodium,
clonazepam, primidone, phenobarbitol, phenobarbitol sodium,
carbamazepine, amobarbital sodium, methsuximide, metharbital,
mephobarbital, mephenytoin, phensuximide, paramethadione, ethotoin,
phenacemide, secobarbitol sodium, clorazepate dipotassium,
trimethadione, ethosuximide, doxepin hydrochloride, amoxapine,
trazodone hydrochloride, amitriptyline hydrochloride, maprotiline
hydrochloride, phenelzine sulfate, desipramine hydrochloride,
nortriptyline hydrochloride, tranylcypromine sulfate, fluoxetine
hydrochloride, doxepin hydrochloride, imipramine hydrochloride,
imipramine pamoate, nortriptyline, amitriptyline hydrochloride,
isocarboxazid, desipramine hydrochloride, trimipramine maleate,
protriptyline hydrochloride, hydroxyzine hydrochloride,
diphenhydramine hydrochloride, chlorpheniramine maleate,
brompheniramine maleate, clemastine, azelastine, cyproheptadine
hydrochloride, terfenadine citrate, loratidine, clemastine,
triprolidine hydrochloride, carbinoxamine maleate, diphenylpyraline
hydrochloride, phenindamine tartrate, lamivudine, abacavir,
acyclovir, gancyclovir, valganciclovir, cidofovir, foscarnet,
azatadine maleate, tripelennamine hydrochloride,
dexchlorpheniramine maleate, methdilazine hydrochloride,
trimprazine tartrate, trimethaphan camsylate, phenoxybenzamine
hydrochloride, pargyline hydrochloride, deserpidine, diazoxide,
guanethidine monosulfate, minoxidil, rescinnamine, sodium
nitroprusside, rauwolfia serpentina, alseroxylon, phentolamine
mesylate, reserpine, calcitonin, parathyroid hormone, acitretin,
amikacin sulfate, aztreonam, benzydamine, calcipotriol,
chloramphenicol, chloramphenicol palmitate, chloramphenicol sodium
succinate, ciprofloxacin hydrochloride, clindamycin hydrochloride,
clindamycin palmitate, clindamycin phosphate, efalizumab,
reslizumab, mepolizumab, anrukinzumab, metronidazole, metronidazole
hydrochloride, gentamicin sulfate, lincomycin hydrochloride,
tobramycin sulfate, tacrolimus, vancomycin hydrochloride, polymyxin
B sulfate, colistimethate sodium, colistin sulfate, tetracycline,
griseofulvin, keloconazole, interferon gamma, zidovudine,
amantadine hydrochloride, ribavirin, acyclovir, pentamidine e.g.,
pentamidine isoethionate, cephalosporins (e.g., cefazolin sodium,
cephradine, cefaclor, cephapirin sodium, ceftizoxime sodium,
cefoperazone sodium, cefotetan disodium, cefutoxime axotil,
cefotaxime sodium, cefadroxil monohydrate, ceftazidime, cephalexin,
cephalothin sodium, cephalexin hydrochloride monohydrate,
cefamandole nafate, cefoxitin sodium, cefonicid sodium, ceforanide,
ceftriaxone sodium, ceftazidime, cefadroxil, cephradine, cefuroxime
sodium, and the like), penicillins (e.g., ampicillin, amoxicillin,
penicillin G benzathine, cyclacillin, ampicillin sodium, penicillin
G potassium, penicillin V potassium, piperacillin sodium, oxacillin
sodium, bacampicillin hydrochloride, cloxacillin sodium,
ticarcillin disodium, azlocillin sodium, carbenicillin indanyl
sodium, penicillin G potassium, penicillin G procaine, methicillin
sodium, nafcillin sodium, and the like), erythromycins (e.g.,
erythromycin ethylsuccinate, erythromycin, erythromycin estolate,
erythromycin lactobionate, erythromycin siearate, erythromycin
ethylsuccinate, and the like), tetracyclines (e.g., tetracycline
hydrochloride, doxycycline hyclate, minocycline hydrochloride,
GM-CSF, ephedrine, pseudoephedrine, ammonium chloride, androgens
(e.g., danazol, testosterone cypionate, fluoxymesterone,
ethyltostosterone, testosterone enanihate, methyltestosterone,
fluoxymesterone, testosterone cypionate), estrogens (e.g.,
estradiol, estropipate, conjugated estrogens), progestins (e.g.,
methoxyprogesterone acetate, norethindrone acetate), levothyroxine
sodium, human insulin, purified beef insulin, purified pork
insulin, glyburide, chlorpropamide, glipizide, tolbutamide,
tolazamide, rosiglitazone, pioglitazone, troglitazone, clofibrate,
dextrothyroxine sodium, probucol, lovastatin, rosuvastatin, niacin,
DNase, alginase, superoxide dismutase, lipase, calcitonion,
alpha-1-antitrypsin, interferons, sense or anti-sense nucleic acids
encoding any protein suitable for delivery by inhalation,
erythropoietin, famotidine, cimetidine, ranitidine hydrochloride,
omeprazole, esomeprazole, lanzoprazole, meclizine hydrochloride,
nabilone, prochlorperazine, dimenhydrinate, promethazine
hydrochloride, thiethylperazine, scopolamine, sildenafil,
vardenafil, cilomilast, imiquimod or resiquimod. Where appropriate,
these drugs may be delivered in alternative salts forms.
[0079] The medicament may comprise one or more drugs, having one or
more particulate forms, and may include one or more physiologically
acceptable or inert excipients.
* * * * *