U.S. patent application number 16/718732 was filed with the patent office on 2020-04-23 for dry powder inhalation system.
The applicant listed for this patent is MannKind Corporation. Invention is credited to Benoit Adamo, Anthony Bryant, P. Spencer Kinsey, Scott McLean, Dennis Overfield, John M. Polidoro, Carl R. Sahi, Chad C. Smutney.
Application Number | 20200121869 16/718732 |
Document ID | / |
Family ID | 40886853 |
Filed Date | 2020-04-23 |
View All Diagrams
United States Patent
Application |
20200121869 |
Kind Code |
A1 |
Smutney; Chad C. ; et
al. |
April 23, 2020 |
DRY POWDER INHALATION SYSTEM
Abstract
Dry powder inhaler systems for pulmonary delivery of
pharmaceuticals are disclosed.
Inventors: |
Smutney; Chad C.;
(Watertown, CT) ; Kinsey; P. Spencer; (Sandy Hook,
CT) ; Polidoro; John M.; (Tolland, CT) ; Sahi;
Carl R.; (Coventry, CT) ; Adamo; Benoit;
(South Salem, NY) ; McLean; Scott; (Sandy Hook,
CT) ; Overfield; Dennis; (Lyme, CT) ; Bryant;
Anthony; (Stratford, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MannKind Corporation |
Westlake Village |
CA |
US |
|
|
Family ID: |
40886853 |
Appl. No.: |
16/718732 |
Filed: |
December 18, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14863136 |
Sep 23, 2015 |
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16718732 |
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12413405 |
Mar 27, 2009 |
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14863136 |
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61143370 |
Jan 8, 2009 |
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61040112 |
Mar 27, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 2205/581 20130101;
A61M 2202/07 20130101; A61M 15/002 20140204; A61M 15/0015 20140204;
A61M 2016/0027 20130101; A61M 15/0043 20140204; A61M 2205/58
20130101; A61M 2016/0021 20130101; A61M 15/0023 20140204; A61M
2205/582 20130101; A61M 15/0028 20130101; A61M 2202/064
20130101 |
International
Class: |
A61M 15/00 20060101
A61M015/00 |
Claims
1. An inhalation system for pulmonary delivery comprising: a dry
powder inhaler comprising a housing and a mouthpiece, said housing
including an inlet and an outlet port; a cartridge adapted to said
dry powder inhaler and containing a dry powder medicament for
inhalation; said dry powder inhaler system comprising air conduits
configured to have a predetermined airflow distribution around and
through said cartridge operably configured to mix the medicament
with air forming a powder plume for delivery to a patient's
pulmonary system; wherein said predetermined airflow distribution
through said cartridge ranges from about 10 to 30% of total airflow
volume entering said dry powder inhaler during inhalation.
2. The inhalation system of claim 1, wherein the predetermined
airflow distribution around said cartridge ranges from about 70 to
90% of total airflow volume.
3. The inhalation system of claim 1, wherein the dry powder
medicament comprises a diketopiperazine and a pharmaceutically
active ingredient selected from a peptide, a protein, a hormone,
analogs thereof or combinations thereof.
4. The inhalation system of claim 1, wherein the inhaler and
cartridge are configured to provide an airflow resistance ranging
from 0.08 and 0.15 kPa/liters per minute.
5. The inhalation system of claim 1, wherein said housing having a
top wall, a bottom wall, a first side wall and a second side wall;
a mouthpiece engaging section, a mouthpiece storage section, and an
air intake section having a conduit with a first opening to allow
ambient air intake and a second opening in communication with the
mouthpiece engaging section which allows air flow therethrough;
said mouthpiece being separable from said housing and comprising a
chamber structurally configured to house said cartridge and to
engage with said mouthpiece engaging section of said housing; an
oral placement section extending from said chamber and having an
air inlet which communicates with said chamber and an air outlet in
communication with ambient air.
6. The inhalation system of claim 5, wherein said mouthpiece
engaging section of said 5 housing has an outer wall, an inner wall
and a bottom wall contiguous with the said first side wall, said
second side wall and bottom walls respective of said housing, and
configured to adapt to said mouthpiece chamber of said
mouthpiece.
7. The inhalation system of claim 5, wherein said mouthpiece
engaging section further comprises a protrusion from said bottom
wall configured to receive and hold the medicament containing
cartridge.
8. The inhalation system of claim 5, wherein the mouthpiece
engaging section further comprises a securing mechanism from said
inner wall structurally configured to engage said mouthpiece
chamber of said mouthpiece.
9. The inhalation system of claim 5, wherein the mouthpiece chamber
further comprises a flange having gaps which mate said protrusions
or projections from the inner wall of the mouthpiece engaging
section.
10. The inhalation system of claim 5, wherein said mouthpiece is
moveable from a storage position to a cartridge loading position to
an inhalation position, and comprises a mixing chamber configured
to hold the medicament containing cartridge and to have an opening
which aligns with the second opening of the intake section in said
inhalation position.
11. The inhalation system of claim 5, wherein the mouthpiece
chamber comprises an air inlet and is configured to secure the
medicament containing cartridge, and has an indicator to allow
proper cartridge placement in the inhaler.
12. The inhalation system of claim 5, wherein the mouthpiece
comprises a cap over the chamber, movable from a closed to an open
position, having an anvil which engages with the cartridge in a
closed position.
13. The inhalation system of claim 5, wherein the housing further
comprises an air flow control mechanism comprising a check
valve.
14. The inhalation system of claim 5, wherein said dry powder
inhaler system in use has the predetermined air flow distribution
around and through said cartridge of air flow volume entering said
chamber.
15. The inhalation system of claim 14, wherein the predetermined
air flow distribution through said cartridge ranges from about 10%
to about 30% of the air flow volume entering the mixing section and
from about 70% to about 90% of the air flow volume entering the
mouthpiece chamber.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of patent application
Ser. No. 12/413,405 filed Mar. 27, 2009, which claims the benefit
under 35 U.S.C. .sctn. 119(e) of U.S. Provisional Application Ser.
Nos. 61/040,112 filed Mar. 27, 2008 and 61/143,370 filed Jan. 8,
2009; the contents of each of these applications are incorporated
by reference herein in their entirety.
TECHNICAL FIELD
[0002] A pulmonary drug delivery system is disclosed. The system
includes a dry powder inhaler; and a unit dose cartridge for using
with the inhaler. The cartridge can contain a drug delivery
formulation for pulmonary delivery, for example, a formulation
comprising a diketopiperazine and an active ingredient including
peptides and proteins such as insulin and glucagon-like peptide 1.
The dry powder inhaler is compact and comprises a housing, and a
mouthpiece having a chamber to install the unit dose cartridge
containing medicament and can be separated from its housing for
ease of cleaning.
[0003] All references cited in this specification, and their
references, are incorporated by reference herein in their entirety
where appropriate for teachings of additional or alternative
details, features, and/or technical background.
BACKGROUND
[0004] Drug delivery systems for the treatment of disease which
introduce active ingredients into the circulation are numerous and
include oral, transdermal, inhalation, subcutaneous and intravenous
administration. Drugs delivered by inhalation are typically
delivered using positive pressure relative to atmospheric pressure
in air with propellants. Such drug delivery systems deliver drugs
as aerosols, nebulized or vaporized. More recently, drug delivery
to lung tissue has been achieved with dry powder inhalers. Dry
powder inhalers can be breath-activated to deliver drugs by
converting drug particles in a carrier into a fine dry powder which
is entrained into an airflow and inhaled by the patient. Drugs
delivered with the use of a dry powder inhaler can no longer be
intended to treat pulmonary disease only, but also specific drugs
can be used to treat many conditions, including diabetes and
obesity.
[0005] Dry powder inhalers, used to deliver medicaments to the
lungs, contain a dose system of a powder formulation usually either
in bulk supply or quantified into individual doses stored in unit
dose compartments, like hard gelatin capsules or blister packs.
Bulk containers are equipped with a measuring system operated by
the patient in order to isolate a single dose from the powder
immediately before inhalation. Dosing reproducibility requires that
the drug formulation is uniform and that the dose can be delivered
to the patient with consistent and reproducible results. Therefore,
the dosing system must operate to completely discharge all of the
formulation effectively during an inspiratory maneuver when the
patient is taking his/her dose. Flow properties of the powder
formulation, and long term physical and mechanical stability in
this respect, are more critical for bulk containers than they are
for single unit dose compartments. Good moisture protection can be
achieved more easily for unit dose compartments such as blisters,
however, foils used to seal the blisters and subsequent drug
formulation lose viability with long storage.
[0006] Dry powder inhalers such as those describe in U.S. Pat. No.
7,305,986 and U.S. patent application Ser. No. 10/655,153 (US
20040182387), the disclosures of which are incorporated herein by
reference in their entirety for all they disclose regarding dry
powder inhalers, can generate primary drug particles or suitable
inhalation plumes during an inspiratory maneuver by deagglomerating
the powder formulation within a capsule. The amount of fine drug
discharged from the inhaler's mouthpiece during inhalation is
largely dependent on the interparticulate forces in the powder
formulation (between drug and drug particles or between drug and
excipient particles) and the efficiency of the airflow as measured
by pressure drop and flow rate entering and exiting the dry powder
dispenser. The benefits of delivering drugs via the pulmonary
circulation are numerous and include, rapid absorption into the
arterial circulation, avoidance of drug degradation by liver
metabolism, ease of use, i.e., lack of discomfort of administration
by other routes of administration.
[0007] Dry powder inhaler products developed for pulmonary
inhalation have met with limited success to date, due to lack of
practicality. Some of the persistent problems observed with prior
art inhalers, include ruggedness of device, inconsistency in
dosing, inconvenience of the equipment, and/or lack of patient
compliance. Therefore, the inventors have designed and manufactured
a dry powder inhaler with consistent drug delivery properties, ease
of use without discomfort, improved ruggedness, and discrete
geometries which would allow for better patient compliance.
SUMMARY
[0008] Dry powder inhaler systems for pulmonary delivery of
pharmaceuticals are disclosed. The dry powder inhalation systems
comprise a dry powder inhalation device or inhaler and at least one
cartridge containing a pharmaceutical formulation comprising at
least one active ingredient for delivery to the pulmonary
circulation. The present inhalation systems provide rugged devices
which are reusable, use pre-metered unit dose cartridges and can be
separated into their principal component parts for ease of
cleaning. The devices also provide high resistance inhalation
systems which enable deagglomeration of dry powder particles, have
consistent airflow and are simple and easy to use.
[0009] In one embodiment, a dry powder inhaler comprises a housing,
and a mouthpiece, wherein the housing comprises a mouthpiece
engaging section structurally configured to engage with the
mouthpiece, and the mouthpiece being removable at predetermined
positions relative to the housing, and having a conduit permitting
airflow between an air inlet and an air exit port, and comprising a
chamber and an oral placement section; the mouthpiece further being
structurally configured to be moveable within the housing in an
engaged position and releasable from the housing at a predetermined
position. The dry powder inhaler mouthpiece is structurally
configured to receive, hold and/or release a medicament containing
cartridge in the chamber.
[0010] In another embodiment, the housing comprises a container
structurally configured to adapt to the mouthpiece and has one or
more openings for allowing air intake into the mouthpiece chamber.
In such an embodiment, the housing has securing mechanisms to hold
the mouthpiece chamber and permit the mouthpiece assembly to be
moveable within the housing to a storage position, to a cartridge
loading/unloading position, mouthpiece separable position, to an
inhalation position and in reversed order.
[0011] In still another embodiment, the mouthpiece assembly engages
the mouthpiece at the mouthpiece engaging section of the housing.
The housing can comprise an air intake section having an air
conduit with one or more first openings to allow ambient air intake
and a second opening in communication with the mouthpiece engaging
section which allows airflow through the air conduit and out into
the housing engaging section, the engagement of the mouthpiece
substantially prevents ambient air from entering the conduit except
at the one or more first openings in the housing for air intake. In
one embodiment, the housing also comprises a mouthpiece storage
section.
[0012] In yet another embodiment, the dry powder inhaler mouthpiece
assembly can move relative to the housing and the movement of the
mouthpiece within the housing can reconfigure a cartridge seated in
the inhaler from a closed configuration to an open configuration,
or from an open to a closed configuration. Movement of the
mouthpiece within the housing can be of various types, such as
translational or rotational. In one such embodiment, movement about
the housing is rotational, and can be restricted at predetermined
locations relative to the housing to provide registration of
positions of the mouthpiece in use. In one embodiment, for example,
movement of the mouthpiece assembly is rotational and the
mouthpiece can rotate from the storage position to a cartridge
loading/unloading position to an inhalation position. In another
embodiment, the mouthpiece further comprises a mouthpiece oral
placement section and a medicament containing cartridge receiving
section; the cartridge receiving section configured to permit and
direct air flow through and around the cartridge.
[0013] In a further embodiment, the air conduit of the air intake
section of the housing is in communication with the air exit port
of the mouthpiece when the cartridge is in an open configuration.
The airflow conduit is established between one or more first
openings in the housing; then air passes through the airflow
conduit within the housing and exits a second opening of the
mouthpiece engaging section and enters into the mouthpiece chamber
wherein a percentage of intake air volume goes through the
cartridge and a percentage of intake air volume goes around the
cartridge during an inhalation maneuver. In this embodiment, the
airflow path then enters the mouthpiece chamber and enters and
exits the conduit of the mouthpiece oral placement section. In a
further embodiment, with a cartridge containing medicament placed
in the chamber, airflow entering the chamber from the housing
outlet port is diverted so that a percentage of the airflow volume
goes through the cartridge and a percentage of the airflow volume
goes around the cartridge. Both air flow volumes, exiting the
cartridge with a medicament and airflow around the cartridge,
converge prior to entering and exiting the air exit port of the
mouthpiece of the oral placement section.
[0014] In another embodiment, a dry powder inhaler is provided
comprising a housing, and a mouthpiece assembly, the housing having
a top wall, a bottom wall, side walls; a mouthpiece engaging
section, a mouthpiece storage section, and an air intake section
having a conduit with a first opening to allow ambient air intake
and a second opening in communication with the mouthpiece engaging
section which allows air flow therethrough; the mouthpiece
subassembly being removable and comprising a chamber structurally
configured to house a cartridge and to engage with the mouthpiece
engaging section of the housing; an oral placement section
extending from the chamber and having an air inlet which
communicates with the chamber and an air outlet in communication
with ambient air.
[0015] In embodiments described herewith, a breath-powered inhaler
is provided comprising, an inhaler with resistance values that can
be tunable or changed as required by the patient being an adult or
a child. In one embodiment, the resistance values of the inhaler
can be altered by changing the geometries or configuration of the
air conduits so that airflow distribution through the cartridge and
around the cartridge can vary. In one embodiment, inhaler
resistance values can range between 0.08 and 0.15 kPa/liters per
minute. In certain embodiments, flow balance distribution can range
from about 10% to about 30% through the cartridge and from about
70% to 90% going around the cartridge.
[0016] In still a further embodiment, the dry powder inhalation
system comprises a breath-activated dry powder inhaler, a cartridge
containing medicament, wherein the medicament can comprise a
diketopiperazine and an active agent. In some embodiments, the
active agent comprises peptides and proteins. In another
embodiment, the inhalation system comprises a cartridge containing
medicament wherein the peptide or protein can be an endocrine
hormone: including, insulin, glucose-like peptide (GLP-1),
parathyroid hormone, parathyroid hormone related protein (PTHrP),
and the like.
[0017] In one embodiment, the dry powder inhalation system can
comprise a cartridge including a formulation for pulmonary delivery
which can be provided for use with different dosage strengths,
wherein the system can deliver the dosage with consistency and in a
linear manner. In this embodiment, for example, multiple cartridges
of a single dose to be administered to a subject can be
interchangeably replaced or substituted by providing the system
with a single cartridge of the sum of the dosage strength of the
multiple cartridges, wherein the system can deliver a bioequivalent
dose with a single cartridge.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 illustrates a three dimensional side view of an
embodiment of a dry powder inhaler in a storage position.
[0019] FIG. 2 illustrates the back side view of the dry powder
inhaler of FIG. 1 showing the mouthpiece subassembly moved from the
storage position to a cartridge loading position wherein the cap is
opened. In this embodiment, this is also the position at which the
mouthpiece can be separated.
[0020] FIG. 3 illustrates the back side view of the dry powder
inhaler of FIG. 1 showing the mouthpiece subassembly has been moved
to the inhalation position for use.
[0021] FIG. 4 illustrates the back side view of the dry powder
inhaler of FIG. 1 showing the mouthpiece subassembly has been moved
to an unloading position after inhalation.
[0022] FIG. 5 illustrates the dry powder inhaler of FIG. 1, showing
the housing subassembly and the mouthpiece subassembly disengaged
from one another.
[0023] FIG. 6 illustrates a top view section of a housing
subassembly of a dry powder inhaler.
[0024] FIG. 7 illustrates the dry powder inhaler shown in FIG. 3 in
cross-section.
[0025] FIG. 8 illustrates the dry powder inhaler of FIG. 1, showing
an exploded view of the housing subassembly.
[0026] FIG. 9 illustrates the dry powder inhaler of FIG. 1, showing
the mouthpiece subassembly removed from the housing component.
[0027] FIG. 10 illustrates the dry powder inhaler of FIG. 1,
showing an exploded view of the mouthpiece subassembly.
[0028] FIG. 11 illustrates an alternate embodiment of the dry
powder inhaler system showing the inhaler in a cartridge loading
position. FIG. 11 also depicts a cartridge embodiment for use with
a dry powder inhaler according to the present description.
[0029] FIG. 12 illustrates the embodiment of FIG. 11 with a
cartridge loaded into the dry powder inhaler with the cap open.
[0030] FIG. 13 illustrates the embodiment of FIG. 11 showing the
dry powder inhaler in an inhalation position.
[0031] FIG. 14 illustrates the embodiment of FIG. 13 showing the
dry powder inhaler in inhalation position as a cross-section
through the mid-longitudinal axis.
[0032] FIG. 15 illustrates a cross-section of an embodiment wherein
the dry powder inhaler is shown in the dosing position and
containing a cartridge.
[0033] FIG. 16 illustrates an embodiment of a three dimensional
side view of a cartridge for use with the dry powder inhalation
system.
[0034] FIG. 17 illustrates an embodiment of a three dimensional
back side view cartridge for use with the dry powder inhalation
system.
[0035] FIG. 18 illustrates an embodiment of an exploded three
dimensional view of the cartridge for use with the dry powder
inhalation system.
[0036] FIG. 19 illustrates a mean baseline-corrected GIR (glucose
infusion rate) for two 15 U cartridges and one 30 U cartridge of an
inhalation powder comprising insulin and fumaryl diketopiperazine,
and for 10 IU of RAA.
[0037] FIG. 20A depicts a schematic representation of a cartridge
loaded into a cartridge rig in cross-section for measuring pressure
across the cartridge. FIG. 20B illustrates a diagram of a
resistance circuit illustrating the various resistors associated
with the cartridge rig illustrated in FIG. 20A.
[0038] FIG. 21A illustrates a schematic representation of a portion
of the inhaler in cross-section showing components parts. FIG. 21B
illustrates a diagram of a resistance circuit of an inhaler
embodiment of FIG. 21A used for measuring the resistance and
pressure of the device.
[0039] FIG. 22 depicts a linear regression plot illustrating the
resistance measured through an exemplary cartridge rig tested or
R3, at flow rates between 2 and 9 liters/min.
DETAILED DESCRIPTION
[0040] In embodiments disclosed herein, there are disclosed dry
powder inhalation systems for delivering pharmaceutical medicaments
to the pulmonary circulation. The inhalation systems comprise a
breath-powered or breath activated, dry powder inhaler, one or more
cartridges containing a pharmaceutical formulation comprising one
or more pharmaceutically active substances or active ingredients,
and a pharmaceutically acceptable carrier.
[0041] One embodiment of a dry powder inhaler is shown in FIG. 1.
Therein, dry powder inhaler 100 comprises housing 102, and
removable mouthpiece assembly or subassembly 104. FIG. 1
illustrates dry powder inhaler 100 in a closed or storage position,
wherein mouthpiece oral placement section 106 (illustrated in FIG.
2) is stowed away under cover 108. FIG. 1 also illustrates cover or
lid 110 over mouthpiece chamber 112 (illustrated in FIG. 2). In one
embodiment of FIG. 1, housing 102 is structurally configured to be
relatively rectangular in shape and has top wall 114, bottom wall
116, back wall 118, first side wall 120, second side wall (not
illustrated), mouthpiece engaging section 122, mouthpiece storage
section 124, and an air intake section as part of housing 102.
[0042] FIG. 2 illustrates dry powder inhaler 100 from FIG. 1,
showing the inhaler in a cartridge loading/unloading position with
lid 110 open to allow a mating cartridge to be inserted into the
central cavity of mouthpiece chamber 112. FIG. 2 also illustrates
removable mouthpiece subassembly 104 is movable from the storage
position in the housing to about 90.degree. relative to
longitudinal x-axis 202 of housing 102 rotated about y-axis 204. In
certain embodiments, the cartridge loading/unloading position of
mouthpiece assembly 104 can be any predetermined angle as desired.
As illustrated in FIG. 2, mouthpiece engaging section 122 of
housing 102 is relatively circular in shape on the side wall and is
shorter in height compared to the rest of housing 102 to
accommodate mouthpiece chamber 112 and can form one end of inhaler
100. Housing 102 can also comprise an air conduit with one or more
first openings to allow ambient air intake and a second opening in
communication with mouthpiece engaging section 122 which allows air
flow from the intake section through the conduit into mouthpiece
chamber 112 in the inhalation position.
[0043] FIG. 3 depicts dry powder inhaler 100 illustrated in FIG. 1,
showing removable mouthpiece assembly 104 in an extended or
inhalation position. In this embodiment, removable mouthpiece
assembly 104 is at about 180.degree. angle relative to the
longitudinal x-axis 202 of housing 102 rotated about y-axis 204. In
some embodiments, the inhalation position of mouthpiece assembly
104 can be varied depending on the structural configuration of the
cartridge design to be adapted with the inhaler, and the rotational
degrees a cartridge may be rotated to properly align apertures that
allow air to enter and exit the cartridge carrying a plume of
medicament into mouthpiece exit port 302.
[0044] FIG. 4 illustrates dry powder inhaler 100 of FIG. 1 showing
removable mouthpiece assembly 104 being moveable about the
loading/unloading position after use. It should be noted that lid
110 remains closed during movement of removable mouthpiece assembly
104 about housing 102. FIG. 4 also illustrates mouthpiece oral
placement section 106 can be configured with tongue depressor 402
which acts to properly depress the tongue of a user.
[0045] FIG. 5 illustrates dry powder inhaler 100 of FIG. 1
comprising the component parts, removable mouthpiece assembly 104
and housing 102. Removable mouthpiece assembly 104 comprising
mouthpiece chamber 112 structurally configured with cartridge
holder area 502, one or more belts 504 and one or more flanges 506,
lid 110 and air inlet port 508 which communicates with the housing
second opening to engage with mouthpiece engaging section 122 of
housing 102; mouthpiece oral placement section 106 extending from
mouthpiece chamber 112 and having air inlet port 508 which
communicates with mouthpiece chamber 112 and mouthpiece exit port
302 which is in communication with ambient air. Drive key 510
structurally configured to have indicator 512, for example, in the
shape of a tear drop for proper placement of a cartridge in dry
powder inhaler 100 is also shown in FIG. 2 and FIG. 5. Proper
alignment of a cartridge in the inhaler indicates the correct
relative rotational orientation and determines successful cartridge
seating, insertion and emptying in use. In such an embodiment, a
cartridge cannot be properly seated unless tear drop 1602 of
cartridge 1600 (FIG. 11) and drive key 510 align with one
another.
[0046] Lid 110 is positioned over mouthpiece chamber 112 and is
mechanically connected to removable mouthpiece assembly 104 by
hinge 514. Lid 110 has an outer surface and an inner surface and it
is structurally configured with an anvil in its inner top surface
and relatively centered within the top. Lid 110 can only be opened
when removable mouthpiece assembly 104 is in the loading/unloading
position. When removable mouthpiece assembly 104 is engaged into
housing 102 an interlocking mechanism prevents movement to a
dosing/inhalation position or to a storage position when lid 110 is
opened or raised. The interlocking mechanism can comprise, for
example, one or more belts or flexible radial arms, which are
incorporated into the walls of mouthpiece chamber 112 and act as a
self-synching mechanism 602 in FIG. 6. The interlocking mechanism
allows removable mouthpiece assembly 104 to obtain proper
registration of the various positions when dry powder inhaler 100
is in use. Lid 110 can be maintained in a closed position by a
locking mechanism, for example, a spring loaded boss such as a
lock-out button which can engage a receiving detent within housing
102. In an alternate embodiment, the locking mechanism comprises an
upward extension of the housing wall. The locking mechanism 602 can
also serve to secure the mouthpiece subassembly against further
rotation. Position registration of removable mouthpiece assembly
104 allows the inhaler to be properly used and prevents movement of
removable mouthpiece assembly 104 to the dosing position without
lid 110 being depressed.
[0047] FIG. 5 also illustrates housing 102 separated from removable
mouthpiece assembly 104 showing mouthpiece engaging section 122
having an opening or cavity 516 with top wall 114 partially
discontinuous to adapt, receive and hold removable mouthpiece
assembly 104 and structurally configured to accommodate the
mouthpiece. Housing 102 is configured to have an upward projection
of the wall or second flange 518 around the top outer portion of
mouthpiece engaging section 122 and a protrusion configured as a
drive key in its bottom wall configured to mate with a keying
structure of a cartridge. The proper alignment of a cartridge
within dry powder inhaler 100 is dependent on drive key 510 having
an indicator 512 and one or more indentation 126 (FIG. 2) in
removable mouthpiece assembly 104 and drive key 510 and of housing
102.
[0048] Housing 102 comprises mouthpiece engaging section 122 having
an outer wall, an inner wall and a bottom wall contiguous with the
side and bottom walls respective of housing 102, and configured to
adapt to the mixing section of removable mouthpiece assembly 104.
FIG. 6 illustrates a parallel cross-section through the
mid-longitudinal plane of housing 102 containing a portion of
mouthpiece chamber 112. FIG. 6 also illustrates interlocking
mechanism 604 (belts 504 in FIG. 5); chamber inner wall 606
defining a space for housing a cartridge. Circular structure or
plug 608 is the wall of the air conduit of housing 102 which is
continuous with back wall 118 of housing 102.
[0049] FIG. 7 illustrates a cross sectional view of dry powder
inhaler 100 in a dosing or inhalation position. As seen in FIG. 7,
housing 102 has a substantially rectangular shape, however other
shapes are also suitable. Housing 102 comprises one or more inlet
ports or first openings 702, air conduit 704, housing piston 706
and spring 708, and outlet port 710 opening into mouthpiece
engaging section 122 and aligns with the inlet port of mouthpiece
chamber 112. Air conduit 704 has one or more openings 712 that
allow airflow to enter.
[0050] Mouthpiece engaging section 122 is partially configured in
the shape of a cup further comprising second drive key 802 as seen
in FIG. 8 from bottom wall 116 configured to receive and hold a
medicament containing cartridge. FIG. 7 also shows the engagement
between flange 506 of mouthpiece chamber 112 in housing 102; hinge
514, lid 110 and mouthpiece oral placement section 106 with tongue
depressor 402 and airflow conduit 714 of removable mouthpiece
assembly 104.
[0051] FIG. 8 depicts an exploded view of housing 102 illustrating
integral components of dry powder inhaler 100, including plug 608,
piston 706 and spring 708 which assemble into air conduit 704;
housing 102 outer structure comprising back wall 118, side wall
120, top wall 114, and bottom wall 116; mouthpiece engaging section
122 with second drive key 802, and slide door 804 which covers the
storage compartment for mouthpiece oral placement section 106. Air
conduit 704 is configured to have an aperture or opening 712 which
allows and directs airflow entering housing 102 into mouthpiece
engaging section 122 during an inspiratory maneuver. Mouthpiece
engaging section 122 can also comprise a securing mechanism which
can comprise protrusions or projections from the inner wall of the
chamber which mates with flange 506 and mating structure 902 as
seen in FIG. 9 of mouthpiece chamber 112. In this embodiment,
piston 706 and compression spring 708 act as an indicator mechanism
positioned in air conduit 704 of housing 102 structurally
configured to indicate inspiratory effort. Piston 706 and spring
708 can be placed at other positions in the airflow pathway of dry
powder inhaler 100. During an inspiratory maneuver, airflow
entering the air conduit 704 within housing 102 goes around piston
706, and moves piston 706 to compress spring 708. This airflow
control mechanism during inhalation indicates inspiratory effort
through a tactile sensation. In one embodiment, the mechanism
indicates inspiratory effort through an audible click. In another
embodiment, the mechanism indicates inspiratory effort through a
tactile sensation and/or an audible click. Mouthpiece engaging
section 122 of housing 102 has one or more protrusions such as
mating structures 902 that mates with mouthpiece chamber 112 to
secure mouthpiece when dry powder inhaler 100 is in use.
[0052] In operation, removable mouthpiece assembly 104 is rotated
from a storage position to a cartridge loading/unloading position
wherein lid 110 is opened and a cartridge containing medicament is
placed into mouthpiece chamber 112 and securely seated. Lid 110
contains an anvil 1102 (FIG. 11) inside which, if a cartridge is
inserted in the correct position, the anvil will further insure the
cartridge achieves a proper vertical alignment. A downward push of
lid 110 closes the cover and removable mouthpiece assembly 104 can
rotate to the dosing position, wherein a registration securement
holds removable mouthpiece assembly 104 in place. If the proper
vertical alignment is not achieved lid 110 cannot be fully closed
and subsequent removable mouthpiece assembly 104 rotation cannot
occur. This provides an interlock mechanism.
[0053] FIG. 9 illustrates removable mouthpiece assembly 104 which
has been separated from housing 102. Removable mouthpiece assembly
104 comprises mouthpiece chamber 112, lid 110 articulated to
removable mouthpiece assembly 104 so that in a closed position lid
110 covers mouthpiece chamber 112, and mouthpiece oral placement
section 106 having airflow conduit 714 with mouthpiece exit port
302. Mouthpiece chamber 112 comprises air inlet port 508, one or
more flanges 506 having gaps and mating structure 902 for mating
with and securing removable mouthpiece assembly 104 with housing
102. Flange 506 positioned at the bottom end of mouthpiece chamber
112 is provided which is structurally configured to engage with
housing 102, and comprises multiple segments having gaps in between
the segments; the gaps section contains mating structure 902 for
mating with housing 102. The multiple segments of flange 506 and
gaps between the segments can be position at predetermined
positions of mouthpiece chamber 112 to effectuate proper securement
of removable mouthpiece assembly 104 in housing 102.
[0054] FIG. 10 is an exploded view of removable mouthpiece assembly
104. Mouthpiece chamber 112 comprises drive key 510 with indicator
512, lid 110, mouthpiece oral placement section 106, cartridge
securing mechanism 1002, a radial spring 1004, one or more belts
504 and interlock detents 1006.
[0055] In embodiments described herein, dry powder inhaler 100 is
structurally configured to effectuate a tunable airflow resistance,
which is modular. The resistance of dry powder inhaler 100 can be
modified, by varying the cross-sectional area at any section of air
conduit 704 of the inhaler. In one embodiment, dry powder inhaler
100 can have a airflow resistance value of from about 0.08 to about
0.13 square root of kPa/liters per minute.
[0056] In an alternate embodiment illustrated in FIGS. 11-14, dry
powder inhaler 100 comprises alternate housing 1104 configured to
be compact and comprises a square-shape configuration which snuggly
fits with removable mouthpiece assembly 104. Removable mouthpiece
assembly 104 is similar in structure, if not identical in some
embodiments, to the embodiment described with respect to FIGS.
1-10. FIG. 11 depicts alternate dry powder inhaler 1100 in the
cartridge load/unload position with lid 110 open, mouthpiece oral
placement section 106, mouthpiece exit port 302, anvil 1102,
mouthpiece chamber 112 and interlocking mechanism 604 (FIG. 6).
Cartridge 1600 has tear drop 1602 indicator for aligning to the
indicator 512 of mouthpiece chamber 112 for proper insertion.
Alternate housing 1104 in this embodiment, has an air inlet located
in one of the side walls; however, in alternate embodiments the air
inlet can be one or more holes placed in other positions, for
example, in alternate housing back wall 1106. Alternate dry powder
inhaler 1100 can have one or more openings in the housing of
variable size or shape and locations.
[0057] Cartridges such as cartridge 1600 can be adapted to the dry
powder inhaler containing a dry powder medicament for inhalation,
and are configured to deliver a single unit dose of a medicament.
In one embodiment, cartridge 1600 can be structurally configured to
contain a dose of, for example, 0.5 mg to about 30 mg of dry powder
for inhalation.
[0058] FIG. 12 illustrates an alternate dry powder inhaler 1100
with cartridge 1600 loaded and ready for closure of lid 110. As can
be seen, lid 110 is in the open position, mouthpiece chamber 112
and alternate housing 1104 with alternate air inlet 1202. FIG. 13
depicts the dry powder inhaler system of FIG. 12 in the dosing
position and ready for inhalation.
[0059] FIG. 14 depicts a cross-section of alternate dry powder
inhaler 1100 of FIG. 13, showing the internal features of the
inhaler and cartridge system. Lid 110 securely holds cartridge 1600
by way of anvil 1102, which is then securely installed in
mouthpiece chamber 112. The airflow conduit 714 of mouthpiece oral
placement section 106 with mouthpiece inlet port 1402 and
mouthpiece exit port 302.
[0060] In some embodiments, as shown in FIG. 15, dry powder inhaler
100 comprises a removable mouthpiece assembly 104 comprising lid
110 over cartridge holder area 502 movable from a closed to an open
position, having anvil 1102 which engages with cartridge 1600 in a
closed position, wherein the housing further comprises an air flow
control mechanism comprising check valve 1502.
[0061] In embodiments described herein, the dry powder inhaler
system in use has a predetermined airflow distribution around and
through a cartridge operably configured to mix a medicament with
air forming a powder plume for delivery to a patient's pulmonary
system. Predetermined airflow distribution through the cartridge
can range from about 10 to about 30% of total airflow volume
entering the dry powder inhaler during inhalation. Predetermined
airflow distribution around the cartridge can range from about 70
to about 90% of total airflow volume. Predetermined cartridge
bypass airflow and exiting airflow through the cartridge converge
to further shear and deagglomerate the powder medicament prior to
exiting the mouthpiece outlet port.
[0062] In one embodiment, the medicament containing cartridge 1600
as shown in FIGS. 16-18 can comprise a structure with a defined
shape having a wall with one or more first apertures 1604, second
aperture 1702 and third aperture 1802, tear drop 1602, grasping
feature 1606, and first inhaler keying mechanism 1608 and second
inhaler keying mechanism 1610. Cartridge 1600 has a closed
configuration moveable to an open configuration for dosing a powder
medicament or from an open to a closed position after use.
Cartridge 1600 further comprises an outer surface and an inner
surface defining an internal volume; wherein the closed
configuration restricts communication, such as air transit to or
through the internal volume, and the open configuration forms an
air passage through the internal volume to allow a powder
medicament contained therein to be aerosolized and delivered to a
patient in an airflow stream created by the user. The open
configuration is established by providing one or more apertures
(e.g. first aperture 1604, second aperture 1702 and third aperture
1802), holes, slits or windows in the cartridge walls that can have
beveled edges to direct airflow. In one embodiment, cartridge 1600
can be configured of two elemental parts, for example, two segments
(e.g. first segment 1804 and second segment 1806) that can have
apertures in their walls that can align with one another in the
open configuration and in opposing positions where the apertures at
not in alignment. In one embodiment, for example, cartridge 1600
can be structurally configured as two separate elements which can
fit into one another and be moveable about one another; each having
openings which can align with one another, similarly as the
capsules described in U.S. Pat. No. 7,305,986, which is fully
incorporated herein by reference as if part of this specification.
In this embodiment, however, cartridge 1600 is designed to
integrally function with the dry powder inhaler and can be moved
within the inhaler to predetermined positions
[0063] In one embodiment, a method of delivering an active
ingredient comprising: a) providing a dry powder inhaler
comprising, a housing and a mouthpiece, the mouthpiece comprising a
chamber containing a cartridge with a dry powder formulation
comprising a diketopiperazine and the active agent; the inhaler
having a flow distribution of about 10% to 30% of the airflow going
through the cartridge, and b) delivering the active ingredient to
an individual in need of treatment by inhaling deep and rapidly for
about 4 to 6 seconds and optionally repeating step b).
[0064] In embodiments described herein, the dry powder inhaler can
deliver a dose of a dry powder formulation to a patient at pressure
differentials between 2 and 20 kPa.
[0065] In still yet a further embodiment, the method of treating
hyperglycemia and/or diabetes comprises the administration of an
inhalable dry powder composition comprising a diketopiperazine
having the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine,
wherein X is selected from the group consisting of succinyl,
glutaryl, maleyl, and fumaryl. In this embodiment, the dry powder
composition can comprise a diketopiperazine salt. In still yet
another embodiment of the present invention, there is provided a
dry powder composition, wherein the diketopiperazine is
2,5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine (FDKP), having
the structure:
##STR00001##
with or without a pharmaceutically acceptable carrier, or
excipient.
[0066] In one embodiment, the inhalation system comprises a
breath-activated dry powder inhaler, a cartridge containing
medicament, wherein the medicament can comprise a diketopiperazine
and an active agent. In some embodiments, the active agent
comprises peptides and proteins. In another embodiment, the
inhalation system comprises a cartridge containing medicament
wherein the peptide or protein can be an endocrine hormone,
including, insulin, GLP-1, calcitonin, parathyroid hormone,
parathyroid hormone related protein (PTHrP), and analogs thereof
and the like.
[0067] In another embodiment, the dry powder medicament may
comprise a diketopiperazine and a pharmaceutically active
ingredient. In this embodiment, the pharmaceutically active
ingredient can be any type. In certain embodiments, the active
ingredient comprises a peptide, a protein, a hormone, analogs
thereof or combinations thereof, wherein the active ingredient is
insulin, parathyroid hormone 1-34, glucagon-like peptide-1 (GLP-1),
oxyntomodulin, peptide YY, interleukin 2-inducible tyrosine kinase,
Bruton's tyrosine kinase (BTK), inositol-requiring kinase 1 (IRE1),
heparin, or analogs thereof. In a particular embodiment, the
pharmaceutical composition comprises fumaryl diketoperazine and
insulin.
[0068] In a particular embodiment, the dry powder inhalation system
can comprise a cartridge including a formulation for pulmonary
delivery comprising FDKP and a peptide including, for example,
insulin or GLP-1, which can be provided for use in different dosage
strength in a single or multiple cartridges. In one embodiment, the
system can deliver the dosage efficiently, with consistency and in
a linear manner. In this embodiment, for example, multiple
cartridges of a single dose to be administered to a subject can be
interchangeably replaced or substituted by a providing the system
with a single cartridge having the sum of the dosage strength of
the multiple cartridges. In further embodiment, the system can
deliver a proportional, bioequivalent dose with a single cartridge.
In an exemplary embodiment using the system for treating diabetes
with inhalable insulin powders, the system can use two 15 U
cartridges of an inhalation powder comprising insulin and FDKP or
the system can use one 30 U single cartridge containing an
inhalation powder comprising FDKP and deliver bioequivalent doses
of insulin to a patient. Similarly, the system can be used to
deliver higher doses, for example, three 15 U cartridges of an
inhalation powder comprising insulin and FDKP can be used, or one
15 U cartridge plus one 30 U cartridge, or a single 45 U cartridge
containing the inhalable insulin and FDKP formulation; or four 15 U
cartridges of an insulin and FDKP formulation can be
interchangeable with one 60 U cartridge of insulin and FDKP
formulation. Alternatively, two 30 U cartridges containing an
inhalable insulin and FDKP formulation can be interchanged for one
60 U cartridge of the insulin and FDKP formulation.
[0069] In the embodiments described herein, the dry powder
inhalation system accomplishes insulin exposure proportional to a
dosage so that the dosages are interchangeable. In an embodiment,
the dosage can be provided as filled dose.
EXAMPLES
[0070] The following examples are included to demonstrate certain
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
elucidate representative techniques that function well in the
practice of the present invention. However, those of skill in the
art should, in light of the present disclosure, appreciate that
many changes can be made in the specific embodiments that are
disclosed and still obtain a like or similar result without
departing from the spirit and scope of the invention.
Example 1
Dosage Strength Interchangeability
[0071] The study was conducted in subjects with type 1 diabetes
mellitus. This study was conducted to determine if a formulation
for pulmonary delivery comprising insulin and a diketopiperazine in
the formulation, 1) could be delivered consistently using different
dosage strengths and 2) if linearity of dosing could be achieved
with proportional doses, given that interchangeability of dosage
strengths can be important for patient safety. A prior art marketed
inhaled insulin did not achieve this and dose combinations were
nonequivalent leading to a potential risk of incorrect dosing.
Therefore, an important goal in the development of the pulmonary
delivery system with a formulation comprising insulin and FDKP
(insulin-FDKP) was to achieve dose linearity across the therapeutic
dose range.
[0072] In the study, comparisons of insulin exposure following
inhalation of two 15 U cartridges of an insulin inhalation powder
to one 30 U cartridge of insulin inhalation powder were made. In
addition, insulin bioavailability from a 30 U cartridge of
insulin-FDKP inhalation powder was calculated, compared to a 10-IU
subcutaneous (sc) injection of insulin lispro (rapid acting
analogue [RAA]).
[0073] A phase I, open-label, single-dose, repeat administration
study in subjects with type 1 diabetes (T1DM) was conducted to
assess the pharmacokinetic profile or PK of 30 U of insulin-FDKP
dosed as a single 30 U cartridge and compared to two 15 U
cartridges administered with the present inhalation system. A 10 U
subcutaneous injection of the rapid acting insulin analogue (RAA,
HUMALOG.RTM. (Eli Lilly and Company, Indianapolis, Ind.)) was also
tested. Subjects (age: 19-61 yrs) were randomized to 1 of 6
sequences. Fasted subjects received insulin-FDKP or RAA 4 to 6 hrs
after initiating a hyperinsulinemic-euglycemic clamp. Randomization
determined the order of insulin-FDKP dosing (first 2 treatment (tx)
visits), and the location of the RAA injection (abdomen, arm or
leg; 3.sup.rd tx visit). After dosing blood samples were taken and
analyzed for insulin, insulin lispro and fumaryl diketopiperazine
(FDKP (insulin-FDKP tx only)). When studying insulin-FDKP, the
basal insulin infusion was performed with HUMALOG.RTM., and when
studying HUMALOG.RTM., regular human insulin was used. The
analytical methodologies enabled the independent measurement of
each insulin tested.
[0074] Table 1 shows the results from the study. The mean insulin
exposures (AUC.sub.0-360) of a single 30 U cartridge or two 15 U
cartridges were comparable. FDKP mean exposure (AUC.sub.inf) was
also similar. Insulin and FDKP exposure, t.sub.max and t.sub.1/2
(FDKP) were the same regardless of the number of cartridges. Due to
the significantly different PK profiles of insulin-FDKP and RAA,
the mean relative exposure (AUC) ratio is dependent upon the time
interval studied. The mean relative insulin exposure (insulin-FDKP:
HUMALOG.RTM. AUC, dose normalized geometric means) when assessed at
time intervals of 0-180 min and 0-360 min was 24% to 18%.
TABLE-US-00001 TABLE 1 2 .times. 15 U TI 1 .times. 30 U TI 10 IU
Insulin PK parameters cartridges cartridge Humalog AUC.sub.0-360
(.mu.U*min/mL) 3337 3397 5915 AUC.sub.0-180 (.mu.U*min/mL) 3121
3199 4432 C.sub.max (.mu.U/mL) 65.72 69.08 42.60 t.sub.max (min) 10
10 60 90% CI (Geometric Mean 0.846, 1.141 ND Ratio:AUC.sub.0-360)
FDKP PK parameters AUC.sub.0-480 (ng*min/mL) 19552 20159 --
AUC.sub.0-inf (ng*min/mL) 23146 24355 -- C.sub.max (ng/mL) 118 131
-- t.sub.max (min) 6 5 -- 90% CI(Geometric Mean 0.867, 1.084 --
Ratio:AUC.sub.0-480)
[0075] This study also evaluated the effects of the dosages
administered and the glucose infusion rate (GIR) requirements of
the patients in the study. FIG. 19 illustrates the results of the
GIR evaluation. The data show the mean baseline-corrected glucose
infusion rate (GIR) for two 15 U cartridges and one 30 U cartridge
of insulin-FDKP inhalation powder and for the 10 IU of RAA. GIRs
after both treatments of insulin-FDKP inhalation powders reached a
maximum level by approximately 30 minutes after administration,
whereas GIR peaked approximately 150 minutes after administration
of sc RAA. The GIRs for insulin-FDKP inhalation powder returned
toward baseline by approximately 180 minutes versus 300 minutes for
RAA. In conclusion, the glucose-lowering effect of insulin-FDKP
inhalation powder of both dosage forms tested was comparable based
on GIR AUC, GIR.sub.max, and GIRt.sub.max.
Example 2
Dry Powder Inhaler Resistance Value Measurements
[0076] The total inhaler and cartridge resistance can be measured
due to inlet and outlet ports of a cartridge acting as resistors in
series. First, the resistance due to the inlet port is measured in
the cartridge rig. The representation of a circuit diagram form for
the cartridge rig is illustrated in FIGS. 20A and 20B, wherein the
cartridge sits in the holder in an open configuration and the
circuitry is defined such that R3 represents the resistance to
airflow into the cartridge; R4 represents the resistance to airflow
leaving the cartridge; Pa is the pressure differential across the
cartridge and P represents the pressure measured across the inlet
and outlet ports. Secondly, the resistance due to the inhaler
system comprising the inhaler and cartridge is determined as
illustrated in FIGS. 21A and 21B, wherein R1 represents the
resistance due to the float or valve; R2 represents the resistance
to air flow around the cartridge; R3 represents the resistance to
airflow through the cartridge; R4 represents the resistance to
airflow leaving the cartridge; P represents the measured pressure;
Pa represents the pressure across the system and F represents the
total flow measurement. Once values are determined for the
resistors and having pressure drop measurements, the flow balance
distribution through and around the cartridge can be
determined.
[0077] Measurements were made of the cartridge and
cartridge/inhaler system dosing configuration and the resistance to
airflow through the cartridge, R3 was determined from the
formula:
R 3 = P F ##EQU00001##
[0078] Based on the measurements made as illustrated in FIGS.
20A-21B, the resistance due to the inlet and outlet ports were
determined and the values used to calculate the flow balance of the
system in particular the flow balance through the cartridge using
the formula above, which is determined as the P divided by R3. The
flow balance distribution through the cartridge for the present
inhaler and cartridge system was calculated to be in the range from
about 10% to about 30% with an average of approximately 15.92%.
[0079] The resistance for the inhaler cartridge system tested
herewith can be determined experimentally from the values obtained
in the same manner. The resistance for the present inhalers when
calculated from the measurements resulted in airflow resistance
values of between 0.08 and 0.15 kPa/liters per minute. FIG. 22
depicts a linear regression plot illustrating the resistance
measured through an exemplary cartridge rig tested or R3, at flow
rates between 2 and 9 liters/min. As shown in FIG.22, the
resistance through the cartridge (R.sup.2) tested was determined as
equaling to 0.999 kPa/liters per minute.
[0080] Therefore, the inhalers can be structurally configured to
have tunable airflow resistance by varying the cross-sectional area
at any section of the airflow pathway of the inhaler and cartridge
system.
[0081] The preceding disclosures are illustrative embodiments. It
should be appreciated by those of skill in the art that the
techniques disclosed herein elucidate representative techniques
that function well in the practice of the present disclosure.
However, those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments that are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention.
[0082] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as molecular weight,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the specification and
attached claims are approximations that may vary depending upon the
desired properties sought to be obtained by the present invention.
At the very least, and not as an attempt to limit the application
of the doctrine of equivalents to the scope of the claims, each
numerical parameter should at least be construed in light of the
number of reported significant digits and by applying ordinary
rounding techniques. Notwithstanding that the numerical ranges and
parameters setting forth the broad scope of the invention are
approximations, the numerical values set forth in the specific
examples are reported as precisely as possible. Any numerical
value, however, inherently contains certain errors necessarily
resulting from the standard deviation found in their respective
testing measurements.
[0083] The terms "a," "an," "the" and similar referents used in the
context of describing the invention (especially in the context of
the following claims) are to be construed to cover both the
singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. Recitation of ranges of values
herein is merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range. Unless otherwise indicated herein, each individual value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed. No
language in the specification should be construed as indicating any
non-claimed element essential to the practice of the invention.
[0084] Groupings of alternative elements or embodiments of the
invention disclosed herein are not to be construed as limitations.
Each group member may be referred to and claimed individually or in
any combination with other members of the group or other elements
found herein. It is anticipated that one or more members of a group
may be included in, or deleted from, a group for reasons of
convenience and/or patentability. When any such inclusion or
deletion occurs, the specification is deemed to contain the group
as modified thus fulfilling the written description of all Markush
groups used in the appended claims.
[0085] Certain embodiments of this invention are described herein,
including the best mode known to the inventors for carrying out the
invention. Of course, variations on these described embodiments
will become apparent to those of ordinary skill in the art upon
reading the foregoing description. The inventor expects skilled
artisans to employ such variations as appropriate, and the
inventors intend for the invention to be practiced otherwise than
specifically described herein. Accordingly, this invention includes
all modifications and equivalents of the subject matter recited in
the claims appended hereto as permitted by applicable law.
Moreover, any combination of the above-described elements in all
possible variations thereof is encompassed by the invention unless
otherwise indicated herein or otherwise clearly contradicted by
context.
[0086] Furthermore, numerous references have been made to patents
and printed publications throughout this specification. Each of the
above-cited references and printed publications are individually
incorporated herein by reference in their entirety.
[0087] Specific embodiments disclosed herein may be further limited
in the claims using consisting of or and consisting essentially of
language. When used in the claims, whether as filed or added per
amendment, the transition term "consisting of excludes any element,
step, or ingredient not specified in the claims. The transition
term "consisting essentially of limits the scope of a claim to the
specified materials or steps and those that do not materially
affect the basic and novel characteristic(s). Embodiments of the
invention so claimed are inherently or expressly described and
enabled herein.
[0088] In closing, it is to be understood that the embodiments of
the invention disclosed herein are illustrative of the principles
of the present invention. Other modifications that may be employed
are within the scope of the invention. Thus, by way of example, but
not of limitation, alternative configurations of the present
invention may be utilized in accordance with the teachings herein.
Accordingly, the present invention is not limited to that precisely
as shown and described.
* * * * *