U.S. patent application number 17/158997 was filed with the patent office on 2021-05-20 for dry powder inhaler.
The applicant listed for this patent is MannKind Corporation. Invention is credited to Benoit Adamo, John J. Freeman, JR., Joseph Guarneri, P. Spencer Kinsey, Brendan Laurenzi, Chad C. Smutney.
Application Number | 20210146071 17/158997 |
Document ID | / |
Family ID | 1000005362432 |
Filed Date | 2021-05-20 |
View All Diagrams
United States Patent
Application |
20210146071 |
Kind Code |
A1 |
Kinsey; P. Spencer ; et
al. |
May 20, 2021 |
DRY POWDER INHALER
Abstract
A dry powder inhaler including replaceable cartridges containing
a dry powder for local or systemic delivery through the pulmonary
tract and lungs is disclosed. The inhalers are used with inhalable
dry powders, including medicament formulations comprising active
agents for local or systemic delivery and for the treatment of
diseases such as, pulmonary hypertension, cardiovascular disease,
anaphylaxis, diabetes, obesity, cancer, and other diseases, or
symptoms associated with these and other diseases, such as nausea,
vomiting, pain and inflammation.
Inventors: |
Kinsey; P. Spencer; (Sandy
Hook, CT) ; Laurenzi; Brendan; (Rutland, MA) ;
Smutney; Chad C.; (Watertown, CT) ; Adamo;
Benoit; (South Salem, NY) ; Guarneri; Joseph;
(Stamford, CT) ; Freeman, JR.; John J.; (New
Fairfield, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MannKind Corporation |
Westlake Village |
CA |
US |
|
|
Family ID: |
1000005362432 |
Appl. No.: |
17/158997 |
Filed: |
January 26, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16601440 |
Oct 14, 2019 |
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17158997 |
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15418388 |
Jan 27, 2017 |
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16601440 |
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62289095 |
Jan 29, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/5575 20130101;
A61M 2202/064 20130101; A61K 31/495 20130101; A61M 2205/583
20130101; A61K 31/473 20130101; A61K 9/0075 20130101; A61K 31/137
20130101; A61M 15/0091 20130101; A61M 2205/10 20130101; A61M
2205/121 20130101; A61M 2206/14 20130101; A61M 15/0025 20140204;
A61M 15/0028 20130101; A61K 31/661 20130101; A61M 15/0021 20140204;
A61M 2205/128 20130101; A61M 15/0045 20130101; A61M 2207/00
20130101; A61K 31/352 20130101 |
International
Class: |
A61M 15/00 20060101
A61M015/00; A61K 9/00 20060101 A61K009/00; A61K 31/352 20060101
A61K031/352; A61K 31/495 20060101 A61K031/495; A61K 31/661 20060101
A61K031/661 |
Claims
1. A composition comprising microcrystalline particles of fumaryl
diketopiperazine and treprostinil, wherein the treprostinil content
is up to about 20% (w/w).
2. The composition of claim 1, wherein the treprostinil content is
from about 0.5 to about 10% (w/w).
3. The composition of claim 1, further comprising a
pharmaceutically acceptable carrier or excipient.
4. The composition of claim 3, wherein the pharmaceutically
acceptable carrier or excipient is an amino acid, a sugar, a
vitamin, a buffer, a surfactant, or a phospholipid.
5. The composition of claim 4, wherein the amino acid is glycine,
L-leucine, isoleucine, trileucine, or methionine.
6. The composition of claim 4, wherein the sugar is lactose,
mannose, sucrose, mannitol, or trehalose. The composition of claim
1 further comprising a cannabinoid.
8. The composition of claim 4, wherein the surfactant is
polysorbate 80.
9. The composition of claim 4, wherein the phospholipid is
phosphotidylcholine.
10. The composition of claim 1, wherein the composition is a
spray-dried powder.
11. A method for treating pulmonary hypertension, the method
comprising: administering a dry powder composition comprising
microcrystalline particles of fumaryl diketopiperazine and
treprostinil, wherein the treprostinil content is up to about 20%
(w/w) in the composition, and treating the pulmonary
hypertension.
12. The method of claim 11, wherein the administering is by a dry
powder inhaler.
13. The method of claim 11, wherein the treprostinil content is
from about 0.5% (w/w) to about 10% (w/w).
14. The method of claim 11, wherein the dry powder composition
further comprises a cannabinoid.
15. The method of claim 12, wherein the dry powder inhaler is
configured to have flow conduits with a total resistance to flow in
a dosing configuration ranging in value from 0.065 to about 0.200
(kPa)/liter per minute.
16. The method of claim 11, wherein the administering provides a
dose of about 1 mg to about 15 mg of the dry powder
composition.
17. The method of claim 11, wherein the administering is oral.
18. The method of claim 11, wherein the administering is by
inhalation.
19. The method of claim 12, wherein the dry powder inhaler includes
a housing and a body, wherein the body comprises a mounting area
for a cartridge that includes the dry powder composition, and the
body and the housing are movable relative to one another linearly
and are operably configured to engage one another by insertion to
effectuate the cartridge to be reconfigured to attain an airflow
pathway for discharging a powder dose upon an inhalation.
20. A dry powder comprising microcrystalline particles of fumaryl
diketopiperazine and treprostinil, wherein the dry powder
composition is formed by spray drying a solution including about
0.2 to about 1.0 w/w treprostinil in ethyl alcohol and a suspension
of FDKP microcrystallites.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
16/601,440, filed Oct. 14, 2019, which is a continuation of U.S.
Ser. No. 15/418,388, filed Jan. 27, 2017, which claims benefit
under 35 U.S.C. .sctn. 119(e) from U.S. Provisional Patent
Application Ser. No. 62/289,095, filed Jan. 29, 2016, the contents
of which are incorporated herein by reference in their
entirety.
TECHNICAL FIELD
[0002] The present disclosure relates to dry powder inhalers with
replaceable cartridges comprising a dry powder for local or
systemic delivery of an active ingredient to and/or through the
lungs. The inhalers are used with inhalable dry powders, including
primarily, medicament formulations comprising an active agent or an
active ingredient for the treatment of diseases such as, pulmonary
hypertension, cardiovascular disease, diabetes, obesity, and
cancer, or symptoms associated with these and other diseases, for
example, nausea, vomiting, pain, and inflammation.
[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 to lung tissue has been achieved using a
variety of devices for inhalation, including nebulizers and
inhalers, such as metered dose inhalers and dry powder inhalers to
treat local disease or disorders. 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.
[0005] Dosing reproducibility with inhalers requires that the drug
formulation is uniform and that the dose be delivered to a subject
with consistency and reproducible results. Therefore, the dosing
system ideally should operate to completely discharge all of the
formulation effectively during an inspiratory maneuver when the
patient is taking his/her dose. However, complete powder discharge
from the inhaler is not required as long as reproducible dosing can
be achieved. 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, the materials
used to manufacture the blisters allow air into the drug
compartment and subsequently, the formulation loses viability with
prolonged storage, particularly if the formulation to be delivered
is hygroscopic. The ambient air permeating through the blisters
carries in humidity that destabilizes the active ingredient.
Additionally, dry powder inhalers which use blisters to deliver a
medicament by inhalation can suffer with inconsistency of dose
delivery to the lungs due to variations in geometry of the air
conduit architecture resulting from puncturing films or peeling
films of the blisters.
[0006] Dry powder inhalers can be breath activated or
breath-powered and can deliver drugs by converting drug particles
in a carrier into a fine dry powder which is entrained into an air
flow and inhaled by the patient. Drugs delivered with the use of a
dry powder inhaler for local lung delivery to treat allergy, asthma
and/or chronic obstructive pulmonary disease (COPD), include,
multi-dose inhalers such as FLOVENT.RTM. DISKUS, ADVAIR.RTM.
DISKUS, and PULMICORT.RTM. FLEXHALER to name a few. Dry powder
inhalers are no longer only intended to treat pulmonary disease,
but can also be used to treat systemic disease so that the drug is
delivered to the lungs and absorbed into the systemic circulation.
For example, the AFREZZA.RTM. inhaler is a unit dose dry powder
inhaler, which delivers a human insulin formulation for the
treatment of diabetes in humans. AFREZZA was approved by the U.S.
Food and Drug Administration for the treatment of diabetes type 1
and type 2 in June 2014. The AFREZZA inhaler is a breath-actuated,
multiple use inhaler which delivers a single dose of insulin
contained in a cartridge to the lungs, wherein the insulin is
absorbed into the circulation for the effective treatment of
hyperglycemia associated with diabetes. Accordingly, dry powder
inhalers can be used to effectuate safe delivery of other active
agents to the systemic circulation to treat an array of diseases or
disorders which include, but not limited to cancer, diabetes,
obesity, cardiovascular disease, neurodegenerative disease or
disorder, etc., and symptoms of such diseases or disorders,
including pain, headaches, nausea, vomiting, tremors, infection,
and the like.
[0007] Dry powder inhalers such as those described in U.S. Pat.
Nos. 7,305,986, 7,464,706, 8,499,757 and 8,636,001, which
disclosures are incorporated herein by reference in their entirety,
can generate primary drug particles, or suitable inhalation plumes
during an inspiratory maneuver by deagglomerating the powder
formulation within a capsule or cartridge comprising a single dose.
The amount of fine powder discharged from the inhaler's mouthpiece
during inhalation is largely dependent on, for example, the
inter-particulate forces in the powder formulation and the
efficiency of the inhaler to separate those particles so that they
are suitable for inhalation. The benefits of delivering drugs via
the pulmonary circulation are numerous and include rapid entry into
the arterial circulation, avoidance of drug degradation by liver
metabolism, and ease of use without discomfort.
[0008] Some dry powder inhaler products developed for pulmonary
delivery have met with some success to date. However, due to lack
of practicality and/or cost of manufacture, there is room for
improvement. Some of the persistent problems observed with prior
art inhalers, include lack of device ruggedness, inconsistency in
dosing, inconvenience of the equipment, poor deagglomeration,
problems with delivery in light of divorce from propellant use,
high manufacturing costs, and/or lack of patient compliance.
Therefore, the inventors have identified the need to design and
manufacture inhalers with consistent improved powder delivery
properties, easy to use, and having discrete configurations which
would allow for better patient compliance.
SUMMARY
[0009] The present disclosure is directed to dry powder inhalers
with replaceable cartridges comprising a dry powder for inhalation
for delivery to the lungs for local or systemic delivery into the
pulmonary circulation. The dry powder inhaler is a breath-powered
inhaler which is compact, reusable or disposable, has various
shapes and sizes, and comprises a system of airflow conduit
pathways for the effective and rapid delivery of powder medicament
to the lungs and the systemic circulation.
[0010] In one embodiment, the dry powder inhaler comprises a unit
dose cartridge, and a dry powder formulation that is to be
aerosolized and delivered to lung tissue for a local tissue effect,
or for absorption into the blood stream in the lungs and be
delivered by the systemic circulation to target tissue or organs of
a subject. In an embodiment, the dry powder can comprise, a carrier
molecule, including pharmaceutically acceptable carriers and
excipients, for example, phospholipids, polymers such as
polyethylene glycol, co-glycolides, a saccharide, a polysaccharide,
or a diketopiperazine, and an active ingredient such as peptides
and proteins, and small molecules, including,
neurotransmitters.
[0011] In one embodiment, the dry powder inhaler is reusable and is
provided with a replaceable cartridge for single use to deliver a
single dose using a single inhalation provided by a subject. In
this embodiment, multiple cartridges of a specific powder content
containing an active ingredient and packaged, for example, in a
blister pack can be provided with a single inhaler for multiple
uses by a subject. In this and other embodiments, a cartridge can
comprise a dry powder formulation for treating a variety of
conditions, diseases or disorders including, bacterial infections
such as methicillin-resistant Staphylococcus aureus; pulmonary
aspergillosis, lung transplant, pulmonary arterial hypertension
(PAH), osteoporosis, obesity, anaphylaxis or symptoms thereof,
neutropenia, chronic obstructive pulmonary disease (COPD), asthma,
allergy, or symptom of a disease or disorder including acute or
chronic pain, nausea and vomiting including chemotherapy-induced
nausea and vomiting, migraines; nervous systems disorders and
diseases, including dementia, Alzheimer's, depression, Parkinson's,
multiple sclerosis or symptoms thereof, and the like.
[0012] In one embodiment, the dry inhaler comprises a body, a
housing, and a mouthpiece configured with the body, wherein the
body comprises a mounting area for a cartridge, and the body and
the housing are movable relative to one another in a linear or
angular motion and at least a portion of the body and the housing
are operably configured to engage one another, for example, by
insertion, to attain a closed position and effectuate a cartridge
positioned in the mounting area to be reconfigured to attain an
airflow pathway for discharging a powder dose contained in the
cartridge. In embodiments herewith, the cartridge is made of rigid
materials and comprises a cup and a lid which are moveable relative
to one another in a translational motion.
[0013] In an example embodiment, a dry powder inhaler comprising a
body, a housing, a cartridge and a mouthpiece is provided, wherein
the inhaler body has a mounting area for the cartridge and the
cartridge comprises a dry powder composition comprising
microcrystalline particles of fumaryl diketopiperazine and a drug,
and wherein said housing translationally glides over the inhaler
body in a proximal to distal direction to open the inhaler, or from
a distal to proximal direction to close the inhaler, and wherein
when the inhaler is closed the inhaler has one or more rigid air
conduits for dispensing the dry powder.
[0014] In another embodiment, the dry powder inhaler comprises a
body, a lid, and a mouthpiece; wherein the mouthpiece and the lid
are configured as one unit and are moveable on the inhaler body by
an angular rotation of the mouthpiece relative to the body. In this
and other embodiments, the body comprises a distal end, a proximal
end, a bottom surface, a top surface, an interior surface, a
cartridge mounting area, and an opening in the top surface for
accessing the interior of the device and the cartridge mounting
area; wherein the mouthpiece is configured to have wing-like
structures extending on a vertical plane to the mouthpiece air
conduit to form a cover or lid-like structure in the shape of a
saddle-like structure, which upon rotation from a vertical angle to
a horizontal plane, the mouthpiece forms a lid over the open area
of the top surface to effectuate closing of the inhaler and form
part of the top portion of the inhaler. In the closed
configuration, a cartridge loaded onto the cartridge mounting area
is translated from a containment position to a dosing position so
that an air conduit is form through the cartridge and powder in the
cartridge can be emitted from the inhaler upon an inhalation
maneuver. In one aspect of this embodiment, the mouthpiece is
configured to have a mechanism for engaging with the cartridge
mounting assembly to effectuate reconfiguration of the cartridge
from containment to dosing configuration. In one embodiment, the
interior surface of the inhaler comprises projections at the
cartridge mounting area designed to hold a cartridge cup upon
loading a cartridge. In one embodiment, the mechanism for engaging
the cartridge mounting area comprises a gear and a rack, which
pivot the inhaler mouthpiece portion away from the inhaler body and
into a vertical position to the inhaler body in a horizontal plane
for opening the inhaler to a loading configuration and pivots to a
horizontal position from a vertical plane to close the inhaler into
a dosing configuration with a cartridge loaded into the
inhaler.
[0015] The dry powder comprises an inhalable dry powder, including
a pharmaceutical formulation comprising an active ingredient for
pulmonary delivery. In some embodiments, delivery is to the deep
lung (that is, to the alveolar region) and in some of these
embodiments, the active agent or active ingredient is absorbed into
the pulmonary circulation for systemic targeted or general use. The
dry powder inhaler with a unit dose cartridge, and a drug delivery
formulation comprising, for example, diketopiperazine and an active
ingredient such as peptides and proteins, including, parathyroid
hormone, insulin, oxyntomodulin and glucagon-like peptide 1. In
some embodiments, the active ingredient comprises one or more of
the active agents, which include, but are not limited to
treprostinil, salmeterol, epinephrine, tacrolimus, vancomycin,
linezolid, filgastrin, fentanyl, cannabinoids, palonosetron,
amphotericin B, phosphodiesterase inhibitors, including, PDE5
inhibitors such as sildenafil, avanafil, verdenafil and tadalafil;
prostaglandins, including prostacyclin (PG 12) and analogs thereof,
neurotransmitter agonists, neurotransmitter antagonists, including
anti-nociceptive agents, opioid analgesics such as delta opioid
agonists and antagonists, kappa opioid receptor agonists and
antagonists, mu opioid receptor agonist and antagonists.
[0016] In one embodiment, the dry powder inhaler comprises a
housing, a moveable member, and a mouthpiece, wherein the moveable
member is operably configured to move a container from a powder
containment position to a dosing position. In this and other
embodiments, the moveable member can be configured as part of a lid
assembly at the proximal end of the inhaler and forms a portion of
the cartridge mounting are. In this embodiment, the mouthpiece is
integrally built with a lid or cover portion which covers the
housing over the cartridge mounting area upon closing the inhaler.
Movement of the mouthpiece in a downwardly direction from the
horizontal plane, moves the lid or cover in an angular direction to
a vertical position and opens the inhaler to give access to the
interior of the inhaler to allow for loading and unloading a
cartridge. Conversely, movement of the mouthpiece in an upwardly
direction from a vertical plane to a horizontal plane induces
closure of the inhaler and automatically generates an opening of an
air pathway between the inhaler and a cartridge loaded onto the
cartridge mounting area.
[0017] In another embodiment, the dry powder inhaler comprises a
body, a housing, and a mouthpiece; the inhaler is structurally
configured to have an open position, a closed position, and a
mechanism operably configured to receive, hold, and reconfigure a
cartridge from a containment position to a dispensing, dosing, or
dose delivery position upon movement of said inhaler from the open
position to the closed position. In versions of this embodiment,
the mechanism can also reconfigure a cartridge installed in the
inhaler from the dosing position to a containment position after
use when the inhaler is opened to unload a used cartridge. In one
embodiment, the mechanism can reconfigure a cartridge to a
disposable or discarding configuration after use.
[0018] In one embodiment, the body of the inhaler comprises a
proximal portion comprising the mouthpiece, a body and a distal
portion comprising a housing which is structurally configured as a
slip-on cover over portions of the body and internal parts of the
inhaler; wherein the housing comprises a distal end and a proximal
end and the proximal end has an opening for adapting and
encapsulating a portion of the inhaler body. In one embodiment, the
proximal end contacts or abuts the inhaler body so as to close the
inhaler from the external environment. From the closed
configuration, the inhaler is opened by movement of an upper
portion of the housing in a distal direction over the body in a
translational motion to attain an inhaler loading and/or unloading
position to insert or remove a cartridge. With a cartridge
installed in the inhaler, translational movement of the upper
portion of the housing over the body in a distal to proximal
direction causes cartridge displacement from a containment
configuration to a dosing configuration, wherein the cartridge
container is pushed to the dosing configuration by a projection
configured in the interior of the housing that extends beyond the
opening at the proximal end when the inhaler is in an open
configuration. Movement of the top portion of the housing is
effectuated by movement of a lever having a button-like structure
at the top end and is attached to the housing and which opens and
closes a cartridge mounting area of the inhaler. In the closed
configuration, a cartridge installed in the inhaler is reconfigured
to form an additional air passageway with the mouthpiece and
ambient air to access a dry powder in cartridge in the dosing
configuration upon inhalation. In this and other embodiments, the
air passageway of a cartridge in a dosing configuration has an air
inlet and an air outlet in communication with an air passageway in
the mouthpiece, wherein the mouthpiece has its own air inlet and an
air outlet.
[0019] In one embodiment, the body of the inhaler comprises a
mouthpiece formed at a proximal end of the body and has an air
conduit which is in communication with the interior of the housing
and can be in direct communication with an air outlet of a
cartridge installed in the inhaler and with ambient air. The
inhaler body also comprises a cartridge mounting area which is
continuous in structure with the mouthpiece and has a distal part
and a proximal part; wherein the proximal part and the distal part
form one single piece with the mouthpiece and is insertable in the
housing. In one embodiment, the body and the housing can be pulled
apart to attain an inhaler open configuration for access to an
internal compartment. In an open configuration of this embodiment,
a cartridge comprising a dry powder can be loaded or installed in a
cartridge mounting area of the body, and the body and housing can
be pushed or pulled to either open or close the inhaler. In one
embodiment, the housing is moveable over the distal part of the
body from an open to a closed configuration, and together they
close the inhaler and effectuate the forming of an air conduit
through a cartridge mounted in the cartridge mounting area. In this
configuration, the inhaler attains a dosing configuration for a
powder in the cartridge to be emitted from the inhaler upon an oral
inhalation through the mouthpiece by a user. In this embodiment of
the dosing configuration, the body and the housing abut one another
and are adapted tightly together by one or more anti-slip
structures to prevent the inhaler from coming apart. Examples of
anti-slip features can include snap rings, or detents, which can
generate a sound to alert a user that the inhaler is ready for
use.
[0020] In one embodiment, the inhaler is substantially rectangular
in shape with a distal side and a proximal side, and the distal
side being shorter in length; wherein the inhaler comprises a
movable housing potion which covers the distal portion of the
inhaler body; movement of the housing over the body, or vice versa,
is effectuated by separating the inhaler body from the housing to
expose the interior of the inhaler; the movement of the housing can
be a pulling or pushing action of the housing over inhaler body,
which have parallel guide rails or tracks extending outwardly from
the longer sides (a first side and a second side) of the inhaler in
a longitudinal plane. In this embodiment, the inhaler body is
designed to have an opening at its distal end to match the opening
at the distal end of the housing to allow and guide ambient air
into an interior chamber of the inhaler upon inhalation. The
housing is also fittingly configured to have grooves or slots for
gliding over the guide rails during opening and closing movements
and also comprises stop ends to prevent disassembly of the inhaler,
and a pushing element for positioning a cartridge in a dosing
configuration after installation and closing of the inhaler when
the housing is moved in a distal to proximal direction. The pushing
element moves the cartridge cup or container relative to the
cartridge lid to form an air passageway through the cartridge and
create an air inlet and an air outlet and allow aerosolization of a
powder in the cup during an inhalation for delivering the
aerosolized particles to the inhaler mouthpiece and into a user. In
another embodiment, the pushing element also moves the cartridge
assembly to position the lid relative to the inlet opening located
in the floor of the mouthpiece. In one aspect of this embodiment,
the dry powder inhaler comprises a housing comprising a pushing
element, wherein the housing positions the cartridge to align with
the mouthpiece by translation of the housing over the inhaler body
from an open configuration to a closed configuration.
[0021] In one embodiment, the dry powder inhaler comprises a
housing having a distal end and configured with an opening for
communicating with ambient air. In one embodiment, the housing is
configured in the shape of a cover which slips over the inhaler
body, to substantially envelop a portion of the body of the
inhaler, the housing moves translationally over the distal part of
the body; wherein the inhaler can attain two configurations, a
first position which opens the inhaler to access its interior
compartment, a chamber; and a second position which abuts the
proximal end to attain closure of the inhaler. In one embodiment,
the distal portion of the housing is also moveable with respect to
the proximal end in a horizontal plane to extend distally and allow
for access to the internal compartment of the inhaler and cover,
surrounding the inhaler body. In versions of this embodiment, the
distal portion of the housing comprises parallel structures or
flanges for engaging portions of the body of the inhaler and forms
a securing mechanism, for example, for locking the body of the
inhaler with the housing to secure the two parts together and
maintain the dosing configuration. In an embodiment, the distal
portion of the housing has an opening at its distal end for
communicating with the interior of the inhaler and an opening which
is configured to slide over the inhaler body. The distal portion of
the housing also comprises an external surface, an interior surface
and a chamber configured to slide over the inhaler body. In one
embodiment, the distal portion of the inhaler comprises parallel
wing-like structure on its upper surface for directing airflow into
the mouthpiece during an inhalation.
[0022] In an alternate embodiment, the mouthpiece is engaged to the
body of the inhaler by various mechanisms including, a moveable
member such as a hinge and is integrally configured with a moveable
assembly, including a rack for moving a cartridge lid relative to
cartridge cup or container. The moveable assembly is configured to
receive and reconfigure a cartridge installed in the inhaler from a
containment position to the dosing position and can be designed to
operate manually or automatically upon movement of the inhaler
components, for example, by closing the device from an open
configuration. In one embodiment, the mechanism for reconfiguring a
cartridge comprises a slide tray or sled attached to the mouthpiece
and movably attached to the housing. In another embodiment, the
mechanism is mounted or adapted to the inhaler and comprises a
geared mechanism integrally mounted within, for example, a hinge of
the inhaler device. In yet another embodiment, the mechanism
operably configured to receive and reconfigure the cartridge from a
containment position to a dosing position comprises a cam that can
reconfigure the cartridge upon rotation of, for example, the
housing or the mouthpiece. In one embodiment, angular rotation of
the mouthpiece from the horizontal plane opens the inhaler to allow
installation or removal of a cartridge and angular movement or the
mouthpiece from a vertical plane to the horizontal plane
effectuates closure of the mouthpiece and automatic reconfiguration
of a cartridge from containment to dosing position. In an
embodiment, the gear mechanism during actuation positions the
cartridge lid relative to the inlet opening in mouthpiece and
effectuates translation of the cup to a dosing configuration.
[0023] In yet another embodiment, a dry powder inhaler comprising a
body and a mouthpiece is provided, wherein the inhaler body is
designed to have a substantially rectangular-shaped body having a
top, bottom, proximal and distal portions, and the top portion has
an opening in the distal half of the inhaler body for allowing
access to the interior compartment of the inhaler and to the
cartridge mounting area. In this embodiment, the inhaler mouthpiece
comprises two air inlets, one for communicating with ambient air at
the distal end of the inhaler and one for communicating with the
cartridge outlet port, and an air outlet at the proximal portion of
the inhaler for inserting into a subject's mouth. In this
embodiment, the body and mouthpiece are engaged together by a gear
and rack and pinion assembly, wherein a moveable cartridge cup
carrier is configured to be actuated by movement of the mouthpiece
in a horizontal plane from about 180.degree. angle parallel to the
inhaler body to about a 90.degree. angle or perpendicular to the
inhaler body, which opens the inhaler to load and/or unload a
cartridge. Movement of the mouthpiece back to 180.degree. and
parallel to the inhaler body closes the inhaler and automatically
reconfigures a cartridge placed into the inhaler to a dosing
configuration by displacing the cartridge cup to generate an air
passageway between the inhaler mouthpiece and the cartridge, and
further creating a cartridge inlet port for ambient air to transit
the interior of the cartridge to aerosolize a powder in the
cartridge upon an inhalation.
[0024] In another embodiment, a dry powder inhaler comprises a
mouthpiece, a sled, slide tray, or a carriage, a housing, a hinge,
and a gear mechanism configured to effectuate movement of the sled
or slide tray; wherein the mouthpiece and the housing are moveably
attached by the hinge.
[0025] Cartridges for use with the dry powder inhaler can be
manufactured to contain any dry powder medicament for inhalation.
In one embodiment, the cartridge is structurally configured to be
adaptable to a particular dry powder inhaler and can be made of any
size and shape, depending on the size and shape of the inhaler to
be used with, for example, if the inhaler has a mechanism which
allows for translational movement or for rotational movement. In
one embodiment, the cartridge can be configured with a securing
mechanism, for example, having a beveled edge on the cartridge top
corresponding to a matching beveled edge in an inhaler so that the
cartridge is secured in use. In one embodiment, the cartridge
comprises a container and a lid or cover, wherein the container can
be adapted to a surface of the lid and can be movable relative to
the lid or the lid can be movable on the container and can attain
various configurations depending on its position, for example, a
containment configuration, a dosing configuration or after use
configuration. During inhalation, a cartridge adapted to the
inhaler in a dosing position allows airflow to enter the enclosure
and mix with the powder to fluidize the medicament. The fluidized
medicament moves within the enclosure such that medicament
gradually exits the enclosure through the dispensing aperture,
wherein the fluidized medicament exiting the dispensing aperture is
sheared and diluted by a secondary flow not originating from within
the enclosure. A cartridge for a dry powder inhaler is described,
comprising4 an enclosure configured to hold a medicament; at least
one inlet port to allow flow into the enclosure, and at least one
dispensing port to allow flow out of the enclosure; the at least
one inlet port is configured to direct at least a portion of the
flow entering the at least one inlet port at the at least one
dispensing port within the enclosure in response to a pressure
differential.
[0026] In some embodiments, the dry powder formulation is dispensed
with consistency from the inhaler in less than about three (3)
seconds, or generally less than one (1) second. In some
embodiments, the inhaler air conduits are designed to yield high
resistance to air flow values of, for example, approximately 0.065
to about 0.200 ( kPa)/liter per minute. Therefore, in the
inhalation system, peak inhalation pressure drops of between 2 and
20 kPa produce resultant peak flow rates of about between 7 and 70
liters per minute. These flow rates result in greater than 75% of
the cartridge contents dispensed in fill masses between 1 and 50
mg. In some embodiments, these performance characteristics are
achieved by end users within a single inhalation maneuver to
produce cartridge dispense percentage of greater than 90%. In
certain embodiments, the inhaler and cartridge system are
configured to provide a single dose by discharging powder from the
inhaler as a continuous flow, or as one or more pulses of powder
delivered to a patient.
[0027] In another embodiment, the inhalation system comprises a
breath-powered dry powder inhaler, a cartridge containing a dry
powder, for delivering to the pulmonary tract and lungs, including
a medicament, wherein the medicament can comprise, for example, a
drug formulation for pulmonary delivery such as a composition
comprising a diketopiperazine in a crystalline form that
self-assembles, an amorphous form, and/or a microcrystalline form
comprising crystallites that do not self-assemble, or combinations
thereof, and an active agent. In alternate embodiments, the dry
powder may be formulated of other carriers and/or excipients other
than diketopiperazines, for example a sugar, including trehalose,
and an active agent. In some embodiments, the active agent
comprises peptides and proteins, such as insulin, glucagon-like
peptide 1, oxyntomodulin, peptide YY, exendin, or any of the
aforementioned active ingredients, analogs thereof, and the like.
The inhalation system can be used, for example, in methods for
treating conditions requiring localized or systemic delivery of a
medicament, for example, in methods for treating diabetes,
pre-diabetes conditions, allergy, infections, including septicemia,
urinary and respiratory tract infection, anaphylaxis, pulmonary
disease, renal, liver, cognitive, neurodegenerative or
cardiovascular disease, blood disorders, cancer and obesity, and
symptoms associated with these disease. In one embodiment, the
inhalation system comprises a kit, including at least one of each
of the components of the inhalation system for treating the disease
or disorder.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 depicts a perspective view of an embodiment of a dry
powder inhaler in a closed position, ready to use
configuration.
[0029] FIG. 2 depicts a perspective view of the dry powder inhaler
of FIG. 1 showing the dry powder inhaler in a fully open, cartridge
loading/unloading position and having a cartridge installed in the
cartridge mounting area, wherein the cartridge is in a powder
containment configuration.
[0030] FIG. 3 depicts a cross-sectional view through the
mid-longitudinal axis of the dry powder inhaler of FIG. 1 showing
the inhaler containing a cartridge installed in the inhaler and in
a powder dosing configuration showing the airflow pathway formed
through the cartridge chamber.
[0031] FIG. 4 depicts a cross-sectional view through the
mid-longitudinal axis of the inhaler in FIG. 1, similarly to FIG.
3, but without a cartridge.
[0032] FIG. 5 depicts a cross-sectional view through the
mid-longitudinal axis of the inhaler in FIG. 1, similarly to FIG.
4, but without a cartridge and in an open configuration.
[0033] FIG. 6 depicts a perspective view of an alternate dry powder
inhaler embodiment shown in a closed position.
[0034] FIG. 7 depicts a perspective view of the dry powder inhaler
of FIG. 6 in an open, cartridge loading/unloading position and
having a cartridge installed in the cartridge mounting area,
wherein the cartridge is in a powder containment configuration.
[0035] FIG. 8 depicts a cross-sectional view through the
mid-longitudinal axis of the dry powder inhaler of FIG. 6 showing
the closed inhaler containing a cartridge in a powder dosing
configuration showing the inhaler airflow pathway formed through
the cartridge chamber.
[0036] FIG. 9 depicts a cross-sectional view through the
mid-longitudinal axis of the inhaler in FIG. 6, similarly to FIG.
8, but without a cartridge.
[0037] FIG. 10 depicts a cross-sectional view through the
mid-longitudinal axis of the inhaler in FIG. 6, similarly to FIG.
9, but without a cartridge and in an open configuration.
[0038] FIG. 11 depicts a perspective view of yet another alternate
embodiment of a dry powder inhaler in the closed or inhalation
position.
[0039] FIG. 12 depicts the dry powder inhaler of FIG. 11 in an
open, cartridge loading/unloading position and having a cartridge
installed in the cartridge mounting area, wherein the cartridge is
in a powder containment configuration.
[0040] FIG. 13 depicts a cross-sectional view through the
mid-longitudinal axis of the dry powder inhaler of FIG. 11, showing
the closed inhaler containing a cartridge in a powder dosing
configuration showing the inhaler airflow pathway formed through
the cartridge chamber.
[0041] FIG. 14 a cross-sectional view through the mid-longitudinal
axis of the inhaler in FIG. 11, similarly to FIG. 13, but without a
cartridge.
[0042] FIG. 15 depicts a cross-sectional view through the
mid-longitudinal axis in a vertical plane of the inhaler in FIG.
12, similarly to FIG. 14, but without a cartridge and in an open
configuration.
[0043] FIG. 16 depicts a perspective view of another alternate dry
powder inhaler embodiment in a closed position and ready for
use.
[0044] FIG. 17 depicts the embodiment of FIG. 16 in an open,
cartridge loading/unloading position and having a cartridge
installed in the cartridge mounting area, wherein the cartridge is
in a powder containment configuration.
[0045] FIG. 18 depicts a cross-sectional view through the
mid-longitudinal axis of the dry powder inhaler of FIG. 16 showing
the closed inhaler containing a cartridge in a powder dosing
configuration showing the inhaler airflow pathway formed through
the cartridge chamber.
[0046] FIG. 19 depicts a cross-sectional view through the
mid-longitudinal axis of the inhaler in FIG. 16, similarly to FIG.
18, but without a cartridge.
[0047] FIG. 20 depicts a cross-sectional view through the
mid-longitudinal axis in a vertical plane of the inhaler in FIG.
17, similarly to FIG. 19, but without a cartridge and in an open
configuration.
DETAILED DESCRIPTION
[0048] In embodiments disclosed herein, dry powder inhalers
comprising a cartridge for delivering dry powders including
pharmaceutical medicaments to a subject by oral inhalation are
described. In one embodiment, the dry powder inhaler is a
breath-powered, dry powder inhaler, and the cartridge is designed
to contain an inhalable dry powder, including but not limited to
pharmaceutical formulations comprising an active ingredient,
including a pharmaceutically active substance and optionally a
pharmaceutically acceptable carrier.
[0049] The dry powder inhalers are provided in various embodiments
of shapes and sizes, and can be reusable, easy to use, inexpensive
to manufacture and/or produced in high volumes in simple steps
using plastics or other acceptable materials. Various embodiments
of the dry powder inhalers are provided herein and in general, the
inhalation systems comprise inhalers, powder-filled cartridges, and
empty cartridges. The present inhalation systems can be designed to
be used with any type of dry powder. In one embodiment, the dry
powder is a relatively cohesive powder which requires optimal
deagglomeration conditions. In one embodiment, the inhalation
system provides a re-useable, miniature breath-powered inhaler in
combination with single-use cartridges containing pre-metered doses
of a dry powder formulation.
[0050] As used herein the term "a unit dose inhaler" refers to an
inhaler that is adapted to receive a single cartridge or container
comprising a dry powder formulation and delivers a single dose of a
dry powder formulation by inhalation from a single container to a
user. It should be understood that in some instances multiple unit
doses will be required to provide a user with a specified
dosage.
[0051] As used herein a "cartridge" is an enclosure configured to
hold or contain a dry powder formulation, a powder containing
enclosure, which has a cup or container and a lid. The cartridge is
made of rigid materials, and the cup or container is moveable
relative to the lid in a translational motion or vice versa.
[0052] As used herein a "powder mass" is referred to an
agglomeration of powder particles or agglomerate having irregular
geometries such as width, diameter, and length.
[0053] As used herein a "unit dose" refers to a pre-metered dry
powder formulation for inhalation. Alternatively, a unit dose can
be a single container having multiple doses of formulation that can
be delivered by inhalation as metered single amounts. A unit dose
cartridge/container contains a single dose. Alternatively it can
comprise multiple individually accessible compartments, each
containing a unit dose.
[0054] As used herein, the term "about" is used to indicate that a
value includes the standard deviation of error for the device or
method being employed to determine the value.
[0055] As used herein, the term "microparticle" refers to a
particle with a diameter of about 0.5 to about 1000 .mu.m,
irrespective of the precise exterior or interior structure.
Microparticles having a diameter of between about 0.5 and about 10
microns can reach the lungs, successfully passing most of the
natural barriers. A diameter of less than about 10 microns is
required to navigate the turn of the throat and a diameter of about
0.5 .mu.m or greater is required to avoid being exhaled. To reach
the deep lung (or alveolar region) where most efficient absorption
is believed to occur, it is preferred to maximize the proportion of
particles contained in the "respirable fraction" (RF), generally
accepted to be those particles with an aerodynamic diameter of
about 0.5 to about 6 though some references use somewhat different
ranges, as measured using standard techniques, for example, with an
Anderson Cascade Impactor. Other impactors can be used to measure
aerodynamic particle size such as the NEXT GENERATION IMPACTOR.TM.
(NGI.TM., MSP Corporation), for which the respirable fraction is
defined by similar aerodynamic size, for example <6.4 In some
embodiments, a laser diffraction apparatus is used to determine
particle size, for example, the laser diffraction apparatus
disclosed in U.S. Pat. No. 8,508,732, which disclosure is
incorporated herein in its entirety for its relevant teachings
related to laser diffraction, wherein the volumetric median
geometric diameter (VMGD) of the particles is measured to assess
performance of the inhalation system. For example, in various
embodiments cartridge emptying of >80%, 85%, or 90% and a VMGD
of the emitted particles of <12.5 .mu.m, <7.0 .mu.m, or
<4.8 .mu.m can indicate progressively better aerodynamic
performance.
[0056] Respirable fraction on fill (RF/fill) represents the
percentage (%) of powder in a dose that is emitted from an inhaler
upon discharge of the powder content filled for use as the dose,
and that is suitable for respiration, i.e., the percent of
particles from the filled dose that are emitted with sizes suitable
for pulmonary delivery, which is a measure of microparticle
aerodynamic performance. As described herein, a RF/fill value of
40% or greater than 40% reflects acceptable aerodynamic performance
characteristics. In certain embodiments disclosed herein, the
respirable fraction on fill can be greater than 50%. In an
exemplary embodiment, a respirable fraction on fill can be up to
about 80%, wherein about 80% of the fill is emitted with particle
sizes <5.8 .mu.m as measured using standard techniques.
[0057] As used herein, the term "dry powder" refers to a fine
particulate composition that is not suspended or dissolved in a
propellant, or other liquid. It is not meant to necessarily imply a
complete absence of all water molecules.
[0058] As used herein, "amorphous powder" refers to dry powders
lacking a definite repeating form, shape, or structure, including
all non-crystalline powders.
[0059] In exemplary embodiments herewith, the present devices can
be manufactured by several methods and from various materials. In
one embodiment, the inhalers and cartridges are made, for example,
by injection molding techniques, thermoforming, blow molding,
pressing, 3D printing, and the like using various types of plastic
materials, including, polypropylene, cyclicolephin co-polymer,
nylon, and other compatible polymers and the like. In certain
embodiments, the dry powder inhaler can be assembled using top-down
assembly of individual component parts. In some embodiments, the
inhalers are generally provided in compact sizes, for example, from
about 1 inch to about 5 inches in dimension, and generally, the
width and height are less than the length of the device. In certain
embodiments the inhaler is provided in various shapes including,
relatively rectangular bodies, although other shapes can be used
such as cylindrical, oval, tubular, squares, oblongs, and circular
forms.
[0060] In embodiments described and exemplified herewith, the
inhalers effectively fluidize, deagglomerate or aerosolize a dry
powder formulation by using at least one relatively rigid flow
conduit pathway for allowing an airflow to enter the inhaler. For
example, the inhaler is provided with a first air flow pathway for
entering and exiting a cartridge containing the dry powder, and a
second air pathway which can merge with the first air flow pathway
exiting the cartridge. The flow conduits, for example, can have
various shapes and sizes depending on the inhaler configuration. In
one embodiment, the inhaler are high resistance inhalers resistance
value of, for example, approximately 0.065 to about 0.200 (
kPa)/liter per minute. Therefore, in the system, peak inhalation
pressure drops of between 2 and 20 kPa produce resultant peak flow
rates of about between 7 and 70 liters per minute. These flow rates
result in greater than 75% of the cartridge contents dispensed in
fill masses between 1 and 50 mg. In some embodiments, these
performance characteristics are achieved by end users within a
single inhalation maneuver to produce cartridge dispense percentage
of greater than 90% of the powder contained in a cartridge.
[0061] An embodiment of dry powder inhaler 10 is exemplified in
FIGS. 1-5. Inhaler 10 comprises two elements, body 12 and
mouthpiece cover 11. In this embodiment, dry powder inhaler 10 is
relatively rectangular, with longer sides extending in the
longitudinal plane and is designed to attain two configurations,
i.e., a first configuration, which is a closed or dosing
configuration as illustrated in FIGS. 1, 3 and 4, and a second
configuration or open or cartridge loading/unloading configuration
as illustrated in FIGS. 2 and 5. As depicted in FIGS. 1-5, dry
powder inhaler 10 has a relatively rectangular body 12 which is
manufactured as a single element and has a proximal end 14 which is
substantially C-shaped comprising a mouthpiece 15 for contacting
the user's lips or oral cavity, and a distal end 16, with a right
side 17, left side 18, top side 19 and bottom side 20. Mouthpiece
15 has an outlet 13 and a first inlet 21 for allowing bypass air to
flow through an air conduit 5 external to the interior of the
inhaler body 12 but in communication with the chamber or interior
of the inhaler body through a second inlet 3 located in the bottom
portion of the mouthpiece in contact with inhaler body 12. The
second inlet specifically is for contacting outlet port or
dispensing port 31 of a cartridge installed in the cartridge
mounting area. FIG. 3 depicts mouthpiece 15 is narrower in shape at
its distal end and tapers outwardly towards the proximal end and is
configured with an air conduit 5 which is similar to its exterior
shape. Mouthpiece 15 is designed as a single element having a
saddle-like or wing-like structures 22, 22' extending partially
outwardly to the junction between top side 19 and downwardly over
the right side 17 and left side 18 forming a portion of the top
side 19 and covering or resting over right side 17 and left side 18
of the inhaler body 12 for closing inhaler 10 as mouthpiece cover
11. To prevent movement of mouthpiece cover 10 during use, locking
mechanisms can be provided, including snap fits, detents such as
detent 25 for adapting to element 26.
[0062] FIGS. 2 and 5 illustrate inhaler 10 in an open configuration
showing the interior of body 12. FIG. 5 depicts inhaler 10 in an
open configuration and FIG. 2 represents inhaler 10 with a
cartridge 24 installed in the cartridge mounting assembly 23. To
attain an open configuration, mouthpiece 11 is pushed downwardly
from its mouthpiece 15, and grasping the distal top portion of
inhaler 12, which actuates the entire element 11 to rotate
angularly to about a 90.degree. to lie perpendicularly with body
12. Movement of the mouthpiece cover 11 is effectuated by providing
the inhaler with a hinge, for example, a rack and pinion comprising
an axle 32 connected to a gear having a rack, which is engaged to a
rack on a moveable cartridge mounting area 23.
[0063] FIG. 3 is a mid-longitudinal section of inhaler 10 with a
cartridge mounted in a dosing position and illustrates the pushing
element 33 of moveable cartridge mounting area 23 fully positioning
the cartridge in the dosing configuration, wherein an air
passageway is created having air inlet 29 and air outlet 31 to
access the interior of the cartridge cup 30. In this embodiment,
upward movement of mouthpiece cover 11, while holding mouthpiece 15
to a horizontal plane, closes the inhaler as shown in FIG. 1 and
while moving, portions of the movable portion of the cartridge
assembly in the cartridge mounting area 23 are pushed distally by a
moveable element in the proximal portion of the cartridge mounting
area, resulting in distal movement of the cartridge lid 28 over the
cartridge cup 30, which cup 30 is retained at the mounting area by
rigid projections 27, 27' from the interior surface from the bottom
side 20 of body 12. After use, by opening inhaler 10, the cartridge
is returned to a discarding/unloading position and the cycle can be
repeated with a new dose. FIG. 4 depicts a mid-longitudinal section
of the inhaler in FIG. 1 in the closed configuration without a
cartridge illustrating the relationship of the interior of the
device.
[0064] FIG. 5 depicts inhaler 10 in an open configuration without a
cartridge through the mid-longitudinal section of the inhaler of
FIG. 1. Illustrating the cartridge mounting area with its rigid
projection protruding from the interior bottom surface 20 of
inhaler body 12, cartridge lid pushing element 33 of moveable
cartridge mounting area 23 for translating a lid over a cup of a
cartridge to attain a dosing configuration upon movement of the
mouthpiece cover 11 to the closed position.
[0065] FIGS. 6-10 illustrate an alternate embodiment, wherein dry
powder inhaler 40 comprises body 42, mouthpiece 45 having at least
two air inlets and one outlet 46, and a cartridge mounting and
reconfiguring mechanism 47. Inhaler 40 also comprises a
discontinuous top side 51, a proximal end 48, a distal end 49, and
a bottom portion 42 which can be configured with segmental rib-like
structures 50. In this embodiment, inhaler 40 is in the closed
position. The distal half of top portion 49 of inhaler body 42 has
an opening or slot 53 in the mid-longitudinal plane for
accommodating moveable lever 52, for engaging with a moveable rack
54 in the interior compartment of inhaler body 42 to effectuate
movement of the cartridge mounting and reconfiguring mechanism 47,
which comprises a rack with pushing elements for translating the
lid of a cartridge over a cup or translating a cup under a secured
lid of a cartridge. In this embodiment, upon manual actuation of
lever 52 distally, the inhaler is configured in the cartridge
loading position. FIG. 7 depicts inhaler 40 in an open
configuration with a cartridge installed or mounted in the
cartridge mounting area 55. In preparing a dose for pulmonary
inhalation, a user can place or install a cartridge 56 in the
inhaler as shown in FIG. 7. After cartridge 56 is installed or
loaded into cartridge mounting area 55, lever 52 is moved
proximally until it cannot move anymore. FIG. 8 depicts a
mid-longitudinal section through inhaler 40 in a closed or dosing
configuration with a cartridge mounted in the cartridge mounting
and reconfiguring area 55 depicting pushing element 66 displacing
cup 58 under lid 59 in the dosing configuration. While lever 52 is
in motion, pushing elements 66 on the interior of the inhaler
engaged to lever 52 actuate the pushing elements 66 of the rack to
move cartridge 56 and reconfigure its lid to create an air conduit
with an air inlet 64, and an air outlet 65 which is in
communication with the second inlet 63 of mouthpiece 45 for
delivering a powder to the mouthpiece air conduit 61, and outlet 46
during an inhalation. Air intake through first inlet 62 bypasses
the cartridge compartment upon inhalation. The discontinuous area
on inhaler top side 51 allows access to cartridge mounting area 55.
FIG. 8 also shows lever 52 engaged to the axle 60 of reconfiguring
mechanism 47.
[0066] FIG. 9 illustrates inhaler 40 closed, similarly to FIG. 8,
except without a cartridge and positioned at the proximal end of
inhaler body 42. In this configuration, FIG. 9 depicts the
relationships of rack 54 comprising pushing elements 66 and the
closed proximity of horizontal first inlet 62 forming almost a
right angle with second inlet 63 of mouthpiece 45 for effectuating
powder deagglomeration by shearing forces during an inhalation of a
powder dose. FIG. 10 illustrates inhaler 40 as depicted in FIG.9
without a cartridge in an open configuration through a
mid-longitudinal section, showing the position of lever 52 and the
rack 54 for holding a cartridge and position in the center portion
of inhaler body 42 end of the inhaler interior. FIG. 10 also shows
rack 54 integrally engaged to the moveable mechanism as depicted by
axle 60 in contact with lever 52 for mechanically pushing rack
54.
[0067] FIGS. 11-15 depicts yet another alternate inhaler, inhaler
70, wherein mouthpiece 71 is moveable relative to inhaler body 72
by a gear mechanism 85 which moves by rotation in the horizontal
plane laterally to an angle of about 90.degree. from the
longitudinal axis A of inhaler 70 to allow access into the interior
of inhaler body 72 to mount or dismount a cartridge. Mouthpiece 71
further comprises air inlet 74, air outlet 73, and a second air
inlet in communication with the interior of inhaler body 72. FIG.
11 depicts inhaler 70 in a closed or dosing configuration. FIG. 12
depicts inhaler 70 in an open configuration for installing or
loading a cartridge, as exemplified by cartridge 76. Inhaler 70 is
designed with a substantially rectangular body 72 having a proximal
end 75, distal end 77, bottom 78, right side 79, left side 80, and
top 81 which is closed at one end and open at its distal end.
Mouthpiece 71 also comprises lateral extensions 82 spanning from
the center air conduit and configured as one piece which cover the
inhaler body top surface 81. Top surface area 81 comprises a stop
end 83 configured to prevent mouthpiece 71 from rotating beyond a
perpendicular plane with inhaler body 72. Movement by rotation of
mouthpiece 71 to the open position actuates a mounting and
reconfiguring mechanism to be accessible at the open area of the
top surface 81 of body 72 as seen in FIG. 12. FIGS. 13 and 14
depict mid-longitudinal sections of inhaler 70 with (FIG. 13) and
without (FIG. 14) a cartridge, respectively, to show the movement
of rack 86 in the closed or dosing configuration by gear mechanism
90. Movement of mouthpiece 71 from right side 79 to left side 80 in
horizontal plane to the inhaler body actuates the gear mechanism to
move cup 92 relative to lid 93 by translational motion in a
proximal direction to create an air flow passageway having air
inlet 94 and air outlet 95 through the cup interior, which
communicates with inlet 89 and air conduit 96 of inhaler 70 for
emitting powder contained in cup 92. In this embodiment, the
mounting and reconfiguring mechanism comprises a shelf structure 99
built within the top surface of mounting area 91 for placing the
cartridge lid 93 which extends outwardly from cup 92 and rests on
shelf structure 99 to be immobilized, while cup 92 is seated in
rack 86 and the cartridge is in a powder containment
configuration.
[0068] In yet another dry powder inhaler embodiment depicted in
FIGS. 16-20, there is provided inhaler 100 comprising a two part
assembly, an inhaler body 101 and a housing or cover 102 which
envelops portions of inhaler body 101. In one embodiment
illustrated in FIG. 16, inhaler 100 comprises inhaler body 101
which comprises a proximal portion 103 comprising mouthpiece 104,
and a distal portion 105, and comprising a housing 102 which is
structurally configured as a slip-on cover over portions of the
body and internal parts of the inhaler; wherein housing 102 as
depicted in FIG. 17 comprises a distal end 107 and a proximal end
106, and proximal end 106 has an opening for adapting and
encapsulating a portion of inhaler body 105 and also comprises
projections 113 from its upper surface which direct airflow to
enter mouthpiece 104 air conduit 115 upon inhalation. In an
embodiment, the proximal end 106 contacts or abuts inhaler body 101
so as to close inhaler 100 from the external environment as
illustrated in FIG. 16. From the closed configuration, inhaler 100
is opened by movement of the housing 102 in a distal direction over
body 105 in a translational motion to attain an inhaler loading
and/or unloading position to insert or remove a cartridge. FIG. 17
illustrates inhaler 100 in an open configuration wherein housing
102 has been pulled apart distally to allow access into inhaler
body distal portion 105. In this and other embodiments, FIG. 17
depicts cartridge 108 installed in cartridge mounting area 109 of
inhaler 100 and showing the lid and outlet port 110 which
communicates with air conduit in mouthpiece spanning inlet 111 and
outlet 112 through secondary inlet port in mouthpiece 104. Mounting
area 109 is configured in the shape of the cartridge 108 for proper
fitting and to indicate a visual cue to a user for proper
orientation of a cartridge during installation.
[0069] FIG. 18 also depicts a mid-longitudinal section of inhaler
100 in a closed, dosing configuration illustrating the position of
a cartridge cup 116 relative to lid 117 upon translational movement
of the housing 102 over body 105 in a distal to proximal direction
which caused cartridge 108 displacement from a containment
configuration to a dosing configuration, wherein cartridge
container cup 116 is pushed to the dosing configuration by a
protruding rigid element in the interior bottom portion of housing
102 that extends beyond the opening 106 at the proximal end 106 in
a horizontal plane. Protruding rigid element 118 can also comprise
one or more vertical projections to facilitate removal of cartridge
108 after use. Moreover, in a closed configuration, a cartridge
installed in inhaler 100 is reconfigured to form an additional air
passageway through cartridge cup 116 from air inlet 119 and air
outlet 120 and with the mouthpiece for ambient air to access a dry
powder in cartridge 108 in the dosing configuration upon
inhalation. In this and other embodiments, upon an inhalation air
enters the air passageway of cartridge 108 in a dosing
configuration through air inlet 119, and aerosolizes a dry powder
particles to be entrained in the air and aerosolized powder then
exits through air outlet 120, which is in communication with an air
inlet in the air conduit 115 of mouthpiece 104 and in mouthpiece
104 air passageway further shearing of powder occurs prior to
powder exiting through mouthpiece outlet 112.
[0070] In one embodiment, the body 101 of the inhaler comprises a
mouthpiece integrally formed at a proximal end of body 101 and
comprises air conduit 115 which is in communication with the
interior of body 101 and housing 102 and can be in direct
communication with an air outlet 120 of cartridge 108 installed in
inhaler 100 and with ambient air. Inhaler body 101 also comprises a
cartridge mounting area 121, which is continuous in structure with
the mouthpiece and has a distal part 105 and a proximal part 103;
wherein proximal part 103 and distal part 105 form one single piece
with mouthpiece 104 and distal part 105 is insertable into housing
102. In one embodiment illustrated in FIGS. 17 and 20, body 101 and
housing 102 can be pulled apart manually to attain an inhaler open
configuration for access to an internal compartment. In an open
configuration of this embodiment, cartridge 108 comprising a dry
powder can be loaded or installed in cartridge mounting area of
body part 105 in a proper orientation as indicated by visual cues,
and body 105 and housing 102 can be pushed or pulled to either open
or close inhaler 100. In one embodiment, the housing is moveable
over distal part 105 of body 101 from an open to a close
configuration, and together they close inhaler 100 when they are in
contact with one another.
[0071] FIGS. 18 and 19 depict inhaler 100 in a closed or dosing
configuration, wherein the closing action effectuates movement of
the cartridge 108 to a dosing position and wherein the cartridge
cup is further pushed with protruding element 118 to be
reconfigured independently of lid 117 to form of an air conduit
through cartridge 108 mounted in the cartridge mounting area 109.
In this configuration, the inhaler attains a dosing configuration
for a powder in cup 116 to be emitted from the inhaler upon an oral
inhalation by a user through mouthpiece 104. In this embodiment
depicted in FIG. 18 and dosing configuration, the body and the
housing abut one another and are adapted tightly together by one or
more anti-slip structures to prevent the inhaler from disassembly.
Examples of anti-slip features are snap rings, or detents, which
can generate a sound to alert a user that the inhaler is ready for
use. FIGS. 17 and 20 depict inhaler 100 in an open configuration.
In this embodiment inhaler 100 is substantially rectangular in
shape with the distal and proximal sides being smaller in length;
wherein movement of housing 102 over body part 105, or vice versa,
is effectuated by pulling or pushing and inhaler body 105, which
movement is facilitated by body comprising guide rails or tracks
123 extending outwardly from the longer sides (a first side and a
second side) of inhaler body 105 in a longitudinal plane. In this
embodiment, inhaler body 105 is designed to have an opening at its
distal end to match the opening at the distal end of the housing to
allow and guide ambient air into the interior chamber of inhaler
100 upon inhalation. Inhaler housing 102 is also fittingly
configured to have grooves or slots 124 for gliding over guide
rails 123 during movement and also comprises one or more stop ends
to prevent disassembly of inhaler 100. Pushing or protruding
element 118 is designed for positioning a cartridge in a dosing
configuration after installation and closing of inhaler 100. The
protruding or pushing element 118 moves cartridge cup or container
116 relative to cartridge lid 117 to form an air passageway through
the cartridge and create an air inlet 119 and an air outlet 120 to
allow aerosolization of a powder in the cup during an inhalation
for delivering the aerosolized particles to the inhaler mouthpiece
air conduit 115 and into the user.
[0072] In versions of inhaler 100, the distal portion of the
housing comprises parallel structures or flanges for engaging
portions of the body of the inhaler to form a securing mechanism,
for example, for locking the body of the inhaler with the housing
to secure the two parts together and maintain the dosing
configuration. In an embodiment, distal portion 107 of housing 102
has an opening at its distal end for communicating with the
interior of inhaler 100 and an opening 106 which is configured to
slide over inhaler body 105. Distal portion 107 of housing 102 also
comprises an external surface, an interior surface and a chamber
configured to envelop inhaler body 105. In one embodiment, housing
102 comprises parallel wing-like structure 113 on its upper surface
for directing airflow into mouthpiece 104 during an inhalation.
Inhaler body part 105 is designed with a groove in its
mid-longitudinal plane for adapting protruding or pushing element
118 to glide to push the cartridge or to stop the housing from
disassembling. Inhaler body part 105 is also configured to have
detents at its distal end for engaging with housing 102 and
securing the two inhaler parts.
[0073] Cartridge embodiments for use with the inhalers are
described in U.S. Pat. No. 8,424,518, which disclosure is
incorporated by reference in its entirety. In summary, a cartridge
for use with the inhaler embodiments disclosed herewith comprises
two parts, although other embodiments may be envisioned. The
cartridges are configured to contain a dry powder medicament in a
storage, tightly sealed or contained position and can be
reconfigured within an inhaler from a powder containment position
to an inhalation or dosing configuration. In certain embodiments,
the cartridge comprises a lid and a cup having one or more
apertures, a containment configuration and dosing configuration, an
outer surface, an inner surface defining an internal volume; and
the containment configuration restricts communication to the
internal volume and the dispensing configuration forms an air
passage through said internal volume to allow an air flow to enter
and exit the internal volume in a predetermined manner. For
example, the cartridge container can be configured so that an
airflow entering the cartridge air inlet is directed across the air
outlets within the internal volume to meter the medicament leaving
the cartridge so that rate of discharge of a powder is controlled;
and wherein airflow in the cartridge can tumble substantially
perpendicular to the air outlet flow direction, mix and fluidize a
powder in the internal volume prior to exiting through dispensing
apertures. Cartridges for use with the instant inhalers can be
provided in individual blisters or grouped in a blister depending
in the need of the subject or the hygroscopicity of the formulation
with respect to stability of powder and/or the active
ingredient.
[0074] In embodiments described herein, the dry powder inhaler and
cartridge form an inhalation system which can be structurally
configured to effectuate a tunable or modular airflow resistance,
as it can be effectuated by varying the cross-sectional area or
geometries of the air conduits at any section of the airflow
pathway of the system. In one embodiment, the dry powder inhaler
system geometries of the air conduits can generate an airflow
resistance value of from about 0.065 to about 0.200 ( kPa)/liter
per minute. In other embodiments, a check valve may be employed to
prevent air flow through the inhaler until a desired pressure drop,
such as 4 kPa has been achieved, at which point the desired
resistance reaches a value within the range given herewith.
[0075] In yet another embodiment, an inhalation system for
delivering a dry powder formulation to a patient is provided. The
system comprises an inhaler including a container mounting area
configured to receive a container and a mouthpiece having at least
two inlet apertures and at least one exit aperture; wherein one
inlet aperture of the at least two inlet apertures is in fluid
communication with the container area, and one of the at least two
inlet apertures is in fluid communication with the at least one
exit aperture via a flow path configured to bypass the container
area to deliver the dry powder formulation to the patient; wherein
the flow conduit configured to bypass the container area delivers
30% to 90% of the total flow going through the inhaler during an
inhalation.
[0076] In another embodiment, a dry powder inhalation system for
delivering a dry powder formulation to a patient is also provided.
The system comprises a dry powder inhaler including a mounting and
reconfiguring region for a cartridge; said dry powder inhaler and
cartridge combined are configured to have at least two airflow
pathways which are rigid flow conduits in a dosing configuration
and a plurality of structural regions that provide a mechanism for
powder deagglomeration of the inhalation system in use; wherein at
least one of the plurality of mechanisms for deagglomeration is an
agglomerate size exclusion aperture in the container region having
a smallest dimension between 0.5 mm and 3 mm.
[0077] In embodiments disclosed herein, a dry powder formulation
can consist of a crystalline powder, an amorphous powder, or
combinations thereof, wherein the powder is dispensed with
consistency from the inhaler in less than about 2 seconds. The
present inhaler system has a high resistance value of approximately
0.065 to about 0.200 ( kPa)/liter per minute. Therefore, in the
system comprising a cartridge, peak inhalation pressure drops
applied of between 2 and 20 kPa produce resultant peak flow rates
of about through the system of between 7 and 70 liters per minute.
These flow rates result in greater than 75% of the cartridge
contents dispensed in fill masses between 1 and 30 mg, or up to 50
mg of powder. In some embodiments, these performance
characteristics are achieved by end users within a single
inhalation maneuver to produce cartridge dispense percentage of
greater than 90%. In certain embodiments, the inhaler and cartridge
system are configured to provide a single dose by discharging
powder from the inhaler as a continuous flow, or as one or more
pulses of powder delivered to a patient. In an embodiment, an
inhalation system for delivering a dry powder formulation to a
patient's lung(s) is provided, comprising a dry powder inhaler
configured to have flow conduits with a total resistance to flow in
a dosing configuration ranging in value from 0.065 to about 0.200 (
kPa)/liter per minute. In this and other embodiments, the total
resistance to flow of the inhalation system is relatively constant
across a pressure differential range of between 0.5 kPa and 7
kPa.
[0078] The structural configuration of the inhaler allows the
deagglomeration mechanism to produce respirable fractions greater
than 50% and particles of less than 5.8 .mu.m. The inhalers can
discharge greater than 85% of a powder medicament contained within
a container during an inhalation maneuver. Generally, the inhalers
herein depicted herewith can discharge greater that 90% of the
cartridge contents or container contents in less than 3 seconds at
pressure differentials between 2 and 5 kPa with fill masses ranging
up to 30 mg or 50 mg.
[0079] While the present inhalers are primarily described as
breath-powered, in some embodiments, the inhaler can be provided
with a source for generating the pressure differential required to
deagglomerate and deliver a dry powder formulation. For example, an
inhaler can be adapted to a gas powered source, such as compressed
gas stored energy source, such as from a nitrogen can, which can be
provided at the air inlet ports. A spacer can be provided to
capture the plume so that the patient can inhale at a comfortable
pace.
[0080] In embodiments described herewith, the inhaler can be
provided as a reusable inhalers for delivering a single unit dose.
A reusable inhaler means that it can be used multiple times which
can be predetermined depending on the formulation to be delivered
and discarded once it has reached its maximal usage.
[0081] These present devices and systems are useful in pulmonary
delivery of powders with a wide range of characteristics.
Embodiments include systems comprising an inhaler, an integral or
installable unit dose cartridge comprising the desirable powder
doses. Pulmonary delivery of powders include carriers and
excipients which safety and efficacy have been proven in
commercially available products. An exemplary embodiment is fumaryl
diketopiperazine, also known as
3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; FDKP. FDKP
produces microparticles which can be self-assembled aggregates of
crystalline plates in suspension; can be manufactured as amorphous
powders or combinations thereof depending on the process used as
disclosed in U.S. Pat. Nos. 7,820,676; 7,709,639 and 8,551,528,
which disclosures are incorporated herein by reference for their
relevant subject matter. Dry powders manufactured using
diketopiperazines can be made by lyophilizing, or spray-drying
solution or suspensions of the various desired formulations. DKP
crystalline microparticles with a specific surface area (SSA) of
between about 35 and about 67 m2/g exhibit characteristics
beneficial to delivery of drugs to the lungs such as improved
aerodynamic performance and improved drug adsorption. In some
embodiments, high capacity crystalline FDKP microparticles for use
in formulations containing peptides, for example, have a specific
surface area which is less than 35 m2/g and specific surface area
of these particles can range from about 19 m2/g to about 30 m2/g or
from about 28 m2/g to about 71 m2/g, or from about 19 m2/g to about
57 m2/g depending on the amount of active agent. In some
embodiments, microparticles of FDKP with a peptide active agent as
exemplified by insulin can have specific surface area ranging from
about 4 m2/g to about 30 m2/g and have improved aerodynamic
properties as measured by flyability and flowability.
[0082] In one embodiment, the dry powder medicament may comprise,
for example, a diketopiperazine and a pharmaceutically active
ingredient. In this embodiment, the pharmaceutically active
ingredient or active agent can be any type depending on the disease
or condition to be treated. In another embodiment, the
diketopiperazine can include, for example, symmetrical molecules
and asymmetrical diketopiperazines having utility to form
particles, microparticles and the like, which can be used as
carrier systems for the delivery of active agents to a target site
in the body. The term "active agent" is referred to herein as the
therapeutic agent, or molecule such as protein or peptide or
biological molecule, and small molecules, including
neurotransmitters that can be encapsulated, associated, joined,
complexed or entrapped within or adsorbed onto the diketopiperazine
formulation. Any form of an active agent can be combined with a
diketopiperazine. The drug delivery system can be used to deliver
biologically active agents having therapeutic, prophylactic or
diagnostic activities.
[0083] The fumaryl diketopiperazine 3 ,6-bi
s(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; FDKP) is one
preferred diketopiperazine for pulmonary applications:
##STR00001##
[0084] Microparticles for pulmonary delivery having a diameter of
between about 0.5 and about 10 .mu.m can reach the lungs and can
reach the systemic circulation and deliver an active agent. A
diameter of less than about 10 .mu.m is required to navigate the
turn of the throat and a diameter of about 0.5 .mu.m or greater is
required to avoid being exhaled. Generally, microparticles having
diameters greater than 10 .mu.m or greater than 20 .mu.m are useful
for local delivery to the respiratory tract and lungs.
[0085] Microparticles having a diameter of between about 0.5 and
about 10 microns can reach the lungs, successfully passing most of
the natural barriers. A diameter of less than about 10 microns is
required to navigate the turn of the throat and a diameter of about
0.5 microns or greater is required to avoid being exhaled.
Embodiments disclosed herein show that microparticles with a
specific surface area (SSA) of between about 4 and about 71 m2/g
exhibit characteristics beneficial to delivery of drugs to the
lungs such as improved aerodynamic performance and improved drug
adsorption. In some embodiments herewith, there is provided a
composition comprising crystalline fumaryl diketopiperazine (FDKP)
microparticles having a specific trans isomer content of about 35
to about 65%, or 45 to about 63%, or 45 to about 60%.
[0086] In certain embodiments, a diketopiperazine based composition
for pulmonary delivery is provided with an active agent, wherein
the diketopiperazine is fumaryl diketo piperazine and comprises a
plurality of substantially uniformly formed, microcrystalline
particles, wherein the particles have a substantially hollow
spherical structure and comprise a shell comprising crystallites of
a diketopiperazine that do not self-assemble, and the particles
have a volumetric mean geometric diameter less than equal to 5
.mu.m; wherein the particles are formed by a method comprising the
step of combining diketopiperazine in a solution and a solution of
acetic acid without the presence of a surfactant and concurrently
homogenizing in a high shear mixer at high pressures of up to 2,000
psi to form a precipitate; washing the precipitate in suspension
with deionized water; concentrating the suspension and drying the
suspension in a spray drying apparatus.
[0087] In some embodiments, a diketopiperazine-based composition
for pulmonary delivery is provided with an active agent, wherein
the diketopiperazine is a salt of fumaryl diketopiperazine,
including sodium, magnesium, and the composition comprises the
amorphous powder.
[0088] A system for the delivery of an inhalable dry powder is also
provided, comprising: a) a dry powder comprising a medicament, and
b) an inhaler comprising a powder containing cartridge, the
cartridge comprising a gas inlet and a gas outlet, and a housing in
which to mount the cartridge and defining two flow pathways, a
first flow pathway allowing gas to enter the gas inlet of the
cartridge, a second flow pathway allowing gas to bypass the
enclosure gas inlet, and a mouthpiece and upon applying a pressure
drop of .gtoreq.2 kPa across the inhaler plume of particles is
emitted from the mouthpiece wherein 50% of said emitted particles
have a VMAD of .ltoreq.10 wherein flow bypassing the cartridge gas
inlet is directed to impinge upon the flow exiting the enclosure
substantially perpendicular to the gas outlet flow direction.
[0089] Active agents for use in the compositions and methods
described herein can include any pharmaceutical agent. These can
include, for example, synthetic organic compounds, proteins and
peptides, polysaccharides and other sugars, lipids, inorganic
compound, and nucleic acid sequences, having therapeutic,
prophylactic, or diagnostic activities. Peptides, proteins, and
polypeptides are all chains of amino acids linked by peptide
bonds.
[0090] Examples of active agents that can be delivered to a target
or site in the body using the diketopiperazine formulations,
include hormones, anticoagulants, immunomodulating agents,
vaccines, cytotoxic agents, neurotransmitters agonists and
antagonists, antibiotics, vasoactive agents, neuroactive agents,
anaesthetics or sedatives, steroids, decongestants, antivirals,
antisense, antigens, and antibodies. More particularly, these
compounds include insulin, heparin (including low molecular weight
heparin), calcitonin, felbamate, sumatriptan, parathyroid hormone
and active fragments thereof, growth hormone, erythropoietin, AZT,
DDI, granulocyte macrophage colony stimulating factor (GM-CSF),
lamotrigine, chorionic gonadotropin releasing factor, luteinizing
releasing hormone, beta-galactosidase, exendin, vasoactive
intestinal peptide, and argatroban. Antibodies and fragments
thereof can include, in a non-limiting manner, anti-SSX-241-49
(synovial sarcoma, X breakpoint 2), anti-NY-ESO-1 (esophageal tumor
associated antigen), anti-PRAME (preferentially expressed antigen
of melanoma), anti-PSMA (prostate-specific membrane antigen),
anti-Melan-A (melanoma tumor associated antigen) and
anti-tyrosinase (melanoma tumor associated antigen).
[0091] In certain embodiments, a dry powder formulation for
delivering to the pulmonary circulation comprises an active
ingredient or agent, including a peptide, a protein, a hormone,
analogs thereof or combinations thereof, wherein the active
ingredient is insulin, calcitonin, growth hormone, erythropoietin,
granulocyte macrophage colony stimulating factor (GM-CSF),
chorionic gonadotropin releasing factor, luteinizing releasing
hormone, follicle stimulating hormone (FSH), vasoactive intestinal
peptide, parathyroid hormone (including black bear PTH),
parathyroid hormone related protein, glucagon-like peptide-1
(GLP-1), exendin, oxyntomodulin, peptide YY, interleukin
2-inducible tyrosine kinase, Bruton's tyrosine kinase (BTK),
inositol-requiring kinase 1 (IRE1), or analogs, active fragments,
PC-DAC-modified derivatives, or O-glycosylated forms thereof. In
particular embodiments, the pharmaceutical composition or dry
powder formulation comprises fumaryl diketopiperazine and the
active ingredient is one or more selected from insulin, parathyroid
hormone 1-34, GLP-1, oxyntomodulin, peptide YY, heparin,
adiponectin, cholecystokinin (CCK), secretin, gastrin, glucagon,
motilin, somatostatin, brain natriuretic peptide (BNP), atrial
natriuretic peptide (ANP), IGF-1, growth hormone releasing factor
(GHRF), integrin beta-4 precursor (ITB4) receptor antagonist,
nociceptin, nocistatin, orphanin FQ2, calcitonin, CGRP,
angiotensin, substance P, neurokinin A, cannabinoids, including,
tetrahydrocannabinol, cannabidiol; pancreatic polypeptide,
neuropeptide Y, delta-sleep-inducing peptide, vasoactive intestinal
peptide, combinations of one or more active agents thereof and/or
analogs thereof.
[0092] Other active agents that can be used in dry powders for
pulmonary delivery include, treprostinil, salmeterol, epinephrine,
tacrolimus, vancomycin, linezolid, filgastrin, fentanyl,
cannabinoids, including cannabidiol and tetrahydrocannabinol,
palonosetron, amphotericin B, phosphodiesterase inhibitors,
including, PDE5 inhibitors such as sildenafil, avanafil, verdenafil
and tadalafil; prostaglandins, including, prostacyclin,
neurotransmitter agonists, neurotransmitter antagonists, including
anti-nociceptive agents, including opioid analgesics such as delta
opioid agonists and antagonists, kappa opioid receptor agonists and
antagonists, .mu. opioid receptor agonist and antagonists and/or
combinations of one or more of the aforementioned active
agents.
[0093] The present disclosure also provides improved
microcrystalline particles, compositions, methods of making the
particles, and methods that allow for improved delivery of drugs to
the lungs for treating diseases and disorders in a subject.
Embodiments disclosed herein achieve improved delivery by providing
crystalline diketopiperazine compositions comprising
microcrystalline diketopiperazine particles having high capacity
for drug adsorption yielding powders having high drug content of
one or more active agents. Powders made with the present
microcrystalline particles can deliver increased drug content in
lesser amounts of powder dose, which can facilitate drug delivery
to a patient. The powders can be made by various methods including,
methods utilizing surfactant-free solutions or solutions comprising
surfactants depending on the starting materials.
[0094] In alternate embodiments disclosed herein can comprise a dry
powder for inhalation comprising a plurality of substantially
uniform, microcrystalline particles, wherein the microcrystalline
particles can have a substantially hollow spherical structure and
comprise a shell which can be porous, comprising crystallites of a
diketopiperazine that do not self-assemble in a suspension or in
solution. In certain embodiments, the microcrystalline particles
can be substantially hollow spherical and substantially solid
particles comprising crystallites of the diketopiperazine depending
on the drug and/or drug content provided and other factors in the
process of making the powders. In one embodiment, the
microcrystalline particles comprise particles that are relatively
porous, having average pore volumes of about 0.43 cm.sup.3/g,
ranging from about 0.4 cm.sup.3/g to about 0.45 cm.sup.3/g, and
average pore size ranging from about 23 nm to about 30 nm, or from
about 23.8 nm to 26.2 nm as determined by BJH adsorption.
[0095] Certain embodiments disclosed herein comprises powders
comprising a plurality of substantially uniform, microcrystalline
particles, wherein the particles have a substantially spherical
structure comprising a shell which can be porous, and the particles
comprise crystallites of a diketopiperazine that do not
self-assemble in suspension or solution, and have a volumetric
median geometric diameter less than 5 .mu.m; or less than 2.5
.mu.m.
[0096] In a particular embodiment herein, up to about 92% of the
microcrystalline particles have a volumetric median geometric
diameter of 5.8 .mu.m. In one embodiment, the particle's shell is
constructed from interlocking diketopiperazine microcrystals having
one or more drugs adsorbed on their surfaces. In some embodiments,
the particles can entrap the drug in their interior void volume
and/or combinations of the drug adsorbed to the crystallites'
surface and drug entrapped in the interior void volume of the
spheres.
[0097] In certain embodiments, a diketopiperazine composition
comprising a plurality of substantially uniformly formed,
microcrystalline particles is provided, wherein the particles have
a substantially hollow spherical structure and comprise a shell
comprising crystallites of a diketopiperazine that do not
self-assemble; wherein the particles are formed by a method
comprising the step of combining diketopiperazine having a trans
isomer content ranging from about 45% to 65% in a solution and a
solution of acetic acid without the presence of a surfactant and
concurrently homogenizing in a high shear mixer at high pressures
of up to 2,000 psi to form a precipitate; washing the precipitate
in suspension with deionized water; concentrating the suspension
and drying the suspension in a spray drying apparatus.
[0098] The method can further comprise the steps of adding with
mixing a solution comprising an active agent or an active
ingredient such as a drug or bioactive agent prior to the spray
drying step so that the active agent or active ingredient is
adsorbed and/or entrapped on or within the particles. Particles
made by this process can be in the submicron size range prior to
spray-drying.
[0099] In certain embodiments, a diketopiperazine composition
comprising a plurality of substantially uniformly formed,
microcrystalline particles is provided, wherein the particles have
a substantially hollow spherical structure and comprise a shell
comprising crystallites of a diketopiperazine that do not
self-assemble, and the particles have a volumetric mean geometric
diameter less than equal to 5.mu.m; wherein the particles are
formed by a method comprising the step of combining
diketopiperazine in a solution and a solution of acetic acid
without the presence of a surfactant and concurrently homogenizing
in a high shear mixer at high pressures of up to 2,000 psi to form
a precipitate; washing the precipitate in suspension with deionized
water; concentrating the suspension and drying the suspension in a
spray drying apparatus.
[0100] The method can further comprise the steps of adding with
mixing a solution comprising an active agent or an active
ingredient such as a drug or bioactive agent prior to the spray
drying step so that the active agent or active ingredient is
adsorbed and/or entrapped on or within the particles. Particles
made by this process can be in the submicron size range prior to
spray-drying.
[0101] In certain embodiments, a diketopiperazine composition
comprising a plurality of substantially uniformly formed,
microcrystalline particles is provided, wherein the
microcrystalline particles have a substantially hollow spherical
structure and comprise a shell comprising crystallites of a
diketopiperazine that do not self-assemble, and the particles have
a volumetric mean geometric diameter less than equal to 5 .mu.m;
wherein the particles are formed by a method comprising the step of
combining diketopiperazine in a solution and a solution of acetic
acid without the presence of a surfactant and without the presence
of an active agent, and concurrently homogenizing in a high shear
mixer at high pressures of up to 2,000 psi to form a precipitate;
washing the precipitate in suspension with deionized water;
concentrating the suspension and drying the suspension in a spray
drying apparatus.
[0102] In certain embodiments wherein the starting material
comprising the active ingredient is an extract exhibiting a high
degree of viscosity, or a substance having a honey like viscous
appearance, the microcrystalline particles are formed as above and
by washing them in water using tangential flow filtration prior to
combining with the extract or viscous material. After washing in
water, the resultant particle suspension is lyophilized to remove
the water and re-suspended in an alcohol solution, including
ethanol or methanol prior to adding the active ingredient as a
solid, or in a suspension, or in solution. In one embodiment,
optionally, the method of making the composition comprises the step
of adding any additional excipient, including one or more, amino
acid, such as leucine, isoleucine, norleucine, methionine or one or
more phospholipids, for example,
1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), concurrently
with the active ingredient or subsequent to adding the active
ingredient, and prior to spray drying. In certain embodiments,
Formation of the composition comprises the step wherein the extract
comprising desired active agents is optionally filtered or
winterized to separate and remove layers of unwanted materials such
as lipids to increase its solubility.
[0103] The method can further comprise the steps of adding with
mixing a solution, the mixing can optionally be performed with or
without homogenization in a high shear mixer, the solution
comprising an active agent or an active ingredient such as a drug
or bioactive agent prior to the spray drying step so that the
active agent or active ingredient is adsorbed and/or entrapped on
or within the particles. Particles made by this process can be in
the submicron size range prior to spray-drying, or the particles
can be formed from the solution during spray-drying.
[0104] In some embodiments herewith, the drug content can be
delivered on crystalline powders using FDKP and which are
lyophilized or sprayed dried at contents to about 10%, or about
20%, or about 30% or higher. In embodiments using microcrystalline
particles formed from FDKP, or FDKP disodium salt, and wherein the
particles do not self-assemble and comprise submicron size
particles, drug content can typically be greater than 0.01% (w/w).
In one embodiment, the drug content to be delivered with the
microcrystalline particles of from about 0.01% (w/w) to about 75%
(w/w); from about 1% to about 50% (w/w), from about 10% (w/w) to
about 25% (w/w), or from about 10% to about 20% (w/w), or from 5%
to about 30%, or greater than 25% depending on the drug to be
delivered. An example embodiment wherein the drug is a peptide such
as insulin, the present microparticles typically comprise
approximately 10% to 45% (w/w), or from about 10% to about 20%
(w/w) insulin. In certain embodiments, the drug content of the
particles can vary depending on the form and size of the drug to be
delivered. In
[0105] In an embodiment, the compositions for delivering with the
inhalers herein can comprise fumaryl diketopiperazine crystalline
particles and an active agent such as cannabinoids, including
tetrahydrocannabinol (THC) and/or cannabidiol, treprostinil,
palonosetron, parathyroid hormone, sildenafil, or epinephrine. In
composition wherein a cannabinoid is used as an active agent, the
cannabinoid, including, derivatives and/or analog thereof content
can be up to 40% (w/w) with powder delivery greater than 40% of the
inhaler content. In some embodiments, the cannabinoid content in
the composition can range from about 1% to about 30%, from about 5%
to about 25% (w/w) of the powder content. The compositions herein
can also comprise one or more excipients including amino acids such
as leucine, isoleucine, methionine and the like and one or more
phospholipids, for example,
1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) prior to spray
drying in amounts up to about 25% (w/w), ranging from about 1%
(w/w) to about 25%, or 2.5% to 20% (w/w), or 5% to 15% (w/w). In
this embodiment, the inhalers can discharge from about 50% to 100%
of the composition in a single inhalation. In this embodiment, the
compositions can be administered to a subject in need of treatment
as needed.
[0106] In an embodiment wherein epinephrine is used as an active
agent, the content of the epinephrine composition comprises up to
about 30% (w/w); and ranging from about 1% to about 35% of the
powder content. In certain embodiments, compositions comprising
microcrystalline particles can contain from about 2% to about 30%
or from about 0.1% to about 20% (w/w) epinephrine. In this
embodiment, epinephrine powders can be delivered with an inhaler
described herein with a delivery efficiency of the powder greater
than 50% of the dose content. In this embodiment, the compositions
are used for a method of treating symptoms of an allergic response,
prior to onset of anaphylaxis cause by an allergen, such as a nut,
including peanut allergens, antibiotics such as penicillin, and
other substances. The method comprises, providing to a subject in
need of treatment for symptoms of an allergic response and who
exhibits early symptoms of anaphylaxis an inhaler comprising a dose
of about 1 mg to about 15 mg of a composition effective to prevent
the onset of anaphylaxis, and having the subject inhale a dose of a
composition comprising epinephrine in amounts sufficient to prevent
onset of anaphylaxis in the subject.
[0107] In an embodiment wherein treprostinil is used as an active
agent, the dry powder compositions comprise microcrystalline
particles of fumaryl diketopiperazine, wherein the treprostinil is
adsorbed to the particles and wherein the content of the
treprostinil in the composition comprises up to about 20% (w/w) and
ranges from about 0.5% to about 10% (w/w), or from about 1% to
about 5% (w/w) of the dry powder. In one embodiment, the
composition herein can comprise other excipients suitable for
inhalation such as amino acids including methionine, isoleucine and
leucine. In this embodiment, the treprostinil composition can be
used in the prevention and treatment of pulmonary hypertension by
self-administering an effective dose comprising about 1 mg to 15 mg
of a dry powder composition comprising microcrystalline particles
of fumaryl diketopiperazine and treprostinil in a single
inhalation.
[0108] In an embodiment wherein palonosetron is used as an active
agent for inhalation powders, the dry powder content of the
palonosetron in the composition comprises up to about 20% (w/w) and
ranges from about 0.1% to about 20%, or 0.1% to about 10% of the
dry powder content. In one embodiment, palonosetron compositions
can be made comprising fumaryl diketopiperazine disodium salt or
crystalline composite particles of fumaryl diketopiperazine and an
excipient including an amino acid such as leucine, isoleucine or
methionine to improve storage stability to the composition. In this
embodiment, the palonosetron inhalable composition can be used in
the prevention and treatment of chemotherapy-induced nausea and
vomiting by self-administering in a single inhalation using an
inhaler herein a dose of the composition from about 5 to 30 minutes
and preferably from about 5 to 15 minutes prior to or concurrently
with the patient receiving the dose of the chemotherapy.
[0109] In alternate embodiments, the pharmaceutically acceptable
carrier for making dry powders can comprise any carriers or
excipients useful for making dry powders and which are suitable for
pulmonary delivery. Example of suitable carriers and excipients
include, sugars, including saccharides and polysaccharides, such as
lactose, mannose, sucrose, mannitol, trehalose; citrates, amino
acids such as glycine, L-leucine, isoleucine, trileucine,
tartrates, methionine, vitamin A, vitamin E, zinc citrate,
trisodium citrate, zinc chloride, polyvinylpyrrolidone, polysorbate
80, phospholipids including diphosphotidylcholine and the like.
[0110] In one embodiment, a method of self-administering a dry
powder formulation to one's lung(s) with a dry powder inhalation
system is also provided. The method comprises: obtaining a dry
powder inhaler in a closed position and having a mouthpiece;
obtaining a cartridge comprising a pre-metered dose of a dry powder
formulation in a containment configuration; opening the dry powder
inhaler to install the cartridge; closing the inhaler to effectuate
movement of the cartridge to a dose position; placing the
mouthpiece in one's mouth, and inhaling once deeply to deliver the
dry powder formulation.
[0111] In still yet a further embodiment, a method of treating
obesity, hyperglycemia, insulin resistance, pulmonary hypertention,
anaphylaxis, and/or diabetes is disclosed. The method comprises the
administration of an inhalable dry powder composition or
formulation comprising, for example, 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,
there is provided a dry powder composition or formulation, wherein
the diketopiperazine is
2,5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine, with or without
a pharmaceutically acceptable carrier, or excipient.
[0112] An inhalation system for delivering a dry powder formulation
to a patient's lung(s) is provided, the system comprising a dry
powder inhaler configured to have flow conduits with a total
resistance to flow in a dosing configuration ranging in value from
0.065 to about 0.200 ( kPa)/liter per minute.
[0113] In one embodiment, a dry powder inhalation kit is provided
comprising a dry powder inhaler as described above, one or more
medicament cartridges comprising a dry powder formulation for
treating a disorder or disease such as respiratory tract and lung
disease, diabetes and obesity.
[0114] Methods of treating a disease or disorder in a patient with
the dry powder inhaler embodiments disclosed herewith is also
provided. The method of treatment comprises providing to a patient
in need of treatment a dry powder inhaler comprising a cartridge
containing a dose of an inhalable formulation comprising an active
ingredient selected from the group as described above and a
pharmaceutical acceptable carrier and/or excipient; and having the
patient inhale through the dry powder inhaler deeply for about 3 to
4 seconds to deliver the dose. In the method, the patient can
resume normal breathing pattern thereafter.
[0115] The following examples illustrate some of the processes for
making dry powders suitable for using with the inhalers described
herein and data obtained from experiments using the dry
powders.
EXAMPLE 1
[0116] Preparation of surfactant-free dry powder comprising FDKP
microcrystalline powder for use with inhalers: In an example
embodiment, surfactant free dry-powders comprising FDKP
microcrystalline particles were prepared. Using a dual-feed high
shear mixer, approximately equal masses of acetic acid solution
(Table 1) and FDKP solution (Table 2) held at about 25.degree.
C..+-.5.degree. C. were fed at 2000 psi through a 0.001-in2 orifice
to form a precipitate by homogenization. The precipitate was
collected in deionized (DI) water of about equal temperature. The
wt % content of FDKP microcrystallites in the suspension is about
2-3.5%. The suspension FDKP concentration can be assayed for solids
content by an oven drying method. The FDKP microcrystallite
suspension can be optionally washed by tangential flow filtration
using deionized water. The FDKP microcrystallites can be optionally
isolated by filtration, centrifugation, spray drying or
lyophilization.
TABLE-US-00001 TABLE 1 Composition of FDKP Solution Component
Component Range (wt. %) FDKP 2.5-6.25 30% NH4OH Solution 1.6-1.75
Deionized Water 92-95.9
TABLE-US-00002 TABLE 2 Composition of Acetic Acid Solution
Component Component Range (wt. %) Acetic Acid 10.5-13.0 Deionized
Water 87.0-89.5
[0117] Dry powders (A, B, C and D) comprising microcrystalline
particles made by the methods described above were tested for
various characteristics, including surface area, water content and
porosity measurements. Four different powders were used in this
experiments. All powders tested had a residual water content of
0.4%. Table 2a demonstrates data obtained from the experiments.
TABLE-US-00003 TABLE 2a Pore Volume Pore Size Surface Area BJH
Adsorption BJH Adsorption BET Surface cumulative volume of average
pore Powder ID Area (m.sup.2/g) pores (cm.sup.3/g) diameter (4V/A)
(nm) A 61.3 0.43 25.1 B 62.3 0.43 24.4 C 63.0 0.42 23.8 D 59.0 0.44
26.2
[0118] The data in Table 2a show that the surface area of
sprayed-dried, bulk dry powder comprising the microcrystalline
particles of the samples tested ranged from 59 m.sup.2/g to 63
m.sup.2/g. The porosity data indicate that the microcrystalline
particles are relatively porous, having average pore volumes of
about 0.43 cm.sup.3/g and average pore size ranging from about 23.8
nm to 26.2 nm as determined by BJH adsorption. The porosimetry data
indicate that these particles differ from prior art FDKP
microparticles which have been shown to have an average pore volume
of about 0.36 cm.sup.3/g and average pore size from about 20 nm to
about 22.6 nm.
EXAMPLE 2
[0119] Preparation of dry powder comprising microcrystalline FDKP
particles containing epinephrine. An approximately 5 wt % solution
of epinephrine in about 5% aqueous acetic acid was added to a
suspension of FDKP microcrystallites obtained as described in
Example 1. Optionally, leucine was also added to the FDKP
microcrystallite suspension. The mixture was spray dried using a
Buchi B290 spray-dryer equipped with a high efficiency cyclone.
Nitrogen was used as the process gas (60 mm). Mixtures were dried
using 10-20% pump capacity, 90-100% aspiration rate and an inlet
temperature of 170-190.degree. C. The weight % concentrations of
epinephrine and leucine in the resultant powders were 2-30% and
0-20%, respectively. Delivery efficiencies of these powders after
discharge from a dry powder inhaler ranged between approximately
50% and 80%.
EXAMPLE 3
[0120] Preparation of dry powder comprising microcrystalline FDKP
particles containing palonosetron. An approximately 5 wt % solution
of palonosetron hydrochloride in DI water was added to a suspension
of FDKP microcrystallites obtained as described in Example 1.
Optionally, solutions of leucine and methionine in deionized (DI)
water were also added. The mixture was titrated with ammonium
hydroxide to pH 6.5.+-.0.5. The mixture was spray dried using a
Buchi B290 spray-dryer equipped with a high efficiency cyclone.
Nitrogen was used as the process gas (60 mm). Mixtures were dried
using 10-12% pump capacity, 90-100% aspiration rate, and an inlet
temperature of 170-190.degree. C. The weight % concentrations of
palonosetron, leucine, and methionine in the resultant powders were
5%, 0-20%, and 0-10%, respectively. Delivery efficiencies of these
powders after discharge from a dry powder inhaler ranged between
approximately 50% and 70%.
EXAMPLE 4
[0121] Preparation of dry powder comprising microcrystalline FDKP
particles containing treprostinil. A solution containing 0.2-1.0 wt
% treprostinil in ethyl alcohol was added to a suspension of FDKP
microcrystallites obtained as described in Example 1. The mixture
was spray dried using a Buchi B290 spray-dryer equipped with a high
efficiency cyclone. Nitrogen was used as the process gas (60 mm).
Mixture were dried using 10-12% pump capacity, 90-100% aspiration
rate, and an inlet temperature of 170-190.degree. C. The weight %
concentration of treprostinil in the resultant powder was 0.5-10%.
Delivery efficiencies of these powders after discharge from a dry
powder inhaler ranged between approximately 50% and 70%.
EXAMPLE 5
[0122] Preparation of dry powder comprising microcrystalline FDKP
particles containing A9-THC or CBD. Isolated FDKP microcrystalline
particles prepared as in Example 1 were suspended in ethyl alcohol.
An approximately 1-4 wt % solution of cannabis extract, primarily
comprising either .DELTA.9-THC or CBD, in ethanol and the ethanolic
suspension of FDKP microcrystallites was added. Optionally,
solutions of additives dissolved in ethanol were also added. The
mixture was spray dried using a Buchi B290 spray-dryer equipped
with a high efficiency cyclone. Nitrogen was used as the process
gas (60 mm). Mixture were dried using 12-15% pump capacity, 70-100%
aspiration rate, and an inlet temperature of 110-140 .degree. C.
The weight % concentrations of .DELTA.9-THC and additional
additives are provided in Table 3. Delivery efficiencies of these
powders after discharge from a dry powder inhaler ranged between
approximately 50% and 70%.
TABLE-US-00004 TABLE 3 Composition of microcrystalline FDKP
particles containing .DELTA.9-THC or CBD Component Component Range
(wt. %) .DELTA.9-THC and/or 10-40 CBD DPPC 5-15 DSPC 5-15 PVP 0.5-5
PEG 2 PS-80 2
[0123] Dry powders made by the method described above were tested
using a substantially anatomically correct airway (ACA) system as
described in U.S. Pat. No. 9,016,147. The dry powders exhibited
significant degree of stability at room temperature, for example,
at one-month storage, greater than 90% of the THC or CBD remained
active with delivery efficiencies ranging from about 35% to about
75% using this method.
[0124] The preceding disclosures are illustrative embodiments. It
should be appreciated by those of skill in the art that the
devices, techniques and methods disclosed herein elucidate
representative embodiments 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.
[0125] 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 following specification
and attached claims are approximations that may vary depending upon
the desired properties sought to be obtained. 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 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.
[0126] The terms "a" and "an" and "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 otherwise claimed. No language in the
specification should be construed as indicating any non-claimed
element essential to the practice of the invention.
[0127] The use of the term "or" in the claims is used to mean
"and/or" unless explicitly indicated to refer to alternatives only
or the alternatives are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or."
[0128] Groupings of alternative elements or embodiments 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 herein deemed to contain the group as modified
thus fulfilling the written description of all Markush groups used
in the appended claims.
[0129] Preferred embodiments are described herein, including the
best mode known to the inventors for carrying out the invention. Of
course, variations on those preferred embodiments will become
apparent to those of ordinary skill in the art upon reading the
foregoing description. The inventor expects those of ordinary skill
in the art 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.
[0130] Specific embodiments disclosed herein may be further limited
in the claims using consisting of or 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 so claimed are inherently or expressly described and
enabled herein.
[0131] Furthermore, numerous references have been made to patents
and printed publications throughout this specification. Each of the
above cited references and printed publications are herein
individually incorporated by reference in their entirety.
[0132] Further, it is to be understood that the embodiments
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 may be utilized in
accordance with the teachings herein. Accordingly, the present
invention is not limited to that precisely as shown and
described.
* * * * *