Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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COMPOSITIONS, METHODS & SYSTEMS FOR RESPIRATORY DELIVERY
OF TWO OR MORE ACTIVE AGENTS
Technical Field
[0001] The
present disclosure relates generally to compositions, methods and
systems for respiratory delivery of two or more active agents. In
certain
embodiments, the present disclosure relates to compositions, methods, and
systems
for respiratory delivery of two or more active agents, wherein at least one of
the
active agents is selected from long-acting muscarinic antagonist ("LAMA"),
long-
acting 132 adrenergic agonist ("LABA"), and corticosteroid active agents.
Background
[0002]
Methods of targeted drug delivery that deliver an active agent at the site of
action are often desirable. For example, targeted delivery of active agents
can
reduce undesirable side effects, lower dosing requirements and decrease
therapeutic costs. In the context of respiratory delivery, inhalers are well
known
devices for administering an active agent to a subject's respiratory tract,
and several
different inhaler systems are currently commercially available. Three common
inhaler systems include dry powder inhalers, nebulizers and metered dose
inhalers
(MDIs).
[0003]
MDIs may be used to deliver medicaments in a solubilized form or as a
suspension. Typically, MDIs use a relatively high vapor pressure propellant to
expel
aerosolized droplets containing an active agent into the respiratory tract
when the
MDI is activated. Dry powder inhalers generally rely on the patient's
inspiratory
efforts to introduce a medicament in a dry powder form to the respiratory
tract. On
the other hand, nebulizers form a medicament aerosol to be inhaled by
imparting
energy to a liquid solution or suspension.
[0004]
MDIs are active delivery devices that utilize the pressure generated by a
propellant. Conventionally, chlorofluorocarbons (CFCs) have been used as
propellants in MDI systems because of their low toxicity, desirable vapor
pressure
and suitability for formulation of stable suspensions. However, traditional
CFC
propellants are understood to have a negative environmental impact, which has
led
to the development of alternative propellants that are believed to be more
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environmentally-friendly, such as perfluorinated compounds (PFCs) and
hydrofluoroalkanes (HFAs).
[0005] The
active agent to be delivered by a suspension MDI is typically provided
as a fine particulate dispersed within a propellant or combination of two or
more
propellants (i.e., a propellant "system"). In order to form the fine
particulates, the
active agent is typically micronized. Fine particles of active agent suspended
in a
propellant or propellant system tend to aggregate or flocculate rapidly. This
is
particularly true of active agents present in micronized form. In turn,
aggregation or
flocculation of these fine particles may complicate the delivery of the active
agent.
For example, aggregation or flocculation can lead to mechanical failures, such
as
those that might be caused by obstruction of the valve orifice of the aerosol
container. Unwanted aggregation or flocculation of drug particles may also
lead to
rapid sedimentation or creaming of drug particles, and such behavior may
result in
inconsistent dose delivery, which can be particularly troublesome with highly
potent,
low dose medicaments. Another problem associated with such suspension MDI
formulations relates to crystal growth of the drug during storage, resulting
in a
decrease over time of aerosol properties and delivered dose uniformity of such
MDIs. More recently, solution approaches, such as those disclosed in U.S.
Patent
No. 6,964,759, have been proposed for MDI formulations containing
anticholinergics.
[0006] One
approach to improve aerosol performance in dry powder inhalers has
been to incorporate fine particle carrier particles, such as lactose. Use of
such fine
excipients has not been investigated to any great extent for MDIs. A recent
report by
Young et al., "The influence of micronized particulates on the aerosolization
properties of pressurized metered dose inhalers"; Aerosol Science 40, pgs. 324-
337
(2009), suggests that the use of such fine particle carriers in MDIs actually
result in a
decrease in aerosol performance.
[0007] In
traditional CFC systems, when the active agent present in an MDI
formulation is suspended in the propellant or propellant system, surfactants
are often
used to coat the surfaces of the active agent in order to minimize or prevent
the
problem of aggregation and maintain a substantially uniform dispersion. The
use of
surfactants in this manner is sometimes referred to as "stabilizing" the
suspension.
However, many surfactants that are soluble and thus effective in CFC systems
are
not effective in HFA and PFC propellant systems because such surfactants
exhibit
different solubility characteristics in non-CFC propellants.
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Brief Description of the Drawings
[0008] FIG. 1 is a graph, which depicts the delivered dose uniformity of a
co-
suspension formulation containing glycopyrrolate and formoterol fumarate
prepared
according to the present description.
[0009] FIG. 2 is a graph, which depicts the delivered dose ratio of the co-
suspension formulation of FIG. 1.
[0010] FIG. 3 is a graph, which depicts the delivered dose uniformity of a
second
co-suspension formulation prepared according to the present description
[0011] FIG. 4 is a graph, which depicts the delivered dose ratio of the
second co-
suspension formulation of FIG. 3.
[0012] FIG. 5 is a graph, which depicts the delivered dose uniformity of
glycopyrrolate and formoterol fumarate in a co-suspension formulation prepared
according to the present description upon storage under different conditions
as
indicated.
[0013] FIG. 6 is a graph, which depicts the particle size distributions of
exemplary co-suspension formulations prepared according to the present
description
upon storage under different conditions, as indicated.
[0014] FIG. 7 provides graphs illustrating the particle size distributions
achieved
by an exemplary co-suspension including a combination of glycopyrrolate and
formoterol fumarate, upon storage at indicated conditions.
[0015] FIG. 8 provides graphs illustrating the particle size distribution
achieved by
an exemplary co-suspension including a combination of glycopyrrolate and
formoterol fumarate compared to particle size distributions achieved by
formulations
including either glycopyrrolate or formoterol fumarate alone.
[0016] FIG. 9 is a graph, which depicts the serum glycopyrrolate and
formoterol
concentration levels over time achieved after delivery of an exemplary co-
suspension including glycopyrrolate and formoterol fumarate prepared according
to
the present description. The serum concentration time profile of
glycopyrrolate and
formoterol fumarate delivered from the exemplary combination formulation is
compared to that achieved by compositions containing and delivering
glycopyrrolate
or formoterol fumarate alone.
[0017] FIG. 10 is a graph that depicts the formoterol particle size
distribution
achieved by a dual co-suspension prepared according to the present
description,
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which included microcyrstalline formoterol fumarate and glycopyrrolate active
agent
particles compared to a co-suspension only containing crystalline formoterol
fumarate.
[0018] FIG. 11 is a graph that depicts the glycopyrrolate particle size
distribution
achieved by a dual co-suspension prepared according to the present
description,
which included microcrystalline glycopyrrolate active agent particles and
microcrystalline formoterol fumarate active agent particles with two different
particle
size distributions (denoted "fine" and "coarse") or spray dried formoterol
fumarate.
[0019] FIG. 12 is a graph that depicts the formoterol fumarate particle
size
distribution achieved by a second dual co-suspension prepared according to the
present description, which included microcrystalline formoterol fumarate and
microcrystalline glycopyrrolate active agent particles compared to one that
contained
microcrystalline glycopyrrolate active agent particles and spray dried
formoterol
fumarate particles.
[0020] FIG. 13 is a graph, which depicts the delivered dose uniformity of
glycopyrrolate and formoterol fumarate in an exemplary dual co-suspension
formulation prepared according to the present description.
[0021] FIG. 14 depicts the delivered dose uniformity for each active agent
included in an exemplary triple co-suspension composition, which included
microcrystalline glycopyrrolate, formoterol fumarate and mometasone furoate
active
agent particles.
[0022] FIG. 15 is a graph depicting the formoterol fumarate aerodynamic
particle
size distributions achieved in a triple co-suspension prepared according to
the
present description, which included microcystalline glycopyrrolate, formoterol
fumarate and mometasone furoate active agent particles, compared to that
achieved
in a dual co-suspension which included glycopyrrolate and formoterol fumarate.
[0023] FIG. 16 is a graph depicting the glycopyrrolate aerodynamic particle
size
distributions achieved in a triple co-suspension prepared according to the
present
description, which included microcystalline glycopyrrolate, formoterol
fumarate and
mometasone furoate active agent particles, compared to that achieved in a dual
co-
suspension which included glycopyrrolate and formoterol fumarate.
[0024] FIG. 17 is a graph depicting the glycopyrrolate and tiotropium
bromide
aerodynamic particle size distributions achieved by a triple co-suspension
prepared
according to the present description, which, in addition to either
glycopyrrolate or
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tiotropium bromide active agent particles, included formoterol fumarate and
mometasone furoate microcrystalline active agent particles.
[0025] FIG. 18 is a graph depicting the glycopyrrolate aerodynamic size
distribution achieved by a two dual and one single component co-suspension
prepared according to the present description. The dose proportionality
between the
two dual co-suspensions as well as the equivalency between the dual and the
single
component co-suspension is displayed.
[0026] FIG. 19 is a graph depicting the formoterol fumarate aerodynamic
size
distribution achieved by a two dual and two single component co-suspensions
prepared according to the present description. The dose proportionality
between the
two dual and two single component co-suspensions as well as the equivalency
between the dual and the single component co-suspension is displayed.
[0027] FIG. 20 is a graph depicting the dose delivered uniformity of ultra
low
formoterol fumarate single component co-suspensions prepared according to the
present description.
[0028] FIG. 21 is a graph depicting the cumulative response over time on
the first
day of administration of two treatments using combination co-suspension
compositions as described herein (GP/FF 72/9.6 and GP/FF 36/9.6) compared to
two different delivering a single active agent (one delivering only
glycopyrrolate ¨ GP
36, and a second delivering only tiotropium bromide ¨ Spiriva). These
compositions
were administered to patients as part of the clinical study described in
Example 12.
Specifically, the graph illustrates the percent of patients achieving 12`)/0
improvement in FEVi and the time at which such percentages were achieved.
[0029] FIG. 22 ¨ FIG. 24 provide graphs illustrating the mean change from
baseline in FEVi AUC0_12 on treatment day 7 (Day 7) for various study
compositions
administered to patients as part of the clinical study described in Example
12. Two
treatments using combination co-suspension compositions as described herein
(GP/FF 72/9.6 and GP/FF 36/9.6) are compared to a placebo and various
different
active compositions delivering a single active agent (one delivering only
glycopyrrolate ¨ GP 36, a second delivering only tiotropium bromide ¨ Spiriva,
and
three delivering only formoterol fumarate ¨ FF 7.2, FF 9.6, and Foradil).
[0030] FIG. 25 is a graph illustrating the FEVi AUC0_12 on Day 7 for each
of the
active study compositions administered to patients as part of the clinical
study
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described in Example 12. The improvement in FEVi AUC0_12 provided by each of
the
active study compositions relative to placebo is shown.
[0031] FIG. 26 is a graph illustrating the difference between the FEVi AUC0-
12
achieved by the GP/FF 36/9.6 treatment on Day 7 relative to the GP 36, FF 9.6,
Spiriva and Foradil active comparators. As can be easily appreciated by
reference
to FIG. 26, the GP/FF 36/9.6 treatment provided significantly better
improvements in
FEVi AUC0-12.
[0032] FIG. 27 is a graph showing the Peak FEVi on treatment day 1 (Day 1)
and
Day 7 achieved by various study compositions administered to patients as part
of the
clinical study described in Example 12. The Peak FEVi shown represents the
peak
change in FEVi from baseline provided by each of the active study composition
relative to placebo on the study day indicated.
[0033] FIG. 28 is a graph illustrating the difference between the Peak FEVi
achieved by the GP/FF 36/9.6 treatment on Day 1 and Day 7 relative to the
Spiriva
and Foradil active comparators. As can be easily appreciated by reference to
FIG.
28, the GP/FF 36/9.6 treatment provided significantly better improvements in
Peak
FEVi compared to the active comparators.
[0034] FIG. 29 is a graph illustrating the improvements in Morning Trough
FEVi
achieved by various study compositions administered to patients as part of the
clinical study described in Example 12. The graph illustrates the improvement
in
Morning Trough FEVi values provided by each of the active study compositions
relative to placebo.
[0035] FIG. 30 is a graph showing the difference between the increase in
pre-
dose FEVi on Day 7 of the clinical study described in Example 12 provided by
two
treatments using combination co-suspension compositions as described herein
(GP/FF 72/9.6 and GP/FF 36/9.6) relative to the different single active agent
comparators and to each other. As can be easily appreciated by reference to
FIG.
30, the GP/FF 72/9.6 and GP/FF 36/9.6 treatments provided significantly better
improvements in pre-dose FEVi compared to the single active agent comparators,
but did not differ significantly from each other.
[0036] FIG. 31 provides a graph illustrating the Day 1 and 7 peak, and Day
7 pre-
dose improvements in inspiratory capacity (IC) relative to placebo provided by
the
two treatments using combination co-suspension compositions (GP/FF 72/9.6 and
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GP/FF 36/9.6) and the Spiriva active comparator composition administered as
part of
the clinical trial described in Example 12.
[0037]
FIG. 32 provides a graph illustrating the consistent patient response
achieved in the clinical study described in Example 12 regardless of the
severity of
the chronic obstructive pulmonary disease suffered by the patients.
Detailed Description
[0038] The
present disclosure provides compositions, methods, and systems for
respiratory delivery of two or more active agents.
Specifically, in certain
embodiments, the present disclosure includes pharmaceutical compositions,
systems and methods for respiratory delivery of two or more active agents via
an
MDI, and in particular embodiments at least one of the active agents is
selected from
long-acting muscarinic antagonist ("LAMA"), long-acting 132 adrenergic agonist
("LABA"), and corticosteroid active agents. The compositions described herein
may
be formulated for pulmonary or nasal delivery via an MDI. The methods
described
herein include methods of stabilizing formulations including two or more
active
agents for respiratory delivery, as well as methods for pulmonary delivery of
two or
more active agents for treating a pulmonary disease or disorder via an MDI.
Also
described herein are MDI systems for delivery of two or more active agents, as
well
as methods for preparing such systems.
[0039]
Formulating pharmaceutical compositions incorporating two or more active
agents is often challenging due to unpredictable or unexpected interactions
between
the active agents or changes to the formulations resulting from the
incorporation of
multiple active agents. Such interactions are generally known as a
"combination
effect," and in the context of suspension formulations delivered from an MDI,
a
combination effect may be manifest by, for example, a deviation from
similarity
between a formulation including a single active agent and a formulation
including a
combination of two or more active agents in one or more of the following
areas: the
aerosol and particle size distribution characteristics provided by the
formulation;
delivered dose uniformity for one or more of the active agents; deliverability
or
absorption of one or more of the active agents; or the dose proportionality
observed
for one or more of the active agents.
[0040] In
specific embodiments, the co- suspension compositions described
herein avoid combination effects associated with combination formulations. For
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purposes of the present description, a composition avoids combination affects
where, for a selected active agent, the aerosol properties, particle size
distribution
characteristics, and delivered dose uniformity achieved by a combination
formulation
do not deviate from those achieved by a comparable formulation wherein the
only
active agent is the selected active agent. In some embodiments, the lack of a
combination effect is evidenced for a selected active agent where the plasma
concentration over time for a targeted dose of the selected active agent
delivered
from a combination formulation does not deviate from the plasma concentration
over
time achieved when the selected active agent is delivered at the same dose
from a
comparable formulation wherein the only active agent is the selected active
agent.
[0041] As
used herein, the phrases "do not deviate" or "does not deviate" signify
that, for a given parameter, the performance achieved by a combination
formulation
is 20% of that achieved by a comparable formulation including only one of
the
active agents included in the combination formulation. In certain embodiments,
the
performance achieved by a combination formulation does not vary from that
achieved by a comparable formulation including only one of the active agents
included in the combination. For example, a co-suspension as described herein,
including two or more active agents, is considered to exhibit no combination
effect
when, with respect to each such active agent at a given dose, one or more of
the
aerosol properties, the particle size distribution characteristics, the
delivered dose
uniformity, and the plasma concentration over time achieved by the combination
co-
suspension are within 20% of those achieved by a comparable formulation
including only a single active agent. In some embodiments, for each active
agent at
a give dose, one or more of the aerosol properties, the particle size
distribution
characteristics, the delivered dose uniformity, and the plasma concentration
over
time achieved by the combination co-suspension compositions described herein
are
within 15% of those achieved by a comparable formulation including only a
single
active agent. In yet other embodiments, for each active agent at a give dose,
one or
more of the aerosol properties, the particle size distribution
characteristics, the
delivered dose uniformity, and the plasma concentration over time achieved by
the
combination co-suspension compositions described herein are within 10% of
those
achieved by a comparable formulation including only a single active agent.
In
certain embodiments, with respect to each active agent at a given dose, the
combination co-suspension compositions as described herein exhibit no
difference to
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comparable formulations including only one of the active agents included in
the
combination in one or more of the following areas: aerosol properties for the
formulation; the particle size distribution characteristics; delivered dose
uniformity
for; and the plasma concentration over time.
[0042] The
combination of two or more active agents included in the compositions
provided herein may, in some embodiments, provide advantages over
pharmaceutical formulations including only a single active agent. For
instance, when
a combination of two or more active agents is delivered simultaneously, the
therapeutically effective dose of both active agents may be relatively less
than when
any of the combined active agents is delivered alone, thereby avoiding or
reducing
possible side effects. Moreover, combinations of two or more active agents may
achieve a more rapid onset or longer duration of therapeutic benefit than can
be
achieved by delivering one of the combined active agents alone.
[0043] In
specific embodiments, the methods described herein include methods
for treating a pulmonary disease or disorder amenable to treatment by
respiratory
delivery of a co-suspension composition as described herein. For example, the
compositions, methods and systems described herein can be used to treat
inflammatory or obstructive pulmonary diseases or conditions. In
certain
embodiments, the compositions, methods and systems described herein can be
used to treat patients suffering from a disease or disorder selected from
asthma,
chronic obstructive pulmonary disease (COPD), exacerbation of airways hyper
reactivity consequent to other drug therapy, allergic rhinitis, sinusitis,
pulmonary
vasoconstriction, inflammation, allergies, impeded respiration, respiratory
distress
syndrome, pulmonary hypertension, pulmonary vasoconstriction, and any other
respiratory disease, condition, trait, genotype or phenotype that can respond
to the
administration of, for example, a LAMA, LABA, corticosteroid, or other active
agent
as described herein, whether alone or in combination with other therapies. In
certain
embodiments, the compositions, systems and methods described herein can be
used to treat pulmonary inflammation and obstruction associated with cystic
fibrosis.
As used herein, the terms "COPD" and "chronic obstructive pulmonary disease"
encompass chronic obstructive lung disease (COLD), chronic obstructive airway
disease (COAD), chronic airflow limitation (CAL) and chronic obstructive
respiratory
disease (CORD) and include chronic bronchitis, bronchiectasis, and emphysema.
As used herein, the term "asthma" refers to asthma of whatever type or
genesis,
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including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma,
mild asthma,
moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma,
occupational asthma and asthma induced following bacterial infection. Asthma
is
also to be understood as embracing wheezy-infant syndrome.
[0044] When administered to patients suffering from pulmonary disease,
embodiments of the co-suspension compositions described herein provide a
significant increase in one or more measures of lung function or capacity when
compared to compositions delivering only a single active agent. In certain
such
embodiments, the delivery of a co-suspension composition as described herein
including two or more active agents results in a significant increase in one
or both of
FEVi and inspiratory capacity (IC) relative to composition containing only a
single
active agent.
[0045] It
will be readily understood that the embodiments, as generally described
herein, are exemplary. The
following more detailed description of various
embodiments is not intended to limit the scope of the present disclosure, but
is
merely representative of various embodiments. As such, the specifics recited
herein
may include independently patentable subject matter. Moreover, the order of
the
steps or actions of the methods described in connection with the embodiments
disclosed herein may be changed by those skilled in the art without departing
from
the scope of the present disclosure. In other words, unless a specific order
of steps
or actions is required for proper operation of the embodiment, the order or
use of
specific steps or actions may be modified.
I. Definitions
[0046]
Unless specifically defined otherwise, the technical terms, as used herein,
have their normal meaning as understood in the art. The following terms are
specifically defined for the sake of clarity.
[0047] The
term "active agent" is used herein to include any agent, drug,
compound, composition or other substance that may be used on, or administered
to
a human or animal for any purpose, including therapeutic, pharmaceutical,
pharmacological, diagnostic, cosmetic and prophylactic agents and
immunomodulators. The term "active agent" may be used interchangeably with the
terms, "drug," "pharmaceutical," "medicament," "drug substance," or
"therapeutic."
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As used herein the "active agent" may also encompass natural or homeopathic
products that are not generally considered therapeutic.
[0048] The
terms "associate," "associate with" or "association" refers to an
interaction or relationship between a chemical entity, composition, or
structure in a
condition of proximity to a surface, such as the surface of another chemical
entity,
composition, or structure. The
association includes, for example, adsorption,
adhesion, covalent bonding, hydrogen bonding, ionic bonding and electrostatic
attraction, Lifshitz-van der Waals interactions and polar interactions. The
term
"adhere" or "adhesion" is a form of association and is used as a generic term
for all
forces tending to cause a particle or mass to be attracted to a surface.
"Adhere" also
refers to bringing and keeping particles in contact with each other, such that
there is
substantially no visible separation between particles due to their different
buoyancies
in a propellant under normal conditions. In one embodiment, a particle that
attaches
to or binds to a surface is encompassed by the term "adhere." Normal
conditions
may include storage at room temperature or under an accelerative force due to
gravity. As described herein, active agent particles may associate with
suspending
particles to form a co-suspension, where there is substantially no visible
separation
between the suspending particles and the active agent particles or flocculates
thereof due to differences in buoyancy within a propellant.
[0049]
"Suspending particles" refer to a material or combination of materials that
is acceptable for respiratory delivery, and acts as a vehicle for active agent
particles.
Suspending particles interact with the active agent particles to facilitate
repeatable
dosing, delivery or transport of active agent to the target site of delivery,
i.e., the
respiratory tract. The suspending particles described herein are dispersed
within a
suspension medium including a propellant or propellant system, and can be
configured according to any shape, size or surface characteristic suited to
achieving
a desired suspension stability or active agent delivery performance. Exemplary
suspending particles include particles that exhibit a particle size that
facilitates
respiratory delivery of active agent and have physical configurations suited
to
formulation and delivery of the stabilized suspensions as described herein.
[0050] The
term "co-suspension" refers to a suspension of two or more types of
particles having different compositions within a suspension medium, wherein
one
type of particle associates at least partially with one or more of the other
particle
types. The association leads to an observable change in one or more
characteristics
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of at least one of the individual particle types suspended in the suspension
medium.
Characteristics modified by the association may include, for example, one or
more of
the rate of aggregation or flocculation, the rate and nature of separation,
i.e.
sedimentation or creaming, density of a cream or sediment layer, adhesion to
container walls, adhesion to valve components, and rate and the level of
dispersion
upon agitation.
[0051]
Exemplary methods for assessing whether a co-suspension is present can
include the following: If one particle type has a pycnometric density greater
than the
propellant and another particle type has a pycnometric density lower than the
propellant, a visual observation of the creaming or sedimentation behavior can
be
employed to determine the presence of a co-suspension. The term "pycnometric
density" refers to the density of a material that makes up a particle,
excluding voids
within the particle. In
one embodiment, the materials can be formulated or
transferred into a transparent vial, typically a glass vial, for visual
observation. After
initial agitation the vial is left undisturbed for a sufficient time for
formation of a
sediment or cream layer, typically 24 hours. If the sediment or cream layer is
observed to be completely or mostly a uniform single layer, a co-suspension is
present. The term "co-suspension" includes partial co-suspensions, where a
majority of the at least two particle types associate with each other,
however, some
separation (i.e., less than a majority) of the at least two particle types may
be
observed.
[0052] The exemplary co-suspension test may be performed at different
propellant temperatures to accentuate the sedimentation or creaming behavior
of
particle types with a density close to the propellant density at room
temperature. If
the different particle types have the same nature of separation, i.e. all
sediment or all
cream, the presence of a co-suspension can be determined by measuring other
characteristics of the suspension, such as rate of aggregation or
flocculation, rate of
separation, density of cream or sediment layer, adhesion to container walls,
adhesion to valve components, and rate and level of dispersion upon agitation,
and
comparing them to the respective characteristics of the similarly suspended
individual particle types. Various analytical methods generally known to those
skilled
in the art can be employed to measure these characteristics.
[0053] In
the context of a composition containing or providing respirable
aggregates, particles, drops, etc., such as compositions described herein, the
term
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"fine particle dose" or "FPD" refers to the dose, either in total mass or
fraction of the
nominal dose or metered dose, that is within a respirable range. The dose that
is
within the respirable range is measured in vitro to be the dose that deposits
beyond
the throat stage of a cascade impactor, i.e., the sum of dose delivered at
stages 3
through filter in a Next Generation Impactor operated at a flow rate of 30
I/min.
[0054] In the context of a composition containing or providing respirable
aggregates, particles, drops, etc., such as compositions described herein, the
term
"fine particle fraction" or "FPF" refers to the proportion of the delivered
material
relative to the delivered dose (i.e., the amount that exits the actuator of a
delivery
device, such as an MDI) that is within a respirable range. The amount of
delivered
material within the respirable range is measured in vitro as the amount of
material
that deposits beyond the throat stage of a cascade impactor, e.g., the sum of
the
material delivered at stages 3 through filter in a Next Generation Impactor
operated
at a flow rate of 30 I/min.
[0055] As used herein, the term "inhibit" refers to a measurable lessening
of the
tendency of a phenomenon, symptom or condition to occur or the degree to which
that phenomenon, symptom or condition occurs. The term "inhibit" or any form
thereof, is used in its broadest sense and includes minimize, prevent, reduce,
repress, suppress, curb, constrain, restrict, slow progress of and the like.
[0056] "Mass median aerodynamic diameter" or "MMAD" as used herein refers
to
the aerodynamic diameter of an aerosol below which 50% of the mass of the
aerosol
consists of particles with an aerodynamic diameter smaller than the MMAD, with
the
MMAD being calculated according to monograph 601 of the United States
Pharmacopeia ("USP").
[0057] When referred to herein, the term "optical diameter" indicates the
size of a
particle as measured by the Fraunhofer diffraction mode using a laser
diffraction
particle size analyzer equipped with a dry powder dispenser (e.g., Sympatec
GmbH,
Clausthal-Zellerfeld, Germany).
[0058] The term solution mediated transformation refers to the phenomenon
in
which a more soluble form of a solid material (i.e. particles with small
radius of
curvature (a driving force for Ostwald ripening), or amorphous material)
dissolves
and recrystallizes into the more stable crystal form that can coexist in
equilibrium
with its saturated propellant solution.
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[0059] A "patient" refers to an animal in which a combination of active
agents as
described herein will have a therapeutic effect. In one embodiment, the
patient is a
human being.
[0060] "Perforated microstructures" refer to suspending particles that
include a
structural matrix that exhibits, defines or comprises voids, pores, defects,
hollows,
spaces, interstitial spaces, apertures, perforations or holes that allow the
surrounding
suspension medium to permeate, fill or pervade the microstructure, such as
those
materials and preparations described in U.S. Patent No. 6,309,623 to Weers, et
al.
The primary form of the perforated microstructure is, generally, not
essential, and
any overall configuration that provides the desired formulation
characteristics is
contemplated herein. Accordingly, in one embodiment, the perforated
microstructures may comprise approximately spherical shapes, such as hollow,
suspending, spray-dried microspheres. However, collapsed, corrugated, deformed
or fractured particulates of any primary form or aspect ratio may also be
compatible.
[0061] As is true of suspending particles described herein, perforated
microstructures may be formed of any biocompatible material that does not
substantially degrade or dissolve in the selected suspension medium. While a
wide
variety of materials may be used to form the particles, in some embodiments,
the
structural matrix is associated with, or includes, a surfactant such as, a
phospholipid
or fluorinated surfactant. Although not required, the incorporation of a
compatible
surfactant in the perforated microstructure or, more generally, the suspending
particles, can improve the stability of the respiratory dispersions, increase
pulmonary
deposition and facilitate the preparation of the suspension.
[0062] The term "suspension medium" as used herein refers to a substance
providing a continuous phase within which active agent particles and
suspending
particles can be dispersed to provide a co-suspension formulation. The
suspension
medium used in co-suspension formulations described herein includes
propellant.
As used herein, the term "propellant" refers to one or more pharmacologically
inert
substances which exert a sufficiently high vapor pressure at normal room
temperature to propel a medicament from the canister of an MDI to a patient on
actuation of the MDI's metering valve. Therefore, the term "propellant" refers
to both
a single propellant and to a combination of two or more different propellants
forming
a "propellant system."
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[0063] The term "respirable" generally refers to particles, aggregates,
drops, etc.
sized such that they can be inhaled and reach the airways of the lung.
[0064] When used to refer to co-suspension compositions described herein,
the
terms "physical stability" and "physically stable" refer to a composition that
is
resistant to one or more of aggregation, flocculation, and particle size
changes due
to solution mediated transformations and is capable of substantially
maintaining the
MMAD of suspending particles and the fine particle dose. In one embodiment,
physical stability may be evaluated through subjecting compositions to
accelerated
degradation conditions, such as by temperature cycling as described herein.
[0065] When referring to active agents, the term "potent" indicates active
agents
that are therapeutically effective at or below doses ranging from about 0.01
mg/kg to
about 1 mg/kg. Typical doses of potent active agents generally range from
about
100 pg to about 100 mg.
[0066] When referring to active agents, the term "highly potent" indicates
active
agents that are therapeutically effective at or below doses of about 10 pg/kg.
Typical
doses of highly potent active agents generally range up to about 100 pg.
[0067] The terms "suspension stability" and "stable suspension" refer to
suspension formulations capable of maintaining the properties of a co-
suspension of
active agent particles and suspending particles over a period of time. In one
embodiment, suspension stability may be measured through delivered dose
uniformity achieved by co-suspension compositions described herein.
[0068] The term "substantially insoluble" means that a composition is
either totally
insoluble in a particular solvent or it is poorly soluble in that particular
solvent. The
term "substantially insoluble" means that a particular solute has a solubility
of less
than one part per 100 parts solvent. The term "substantially insoluble"
includes the
definitions of "slightly soluble" (from 100 to 1000 parts solvent per 1 part
solute),
"very slightly soluble" (from 1000 to 10,000 parts solvent per 1 part solute)
and
"practically insoluble" (more than 10,000 parts solvent per 1 part solute) as
given in
Table 16-1 of Remington: The Science and Practice of Pharmacy, 21st ed.
Lippincott, Williams & Wilkins, 2006, p. 212.
[0069] The term "surfactant," as used herein, refers to any agent which
preferentially adsorbs to an interface between two immiscible phases, such as
the
interface between water and an organic polymer solution, a water/air interface
or
organic solvent/air interface. Surfactants generally possess a hydrophilic
moiety and
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a lipophilic moiety, such that, upon adsorbing to microparticles, they tend to
present
moieties to the continuous phase that do not attract similarly-coated
particles, thus
reducing particle agglomeration. In some embodiments, surfactants may also
promote adsorption of a drug and increase bioavailability of the drug.
[0070] A
"therapeutically effective amount" is the amount of compound which
achieves a therapeutic effect by inhibiting a disease or disorder in a patient
or by
prophylactically inhibiting or preventing the onset of a disease or disorder.
A
therapeutically effective amount may be an amount which relieves to some
extent
one or more symptoms of a disease or disorder in a patient; returns to normal
either
partially or completely one or more physiological or biochemical parameters
associated with or causative of the disease or disorder; and/or reduces the
likelihood
of the onset of the disease of disorder.
[0071] The
terms "chemically stable" and "chemical stability" refer to co-
suspension formulations wherein the individual degradation products of active
agent
remain below the limits specified by regulatory requirements during the shelf
life of
the product for human use (e.g., 1% of total chromatographic peak area per ICH
guidance Q3B(R2)) and there is acceptable mass balance (e.g., as defined in
ICH
guidance Q1 E) between active agent assay and total degradation products.
II. Compositions
[0072] The
compositions described herein are co-suspensions that include two or
more active agents and include a suspension medium, one or more species of
active
agent particles, and one or more species of suspending particles. Of course,
if
desired, the compositions described herein may include one or more additional
constituents.
Moreover, variations and combinations of components of the
compositions described herein may be used.
[0073] The
co-suspension compositions according to the present description can
be embodied by various different formulations. In
certain embodiments, the
compositions described herein include a first active agent provided in active
agent
particles that are co-suspended with at least one species of suspending
particles that
incorporate a second active agent. In other embodiments, the compositions
described herein include two or more active agents provided in two or more
different
species of active agent particles co-suspended with at least one species of
suspending particles that incorporate an active agent different from that
contained in
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any of the active agent particles. In yet further embodiments, the
compositions
described herein include two or more active agents provided in two or more
different
species of active agent particles co-suspended with at least one species of
suspending particles that incorporate an active agent that may be the same as
or
different from that contained in any of the active agent particles. In still
further
embodiments, the compositions described herein include two or more active
agents
provided in two or more different species of active agent particles co-
suspended with
one or more species of suspending particles that are free of active agent.
Where the
compositions described herein include two or more species of active agent
particles,
such compositions may be referred to as "multi" co-suspensions. For example, a
composition including two species of active agent particles co-suspended with
one or
more species of suspending particles may be referred to as a dual co-
suspension, a
composition including three species of active agent particles co-suspended
with one
or more species of suspending particles may be referred to as a triple co-
suspension, etc.
[0074] In compositions according to the present description, even when
multiple
different species of active agent particles are present in the composition,
the active
agent particles exhibit an association with the suspending particles such that
the
active agent particles and suspending particles co-locate within the
suspension
medium. Generally, due to density differences between distinct species of
particles
and the medium within which they are suspended (e.g., a propellant or
propellant
system), buoyancy forces cause creaming of particles with lower density than
the
propellant and sedimentation of particles with higher density than the
propellant.
Therefore, in suspensions that consist of a mixture of different types of
particles with
different density or different tendencies to flocculate, sedimentation or
creaming
behavior is expected to be specific to each of the different particle types
and
expected to lead to separation of the different particle types within the
suspension
medium.
[0075] However, the combinations of propellant, active agent particles, and
suspending particles described herein provide co-suspensions including
combinations of two or more active agents wherein the active agent particles
and
suspending particles co-locate within the propellant (i.e., the active agent
particles
associate with the suspending particles such that suspending particles and
active
agent particles do not exhibit substantial separation relative to each other,
such as
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by differential sedimentation or creaming, even after a time sufficient for
the
formation of a cream or sediment layer). In particular embodiments, for
example, the
compositions described herein form co-suspensions wherein the suspending
particles remain associated with active agent particles when subjected to
buoyancy
forces amplified by temperature fluctuations and/or centrifugation at
accelerations up
to and over, for example, 1 g, 10 g, 35 g, 50 g, and 100 g. However, the co-
suspensions described herein need not be defined by a specific threshold force
of
association. For example, a co-suspension as contemplated herein may be
successfully achieved where the active agent particles associate with the
suspending particles such that there is no substantial separation of active
agent
particles and suspending particles within the continuous phase formed by the
suspension medium under typical patient use conditions.
[0076] Co-
suspensions of active agent particles and suspending particles
according to the present description provide desirable chemical stability,
suspension
stability and active agent delivery characteristics. For
example, in certain
embodiments, when present within an MDI canister, co-suspensions as described
herein can inhibit one or more of the following: flocculation of active agent
material;
differential sedimentation or creaming of active agent particles and
suspending
particles; solution mediated transformation of active agent material; chemical
degradation of a component of the formulation, including of active agent
material or a
surfactant; and loss of active agent to the surfaces of the container closure
system,
in particular the metering valve components. Such qualities work to achieve
and
preserve aerosol performance as the co-suspension formulation is delivered
from an
MDI such that desirable fine particle fraction, fine particle dose and
delivered dose
uniformity characteristics are achieved and substantially maintained
throughout
emptying of an MDI canister within which the co-suspension formulation is
contained. Additionally, co-suspensions according to the present description
can
provide a physically and chemically stable formulation that provides
consistent
dosing characteristics for two or more active agents, even where such active
agents
are delivered at significantly different doses, while utilizing a relatively
simple HFA
suspension medium that does not require modification by the addition of, for
example, cosolvents, antisolvents, solubilizing agents or adjuvants. Even
further,
compositions prepared as described herein, when delivered from an MDI,
eliminate
or substantially avoid the pharmaceutical effects often experienced with
formulations
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including multiple active agents. For
example, as exemplified by specific
embodiments detailed herein, the combination formulations described herein
provide
delivery characteristics for each of the active agents contained therein
comparable to
delivery characteristics of the same active agents when formulated and
delivered
separately.
[0077]
Providing a co-suspension according to the present description may also
simplify formulation, delivery and dosing of the desired active agents.
Without being
bound by a particular theory, it is thought that by achieving a co-suspension
of active
agent particles and suspending particles, the delivery, physical stability,
and dosing
of an active agent contained within such a dispersion may be substantially
controlled
through control of the size, composition, morphology and relative amount of
the
suspending particles, and is less dependent upon the size and morphology of
the
particles of active agent. Moreover, in specific embodiments, the
pharmaceutical
compositions described herein can be formulated with a non-CFC propellant or
propellant system substantially free of antisolvents, solubilizing agents,
cosolvents,
or adjuvants.
[0078] Co-suspension compositions formulated according to the present
teachings can inhibit physical and chemical degradation of the active agents
included therein. For example, in specific embodiments, the compositions
described
herein may inhibit one or more of chemical degradation, flocculation,
aggregation
and solution mediated transformation of the active agents included in the
compositions. The chemical and suspension stability provided by the co-
suspension
compositions described herein allows the compositions to be dispensed in a
manner
that achieves desirable delivered dose uniformity throughout emptying of an
MDI
canister ("DDU") for multiple active agents, even where at least one of the
active
agents to be delivered may be highly potent and the delivered doses of each of
the
active agents vary considerably.
[0079] Co-
suspension compositions as described herein, which include two or
more active agents, can achieve a DDU of 30%, or better for each of the
active
agents included therein. In one such embodiment, compositions described herein
achieve a DDU of 25%, or better, for each of the active agents included
therein. In
another such embodiment, compositions described herein achieve a DDU of 20%,
or better, for each of the active agents included therein. Moreover, co-
suspension
compositions according to the present description serve to substantially
preserve
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FPF and FPD performance throughout emptying of an MDI canister, even after
being
subjected to accelerated degradation conditions. For instance, compositions
according to the present description maintain as much as 80%, 90%, 95%, or
more,
of the original FPF or FPD performance, even after being subjected to
accelerated
degradation conditions.
[0080] Co-suspension compositions described herein provide the added
benefit
of achieving such performance while being formulated using non-CFC
propellants.
In specific embodiments, the compositions described herein achieve one or more
of
a targeted DDU, FPF or FPD, while being formulated with suspension medium
including only one or more non-CFC propellants and without the need to modify
the
characteristics of the non-CFC propellant, such as by the addition of, for
example,
one or more cosolvent, antisolvent, solubilizing agent, adjuvant or other
propellant
modifying material.
(i) Suspension Medium
[0081] The suspension medium included in a composition described herein
includes one or more propellants. In general, suitable propellants for use as
suspension mediums are those propellant gases that can be liquefied under
pressure at room temperature, and upon inhalation or topical use, are safe and
toxicologically innocuous. Additionally, it is desirable that the selected
propellant be
relatively non-reactive with the suspending particles and active agent
particles.
Exemplary compatible propellants include hydrofluoroalkanes (HFAs),
perfluorinated
compounds (PFCs), and chlorofluorocarbons (CFCs).
[0082] Specific examples of propellants that may be used to form the
suspension
medium of the co-suspensions disclosed herein include 1,1,1,2-
tetrafluoroethane
(CF3CH2F) (HFA-134a), 1,1,1,2,3,3,3-heptafluoro-n-propane (CF3CHFCF3) (HFA-
227), perfluoroethane, monochloro-fluoromethane, 1,1 difluoroethane, and
combinations thereof. Even further, suitable propellants include, for example:
short
chain hydrocarbons; C1-4 hydrogen-containing chlorofluorocarbons such as
CH2CIF,
CCI2FCHCIF, CF3CHCIF, CHF2CCIF2, CHCIFCHF2, CF3CH2CI, and CCIF2CH3; C1-4
hydrogen-containing fluorocarbons (e.g., HFAs) such as CHF2CHF2, CF3CH2F,
CHF2CH3, and CF3CHFCF3; and perfluorocarbons such as CF3CF3 and CF3CF2CF3.
[0083] Specific fluorocarbons, or classes of fluorinated compounds, that
may be
used as suspension media include, but are not limited to, fluoroheptane,
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fluorocycloheptane, fluoromethylcycloheptane, fluorohexane, fluorocyclohexane,
fluoropentane, fluorocyclopentane, fluoromethylcyclopentane, fluorodimethyl-
cyclopentanes, fluoromethylcyclobutane, fluorodimethylcyclobutane,
fluorotrimethyl-
cyclobutane, fluorobutane, fluorocyclobutane, fluoropropane, fluoroethers,
fluoropolyethers and fluorotriethylamines. These compounds may be used alone
or
in combination with more volatile propellants.
[0084] In addition to the aforementioned fluorocarbons and
hydrofluoroalkanes,
various exemplary chlorofluorocarbons and substituted fluorinated compounds
may
also be used as suspension media. In this respect, FC-11 (CCI3F), FC-11B1
(CBrCl2F), FC-11B2 (CBr2CIF), FC12B2 (CF2Br2), FC21 (CHCl2F), FC21B1
(CHBrCIF), FC-21B2 (CHBr2F), FC-31B1 (CH2BrF), FC113A (CCI3CF3), FC-122
(CCIF2CHCl2), FC-123 (CF3CHC12), FC-132 (CHCIFCHCIF), FC-133 (CHCIFCHF2),
FC-141 (CH2CICHCIF), FC-141B (CCI2FCH3), FC-142 (CHF2CH2CI), FC-151
(CH2FCH2CI), FC-152 (CH2FCH2F), FC-1112 (CCIF=CCIF), FC-1121 (CHCI=CFCI)
and FC-1131 (CHCI=CHF) may also be used, while recognizing the possible
attendant environmental concerns. As such, each of these compounds may be
used, alone or in combination with other compounds (i.e., less volatile
fluorocarbons)
to form the stabilized suspensions disclosed herein.
[0085] In some embodiments, the suspension medium may be formed of a single
propellant. In other embodiments, a combination of propellants may be used to
form
the suspension medium. In some embodiments, relatively volatile compounds may
be mixed with lower vapor pressure components to provide suspension media
having specified physical characteristics selected to improve stability or
enhance the
bioavailability of the dispersed active agents. In some embodiments, the lower
vapor
pressure compounds will comprise fluorinated compounds (e.g. fluorocarbons)
having a boiling point greater than about 25 C. In some embodiments, lower
vapor
pressure fluorinated compounds for use in the suspension medium may include
perfluorooctylbromide C8F17Br (PFOB or perflubron), dichlorofluorooctane
C8F16C12,
perfluorooctylethane C8F17C2H5 (PF0E), perfluorodecylbromide C10F21Br (PFDB)
or
perfluorobutylethane C4F9C2H5. In certain embodiments, these lower vapor
pressure
compounds are present in a relatively low level. Such compounds may be added
directly to the suspension medium or may be associated with the suspending
particles.
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[0086] The suspension medium included in compositions as described herein
may be formed of a propellant or propellant system that is substantially free
of
additional materials, including, for example, antisolvents, solubilizing
agents,
cosolvents or adjuvants. For example, in some embodiments, the suspension
medium may be formed of a non-CFC propellant or propellant system, such as an
HFA propellant or propellant system, that is substantially free of additional
materials.
Such embodiments simplify the formulation and manufacture of pharmaceutical
compositions suited for respiratory delivery of the active agents included in
the co-
suspension compositions.
[0087] However, in other embodiments, depending on the selection of
propellant,
the properties of the suspending particles, or the nature of the active agents
to be
delivered, the suspension medium utilized may include materials in addition to
the
propellant or propellant system. Such additional materials may include, for
example,
one or more of an appropriate antisolvent, solubilizing agent, cosolvent or
adjuvant
to adjust, for example, the vapor pressure of the formulation or the
stability, or
solubility of suspended particles. For example, propane, ethanol, isopropyl
alcohol,
butane, isobutane, pentane, isopentane or a dialkyl ether, such as dimethyl
ether,
may be incorporated with the propellant in the suspension medium. Similarly,
the
suspension medium may contain a volatile fluorocarbon. In other embodiments,
one
or both of polyvinylpyrrolidone ("PVP") or polyethylene glycol ("PEG") may be
added
to the suspension medium. Adding PVP or PEG to the suspension medium may
achieve one or more desired functional characteristics, and in one example,
PVP or
PEG may be added to the suspension medium as a crystal growth inhibitor. In
general, where a volatile cosolvent or adjuvant is used, such an adjuvant or
cosolvent may be selected from known hydrocarbon or fluorocarbon materials and
may account for up to about 1% w/w of the suspension medium. For example,
where a cosolvent or adjuvant is incorporated in the suspension medium, the
cosolvent or adjuvant may comprise less than about 0.01%, 0.1%, or 0.5% w/w of
the suspension medium. Where PVP or PEG are included in the suspension
medium, such constituents may be included at up to about 1% w/w, or they may
comprise less than about 0.01%, 0.1%, or 0.5% w/w of the suspension medium.
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(ii) Active agent particles
[0088] The active agent particles included in the co-suspensions described
herein
are formed of a material capable of being dispersed and suspended within the
suspension medium and are sized to facilitate delivery of respirable particles
from
the co-suspension. In one embodiment, therefore, the active agent particles
are
provided as a micronized material wherein at least 90% of the active agent
particles
by volume exhibit an optical diameter of about 7 pm or less. In other
embodiments,
the active agent particles are provided as a micronized material wherein at
least 90%
of the active agent particles by volume exhibit an optical diameter selected
from a
range of about 7 pm to about 1 pm, about 5 pm to about 2 pm, and about 3 pm to
about 2 pm. In other embodiments, the active agent particles are provided as a
micronized material wherein at least 90% of the active agent particles by
volume
exhibit an optical diameter selected from 6 pm or less, 5 pm or less, 4 pm or
less, or
3 pm or less. In another embodiment, the active agent particles are provided
as a
micronized material wherein at least 50% of the active agent particle material
by
volume exhibits an optical diameter of about 4 pm or less. In further
embodiments,
the active agent particles are provided as a micronized material wherein at
least 50%
of the active agent particle material by volume exhibits an optical diameter
selected
from about 3 pm or less, about 2 pm or less, about 1.5 pm or less, and about 1
pm
or less. In still further embodiments, the active agent particles are provided
as a
micronized material wherein at least 50% of the active agent particles by
volume
exhibit an optical diameter selected from a range of about 4 pm to about 1 pm,
about
3 pm to about 1 pm, about 2 pm to about 1 pm, about 1.3 pm , and about 1.9 pm.
[0089] The active agent particles may be formed entirely of active agent or
they
may be formulated to include one or more active agents in combination with one
or
more excipients or adjuvants. In specific embodiments, an active agent present
in
the active agent particles may be entirely or substantially crystalline, i.e.,
a majority
of the active agent molecules are arranged in a regularly repeating pattern,
over a
long range of external face planes. In another embodiment, the active agent
particles may include an active agent present in both crystal and amorphous
states.
In yet another embodiment, the active agent particles may include an active
agent
present in substantially an amorphous state, i.e., the active agent molecules
are
overall noncrystalline in nature and do not have a regularly repeating
arrangement
maintained over a long range. In yet a further embodiment, where two or more
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active agents are present as active agent particles, all such active agents
may be
present in crystalline or substantially crystalline form. In alternative
embodiments
with two or more active agents present, at least one such active agent may be
present in crystalline or substantially crystalline form and at least another
active
agent may be present in an amorphous state.
[0090] Where the active agent particles described herein include two or
more
active agents in combination with one or more excipients or adjuvants, the
excipients
and adjuvants can be selected based on the chemical and physical properties of
the
active agents used. Moreover, suitable excipients for the formulation of
active agent
particles include those described herein in association with the suspending
particles.
In specific embodiments, for example, active agent particles may be formulated
with
one or more of the lipid, phospholipid, carbohydrate, amino acid, organic
salt,
peptide, protein, alditols, synthetic or natural polymer, or surfactant
materials as
described, for example, in association with the suspending particles.
[0091] In other embodiments, for example, an active agent may be added to a
solution of one or more of the lipid, phospholipid, carbohydrate, amino acid,
metal
salt, organic salt, peptide, protein, alditols, synthetic or natural polymer,
or surfactant
materials and spray-dried into a suspending particle that contains the active
agent
within the material forming the suspending particle.
[0092] Any suitable process may be employed to achieve micronized active
agent
material for use as or inclusion in active agent particles or suspending
particles as
described herein. Such processes include, but are not limited to,
micronization by
milling or grinding processes, crystallization or recrystallization processes,
and
processes using precipitation from supercritical or near-supercritical
solvents, spray
drying, spray freeze-drying, or lyophilization. Patent references teaching
suitable
methods for obtaining micronized active agent particles are described, for
example,
in U.S. Patent No. 6,063,138, U.S. Patent No. 5,858,410, U.S. Patent No.
5,851,453,
U.S. Patent No. 5,833,891, U.S. Patent No. 5, 707,634, and International
Patent
Publication No. WO 2007/009164. Where the active agent particles include
active
agent material formulated with one or more excipient or adjuvant, micronized
active
agent particles can be formed using one or more of the preceding processes and
such processes can be utilized to achieve active agent particles having a
desired
size distribution and particle configuration.
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[0093] The
active agent particles may be provided in any suitable concentration
within the suspension medium. For example, in some embodiments, the active
agent particles may be present in concentrations between about 0.01 mg/ml and
about 20 mg/ml. In certain such embodiments, the active agent particles may be
present in a concentration selected from about 0.05 mg/ml to about 20 mg/ml,
about
0.05 mg/ml to about 10 mg/ml, and from about 0.05 mg/ml to about 5 mg/ml.
[0094] A
variety of therapeutic or prophylactic agents can be utilized as active in
the co-suspension compositions disclosed herein. Exemplary active agents
include
those that may be administered in the form of aerosolized medicaments, and
active
agents suitable for use in the compositions described herein include those
that may
be presented in a form or formulated in a manner which is dispersible within
the
selected suspension medium (e.g., is substantially insoluble or exhibits a
solubility in
the suspension medium that substantially maintains a co-suspension
formulation), is
capable of forming a co-suspension with the suspending particles, and is
subject to
respirable uptake in physiologically effective amounts. The active agents that
may
be utilized in forming the active agent particles described herein can have a
variety
of biological activities.
[0095]
Examples of specific active agents that may be included in a composition
according to the present description may for example, short-acting beta
agonists,
e.g., bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline
(isoproterenol),
levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol,
rimiterol,
salbutamol (albuterol), terbutaline, tulobuterol, reproterol, ipratropium and
epinephrine; long-acting 132 adrenergic receptor agonist ("LABA"), e.g.,
bambuterol,
clenbuterol, formoterol, salmeterol; ultra long-acting 132 adrenergic receptor
agonists,
e.g., carmoterol, milveterol, indacaterol, and saligenin- or indole-
containing and
adamantyl-derived 132 agonists; corticosteroids, e.g., beclomethasone,
budesonide,
ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone,
prednisone
and trimacinolone; anti-inflammatories, e.g. fluticasone propionate,
beclomethasone
dipropionate, flunisolide, budesonide, tripedane, cortisone, prednisone,
prednisilone,
dexamethasone, betamethasone, or triamcinolone acetonide; antitussives, e.g.,
noscapine; bronchodilators, e.g., ephedrine, adrenaline, fenoterol,
formoterol,
isoprenaline, metaproterenol, salbutamol, albuterol, salmeterol, terbutaline;
and
muscarinic antagonists, including long-acting muscarinic antagonists ("LAMA"),
e.g.,
glycopyrrolate, dexipirronium, scopolamine, tropicamide,
pirenzepine,
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dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, ipatropium,
atropine,
benzatropin, or oxitropium.
[0096] Where appropriate, the active agents provided in the composition,
including but not limited to those specifically described herein, may be used
in the
form of salts (e.g., alkali metal or amine salts or as acid addition salts) or
as esters,
solvates (hydrates), derivatives, or a free base. Additionally, the active
agents may
be in any crystalline form or isomeric form or mixture of isomeric forms, for
example,
as pure enantiomers, a mixture of enantiomers, as racemates or as mixtures
thereof.
In this regard, the form of the active agents may be selected to optimize the
activity
and/or stability of the active agent and/or to minimize the solubility of the
active agent
in the suspension medium.
[0097]
Because the compositions disclosed provide reproducible delivery of very
low doses of active agents, in certain embodiments, the active agents included
in the
compositions described herein may be selected from one or more potent or
highly
potent active agents. For example, in certain embodiments, the compositions
described herein may include one or more potent active agents that are to be
delivered at a dose selected from between about 100 pg and about 100 mg per
dose, about 100 pg and about 10 mg per dose, and about 100 pg and 1 mg per
dose. In other embodiments, the compositions described herein may include a
combination of two or more potent or highly potent active agents that are to
be
delivered at a dose selected from up to about 80 pg per dose, up to about 40
pg per
dose, up to about 20 pg per dose, up to about 10 pg per dose or between about
10
pg and about 100 pg per dose.
Additionally, in certain embodiments, the
compositions described herein may include a combination of two or more highly
potent active agents that are to be delivered at a dose selected from between
about
0.1 and about 2 pg per dose, about 0.1 and about 1 pg per dose, and about 0.1
and
about 0.5 pg per dose.
[0098] In
certain embodiments, the compositions described herein include a
LABA active agent. In one such embodiment, the composition includes a LABA
active agent in combination with a LAMA active agent or a corticosteroid
active
agent. In another such embodiment, the composition includes a LAMA active
agent
in combination with a LABA active agent and a corticosteroid. In such
embodiments,
a LABA active agent can be selected from, for example, bambuterol,
clenbuterol,
formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or
indole-
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containing and adamantyl-derived (32 agonists, and any pharmaceutically
acceptable
salts, esters, isomers or solvates thereof. In certain such embodiments, the
active
agent is selected from formoterol and its pharmaceutically acceptable salts,
esters,
isomers or solvates thereof.
[0099]
Formoterol can be used to treat inflammatory or obstructive pulmonary
diseases and disorders such as, for example, those described herein.
Formoterol
has the chemical name ( )-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-
methoxypheny1)-1-methylethyl]-amino]ethyl] formanilide, and is commonly used
in
pharmaceutical compositions as the racemic fumarate dihydrate salt. Where
appropriate, formoterol may be used in the form of salts (e.g. alkali metal or
amine
salts or as acid addition salts) or as esters or as solvates (hydrates).
Additionally, the
formoterol may be in any crystalline form or isomeric form or mixture of
isomeric
forms, for example a pure enantiomer, a mixture of enantiomers, a racemate or
a
mixture thereof. In this regard, the form of formoterol may be selected to
optimize
the activity and/or stability of formoterol and/or to minimize the solubility
of formoterol
in the suspension medium. Pharmaceutically acceptable salts of formoterol
include,
for example, salts of inorganic acids such as hydrochloric, hydrobromic,
sulfuric and
phosphoric acids, and organic acids such as fumaric, maleic, acetic, lactic,
citric,
tartaric, ascorbic, succinic, glutaric, gluconic, tricarballylic, oleic,
benzoic, p-
methoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic,
methanesulfonic, p-toluenesulfonic and 3-hydroxy-2-naphthalene carboxylic
acids.
Hydrates of formoterol are described, for example, in U.S. Pat. No. 3,994,974
and
U.S. Pat. No. 5,684,199. Specific crystalline forms are described, for
example, in
W095/05805, and specific isomers of formoterol are described in U.S. Pat. No.
6,040,344.
[0100] In
specific embodiments, the formoterol material utilized to form the
formoterol particles is formoterol fumarate, and in one such embodiment, the
formoterol fumarate is present in the dihydrate form.
Where the compositions
described herein include formoterol, in certain embodiments, the compositions
described herein may include formoterol at a concentration that achieves a
delivered
dose selected from between about 0.5 pg and about 30 pg, 0.5 pg and about 1
pg,
about 1 pg and about 10 pg, about 2 pg and 5 pg, about 2 pg and about 10 pg,
about 5 pg and about 10 pg, and 3 pg and about 30 pg per actuation of an MDI.
In
other embodiments, the compositions described herein may include formoterol in
an
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amount sufficient to provide a delivered dose selected from up to about 30 pg,
up to
about 10 pg, up to about 5 pg, up to about 2.5 pg, up to about 2 pg, or up to
about
1.5 pg per actuation of an MDI. In order to achieve delivered doses as
described
herein, where compositions described herein include formoterol as the active
agent,
in specific embodiments, the amount of formoterol included in the compositions
may
be selected from, for example, between about 0.01 mg/ml and about 1 mg/ml,
between about 0.01 mg/ml and about 0.5 mg/ml, and between about 0.03 mg/ml and
about 0.4 mg/ml.
[0101]
Where the pharmaceutical co-suspension compositions described herein
include a LABA active agent, in certain embodiments, the active agent is
selected
from salmeterol, including any pharmaceutically acceptable salts, esters,
isomers or
solvates thereof. Salmeterol can be used to treat inflammatory or obstructive
pulmonary diseases and disorders such as, for example, those described herein.
Again, where salmerterol is included as the LABA active agent, in some such
embodiments, the compositions may also include a LAMA or corticosteroid active
agent. In
other such embodiments, the compositions include salmeterol in
combination with a LAMA active agent and a corticosteroid.
Salmeterol,
pharmaceutically acceptable salts of salmeterol, and methods for producing the
same are described, for example, in U.S. Patent No. 4,992,474, U.S. Patent No.
5,126,375, and U.S. patent 5,225,445.
[0102]
Where salmeterol is included as a LABA active agent, in certain
embodiments, the compositions described herein may include salmeterol at a
concentration that achieves a delivered dose selected from between about 2 pg
and
about 120 pg, about 4 pg and about 40 pg, about 8 pg and 20 pg, about 8 pg and
about 40 pg, about 20 pg and about 40 pg, and about 12 pg and about 120 pg per
actuation of an MDI. In other embodiments, the compositions described herein
may
include salmeterol in an amount sufficient to provide a delivered dose
selected from
up to about 120 pg, up to about 40 pg, up to about 20 pg, up to about 10 pg,
up to
about 8 pg, or up to about 6 pg per actuation of an MDI. In order to achieve
targeted
delivered doses as described herein, where compositions described herein
include
salmeterol as the active agent, in specific embodiments, the amount of
salmeterol
included in the compositions may be selected from, for example, between about
0.04
mg/ml and about 4 mg/ml, between about 0.04 mg/ml and about 2.0 mg/ml, and
between about 0.12 mg/ml and about 0.8 mg/ml. For example, the compositions
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described herein may include sufficient salmeterol to provide a target
delivered dose
selected from between about 4 pg and about 120 pg, about 20 pg and about 100
pg,
and between about 40 pg and about 120 pg per actuation of an MDI. In still
other
embodiments, the compositions described herein may include sufficient
salmeterol to
provide a targeted delivered dose selected from up to about 100 pg, up to
about 40
pg, or up to about 15 pg per actuation of an MDI.
[0103] In
certain embodiments, the compositions described herein include a long-
acting muscarinic antagonist (LAMA) active agent. Examples of LAMA active
agents
that may be used in the compositions described herein include, glycopyrrolate,
dexipirronium, tiotropium, trospium, aclidinium and darotropium, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof. In
some
embodiments, the compositions described herein include a LAMA active agent in
combination with a LABA active agent or a corticosteroid. In
other such
embodiments, the compositions described herein include a LAMA active agent in
combination with both LABA and corticosteroid active agents. Where the
compositions include a LAMA active agent, in particular embodiments,
glycopyrrolate, including any pharmaceutically acceptable salts, esters,
isomers or
solvates thereof, may be selected.
[0104]
Glycopyrrolate can be used to treat inflammatory or obstructive pulmonary
diseases and disorders such as, for example, those described herein. As an
anticholinergic, glycopyrrolate provides an antisecretory effect, which is a
benefit for
use in the therapy of pulmonary diseases and disorders characterized by
increased
mucus secretions.
Glycopyrrolate is a quaternary ammonium salt. Where
appropriate, glycopyrrolate may be used in the form of salts (e.g. alkali
metal or
amine salts, or as acid addition salts), esters, solvates (hydrates), or
selected
isomers. Additionally, the glycopyrrolate may be in any crystalline form or
isomeric
form or mixture of isomeric forms, for example a pure enantiomer, a mixture of
enantiomers, a racemate or a mixture thereof. In
this regard, the form of
glycopyrrolate may be selected to optimize the activity and/or stability of
glycopyrrolate and/or to minimize the solubility of glycopyrrolate in the
suspension
medium. Suitable counter ions are pharmaceutically acceptable counter ions
including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate,
phosphate,
formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate,
tartrate,
malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or
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triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-
carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate and
benzenesulfonate. In particular embodiments of the compositions described
herein,
the bromide salt of glycopyrrolate, namely 3-[(cyclopentyl-
hydroxyphenylacetyl)oxy]-
1,1-dimethylpyrrolidinium bromide, is used and can be prepared according to
the
procedures set out in U.S. Pat. No. 2,956,062.
[0105]
Where the compositions described herein include glycopyrrolate, in certain
embodiments, the compositions may include sufficient glycopyrrolate to provide
a
delivered dose selected from between about 10 pg and about 100 pg, about 15 pg
and about 100 pg, about 15 pg and about 80 pg, and about 10 pg and about 80 pg
per actuation of an MDI. In other such embodiments, the formulations include
sufficient glycopyrrolate to provide a delivered dose selected from up to
about 100
pg, up to about 80 pg, up to about 40 pg, up to about 20 pg, or up to about 10
pg per
actuation of an MDI. In yet further embodiments, the formulations include
sufficient
glycopyrrolate to provide a delivered dose selected from about 9 pg, 18 pg, 36
pg
and 72 pg per actuation of the MDI. In order to achieve delivered doses as
described
herein, where compositions described herein include glycopyrrolate as the
active
agent, in specific embodiments, the amount of glycopyrrolate included in the
compositions may be selected from, for example, between about 0.04 mg/ml and
about 2.25 mg/ml.
[0106] In other embodiments, tiotropium, including any pharmaceutically
acceptable salts, esters, isomers or solvates thereof, may be selected as a
LAMA
active agent for inclusion in a composition as described herein. Tiotropium is
a
known, long-acting anticholinergic drug suitable for use in treating diseases
or
disorders associated with pulmonary inflammation or obstruction, such as those
described herein. Tiotropium, including crystal and pharmaceutically
acceptable salt
forms of tiotropium, is described, for example, in U.S. Patent No. 5,610,163,
U.S.
Patent No. RE39820, U.S. Patent No. 6,777,423, and U.S. Patent No. 6.908,928.
Where the compositions described herein include tiotropium, in certain
embodiments, the compositions may include sufficient tiotropium to provide a
delivered dose selected from between about 2.5 pg and about 25 pg, about 4 pg
and
about 25 pg, about 2.5 pg and about 20 pg, and about 10 pg and about 20 pg per
actuation of an MDI. In other such embodiments, the formulations include
sufficient
tiotropium to provide a delivered dose selected from up to about 25 pg, up to
about
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20 pg, up to about 10 pg, up to about 5 pg, or up to about 2.5 pg per
actuation of an
MDI. In yet further embodiments, the formulations include sufficient
tiotropium to
provide a delivered dose selected from about 3 pg, 6 pg, 9 pg, and 18 pg per
actuation of the MDI. In order to achieve delivered doses as described herein,
where
compositions described herein include tiotropium as the active agent, in
specific
embodiments, the amount of tiotropium included in the compositions may be
selected from, for example, between about 0.01 mg/ml and about 0.5 mg/ml.
[0107] In
still other embodiments, the compositions described herein include a
corticosteroid.
Such active agents may be selected from, for example,
beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-
prednisolone, mometasone, prednisone and trimacinolone, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof. In
some
embodiments, such compositions include a corticosteroid active agent in
combination with a LAMA or LABA active agent. In other such embodiments, the
compositions include a corticosteroid active agent in combination with a LAMA
and a
LABA active agent. Where the compositions include a corticosteroid active
agent, in
particular embodiments, mometasone may be selected
[0108]
Mometasone, pharmaceutically acceptable salts of mometasone, such as
mometasone furoate, and preparation of such materials are known, and
described,
for example, in U.S. Pat. No. 4,472,393, U.S. Pat. No. 5,886,200, and U.S.
Pat. No.
6,177,560. Mometasone is suitable for use in treating diseases or disorders
associated with pulmonary inflammation or obstruction, such as those described
herein (see, e.g., U.S. Pat. No. 5,889,015, U.S. Pat. No. 6,057,307, U.S. Pat.
No.
6,057,581, U.S. Pat. No. 6,677,322, U.S. Pat. No. 6,677,323 and U.S. Pat. No.
6,365,581).
[0109] Where the compositions described herein include mometasone, in
particular embodiments, the compositions include mometasone, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof, in an
amount
sufficient to provide a target delivered dose selected from between about 20
pg and
about 400 pg, about 20 pg and about 200 pg, about 50 pg and about 200 pg,
about
100 pg and about 200 pg, about 20 pg and about 100 pg, and about 50 pg and
about 100 pg, per actuation of an MDI. In still other embodiments, the
compositions
described herein may include mometasone, including any pharmaceutically
acceptable salts, esters, isomers or solvates thereof, in an amount sufficient
to
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provide a targeted delivered dose selected from up to about 400 pg, up to
about 200
pg, or up to about 100 pg per actuation of an MDI.
[0110] In
other embodiments, the compositions described herein include a
corticosteroid selected from fluticasone and budesonide. Both fluticasone and
budesonide are suitable for use in treatment of conditions associated with
pulmonary
inflammation or obstruction, such as those described herein.
Fluticasone,
pharmaceutically acceptable salts of fluticasone, such as fluticasone
propionate, and
preparation of such materials are known, and described, for example, in U.S.
Pat.
No. 4,335,121, U.S. Pat. No. 4,187,301, and U.S. Pat. Pub. No. U52008125407.
Budesonide is also well known and described, for example, in U.S. Pat. No.
3,929,768. In certain embodiments, compositions described herein may include
fluticasone, including any pharmaceutically acceptable salts, esters, isomers
or
solvates thereof, in an amount sufficient to provide a target delivered dose
selected
from between about 20 pg and about 200 pg, about 50 pg and about 175 pg, and
between about 80 pg and about 160 pg per actuation of an MDI. In other
embodiments, the compositions described herein may include fluticasone,
including
any pharmaceutically acceptable salts, esters, isomers or solvates thereof, in
an
amount sufficient to provide a targeted delivered dose selected from up to
about 175
pg, up to about 160 pg, up to about 100 pg, or up to about 80 pg per actuation
of an
MDI. In
particular embodiments, compositions described herein may include
budesonide, including any pharmaceutically acceptable salts, esters, isomers
or
solvates thereof, in an amount sufficient to provide target delivered dose
selected
from between about 30 pg and about 240 pg, about 30 pg and about 120 pg, and
between about 30 pg and about 50 pg per actuation of an MDI. In still other
embodiments, the compositions described herein may include budesonide,
including
any pharmaceutically acceptable salts, esters, isomers or solvates thereof, in
an
amount sufficient to provide a targeted delivered dose selected from up to
about 240
pg, up to about 120 pg, or up to about 50 pg per actuation of an MDI.
[0111] In
each embodiment, a composition as described herein includes two or
more active agents. In some embodiments, the compositions include a
combination
of two or more species of active agent particles which may be co-suspended
with a
single species of suspending particles. Alternatively, a composition may
include two
or more species of active agent particles co-suspended with two or more
different
species of suspending particles. As yet another alternative, compositions as
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described herein may include a single species of active agent particles
suspended
with a single species of suspending particles, wherein the single species of
active
agent particles incorporates one or more active agents and the single species
of
suspending particles incorporates one or more active agents. Even further, a
composition as described herein may include two or more active agents combined
within a single species of active agent particle. For example, where the
active agent
particles are formulated using one or more excipients or adjuvants in addition
to the
active agent material, such active agent particles may include individual
particles that
include two or more different active agents.
(iii) Suspending Particles
[0112] The
suspending particles included in the co-suspension compositions
described herein work to facilitate stabilization and delivery of the active
agent
included in the compositions. Though various forms of suspending particles may
be
used, the suspending particles are typically formed from pharmacologically
inert
material that is acceptable for inhalation and is substantially insoluble in
the
propellant selected. Generally, the majority of suspending particles are sized
within
a respirable range. In
particular embodiments, therefore, the MMAD of the
suspending particles will not exceed about 10 pm but is not lower than about
500
nm. In an alternative embodiment, the MMAD of the suspending particles is
between about 5 pm and about 750 nm. In yet another embodiment, the MMAD of
the suspending particles is between about 1 pm and about 3 pm. When used in an
embodiment for nasal delivery from an MDI, the MMAD of the suspending
particles
is between 10 pm and 50 pm.
[0113] In
order to achieve respirable suspending particles within the MMAD
ranges described, the suspending particles will typically exhibit a volume
median
optical diameter between about 0.2 pm and about 50 pm. In one embodiment, the
suspending particles exhibit a volume median optical diameter that does not
exceed
about 25 pm. In another embodiment, the suspending particles exhibit a volume
median optical diameter selected from between about 0.5 pm and about 15 pm,
between about 1.5 pm and about 10 pm, and between about 2 pm and about 5 pm.
[0114] The
concentration of suspending particles included in a composition
according to the present description can be adjusted, depending on, for
example, the
amount of active agent particles and suspension medium used. In one
embodiment,
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the suspending particles are included in the suspension medium at a
concentration
selected from about 1 mg/ml to about 15 mg/ml, about 3 mg/ml to about 10
mg/ml, 5
mg/ml to about 8 mg/ml, and about 6 mg/ml. In another embodiment, the
suspending particles are included in the suspension medium at a concentration
of up
to about 30 mg/ml. In yet another embodiment, the suspending particles are
included in the suspension medium at a concentration of up to about 25 mg/ml.
[0115] The relative amount of suspending particles to active agent
particles is
selected to achieve a co-suspension as contemplated herein. A co-suspension
composition may be achieved where the amount of suspending particles, as
measured by mass, exceeds that of the active agent particles. For example, in
specific embodiments, the ratio of the total mass of the suspending particles
to the
total mass of active agent particles may be between about 3:1 and about 15:1,
or
alternatively from about 2:1 and 8:1. Alternatively, the ratio of the total
mass of the
suspending particles to the total mass of active agent particles may be above
about
1, such as up to about 1.5, up to about 5, up to about 10, up to about 15, up
to about
17, up to about 20, up to about 30, up to about 40, up to about 50, up to
about 60, up
to about 75, up to about 100, up to about 150, and up to about 200, depending
on
the nature of the suspending particles and active agent particles used. In
further
embodiments, the ratio of the total mass of the suspending particles to the
total mass
of the active agent particles may be selected from between about 10 and about
200,
between about 60 and about 200, between about 15 and about 60, between about
15 and about 170, between about 15 and about 60, about 16, about 60, and about
170.
[0116] In other embodiments, the amount of suspending particles, as
measured
by mass, is less than that of the active agent particles. For example, in
particular
embodiments, the mass of the suspending particles may be as low as 20% of the
total mass of the active agent particles. However, in some embodiments, the
total
mass of the suspending particles may also approximate or equal the total mass
of
the active agent particles.
[0117] Suspending particles suitable for use in the compositions described
herein
may be formed of one or more pharmaceutically acceptable materials or
excipients
that are suitable for inhaled delivery and do not substantially degrade or
dissolve in
the suspension medium. In one embodiment, perforated microstructures, as
defined
herein, may be used as the suspending particles. Exemplary excipients that may
be
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used in the formulation of suspending particles described herein include but
are not
limited to (a) carbohydrates, e.g., monosaccharides such as fructose,
galactose,
glucose, D-mannose, sorbose, and the like; disaccharides, such as sucrose,
lactose,
trehalose, cellobiose, and the like; cyclodextrins, such as 2-hydroxypropy1-6-
cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans,
starches, chitin, chitosan, inulin, and the like; (b) amino acids, such as
alanine,
glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, leucine,
isoleucine,
valine, and the like; (c) metal and organic salts prepared from organic acids
and
bases, such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium
gluconate, tromethamin hydrochloride, and the like; (d) peptides and proteins
such
as aspartame, trileucine, human serum albumin, collagen, gelatin, and the
like; (e)
alditols, such as mannitol, xylitol, and the like; (f) synthetic or natural
polymers or
combinations thereof, such as polylactides, polylactide-glycolides,
cyclodextrins,
polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohols,
polyanhydrides, polylactams, polyvinyl pyrrolidones, hyaluronic acid,
polyethylene
glycols; and (g) surfactants including fluorinated and nonfluorinated
compounds such
as saturated and unsaturated lipids, nonionic detergents, nonionic block
copolymers,
ionic surfactants and combinations thereof. In particular embodiments,
suspending
particles may include a calcium salt, such as calcium chloride, as described,
for
example, in U.S. Patent No. 7,442,388.
[0118]
Additionally, phospholipids from both natural and synthetic sources may
be used in preparing suspending particles suitable for use in the compositions
described herein. In particular embodiments, the phospholipid chosen will have
a
gel to liquid crystal phase transition of greater than about 40 C. Exemplary
phospholipids are relatively long chain (i.e., 016-022) saturated lipids and
may
comprise saturated phospholipids, such as saturated phosphatidylcholines
having
acyl chain lengths of 16 C or 18 C (palmitoyl and stearoyl). Exemplary
phospholipids
include phosphoglycerides such as
dipalmitoylphosphatidylcholine,
disteroylphosphatidylcholine,
diarachidoylphosphatidylcholine,
dibehenoylphosphatidylcholine, diphosphatidyl glycerol,
short-chain
phosphatidylcholines, long-chain saturated phosphatidylethanolamines, long-
chain
saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, and
long-
chain saturated phosphatidylinositols.
Additional excipients are disclosed in
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International Patent Publication No. WO 96/32149 and U.S. Patent Nos.
6,358,530,
6,372,258 and 6,518,239.
[0119] In particular embodiments, the suspending particles may be formed
using
one or more lipids, phospholipids or saccharides, as described herein. In some
embodiments, suspending particles include one or more surfactants. The use of
suspending particles formed of or incorporating one or more surfactants may
promote absorption of the selected active agent, thereby increasing
bioavailability.
The suspending particles described herein, such as, for example, suspending
particles formed using one or more lipids, can be formed to exhibit a desired
surface
rugosity (roughness), which can further reduce inter-particle interactions and
improve
aerosolization by reducing the surface area available for particle-particle
interaction.
In further embodiments, if suitable, a lipid that is naturally occurring in
the lung could
be used in forming the suspending particles, as such suspending particles that
have the potential to reduce opsonization (and thereby reducing phagocytosis
by
alveolar macrophages), thus providing a longer-lived controlled release
particle in
the lung.
[0120] In another aspect, the suspending particles utilized in the
compositions
described herein may be selected to increase storage stability of the selected
active
agent, similar to that disclosed in International Patent Publication No WO
2005/000267. For example, in one embodiment, the suspending particles my
include pharmaceutically acceptable glass stabilization excipients having a Tg
of at
least 55 C, at least 75 C, or at least 100 C. Glass formers suitable for
use in
compositions described herein include, but are not limited to, one or more of
trileucine, sodium citrate, sodium phosphate, ascorbic acid, inulin,
cyclodextrin,
polyvinyl pyrrolidone, mannitol, sucrose, trehalose, lactose, and, proline.
Examples
of additional glass-forming excipients are disclosed in U. S. Patent Nos. RE
37,872,
5,928,469, 6,258,341, and 6,309,671.
[0121] The suspending particles may be designed, sized and shaped as
desired
to provide desirable stability and active agent delivery characteristics. In
one
exemplary embodiment, the suspending particles comprise perforated
microstructures as described herein. Where perforated microstructures are used
as
suspending particles in the compositions described herein, they may be formed
using one or more excipients as described herein. For example, in particular
embodiments, perforated microstructures may include at least one of the
following:
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lipids, phospholipids, nonionic detergents, nonionic block copolymers, ionic
surfactants, biocompatible fluorinated surfactants and combinations thereof,
particularly those approved for pulmonary use. Specific surfactants that may
be
used in the preparation of perforated microstructures include poloxamer 188,
poloxamer 407 and poloxamer 338. Other specific surfactants include oleic acid
or
its alkali salts. In one embodiment, the perforated microstructures include
greater
than about 10% w/w surfactant.
[0122] In some embodiments, suspending particles may be prepared by forming
an oil-in-water emulsion, using a fluorocarbon oil (e.g., perfluorooctyl
bromide,
perfluorodecalin) which may be emulsified using a surfactant such as a long
chain
saturated phospholipid. The resulting perfluorocarbon in water emulsion may be
then processed using a high pressure homogenizer to reduce the oil droplet
size.
The perfluorocarbon emulsion may be fed into a spray dryer, optionally with an
active agent solution, if it is desirable to include active agent within the
matrix of the
perforated microstructures. As is well known, spray drying is a one-step
process that
converts a liquid feed to a dried particulate form. Spray drying has been used
to
provide powdered pharmaceutical material for various administrative routes,
including inhalation. Operating conditions of the spray dryer (such as inlet
and outlet
temperature, feed rate, atomization pressure, flow rate of the drying air and
nozzle
configuration) can be adjusted to produce the desired particle size producing
a yield
of the resulting dry microstructures. Such methods of producing exemplary
perforated microstructures are disclosed in U.S. Patent No. 6,309,623 to Weers
et al.
[0123] Perforated microstructures as described herein may also be formed
through lyophilization and subsequent milling or micronization. Lyophilization
is a
freeze-drying process in which water is sublimed from the composition after it
is
frozen. This process allows drying without elevated temperatures. In yet
further
embodiments, the suspending particles may be produced using a spray freeze
drying process, such as is disclosed in U.S. Patent 5,727,333.
[0124] Furthermore, suspending particles as described herein may include
bulking agents, such as polymeric particles. Polymeric polymers may be formed
from biocompatible and/or biodegradable polymers, copolymers or blends. In one
embodiment, polymers capable of forming aerodynamically light particles may be
used, such as functionalized polyester graft copolymers and biodegradable
polyanhydrides. For example, bulk eroding polymers based on polyesters
including
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poly(hydroxy acids) can be used. Polyglycolic acid (PGA), polyactic acid (PLA)
or
copolymers thereof may be used to form suspending particles. The polyester may
include a charged or functionalizable group, such as an amino acid. For
example,
suspending particles may be formed of poly(D,L-lactic acid) and/or poly(D,L-
lactic-co-
glycolic acid) (PLGA), which incorporate a surfactant such as DPPC.
[0125]
Other potential polymer candidates for use in suspending particles may
include polyamides, polycarbonates, polyalkylenes such as polyethylene,
polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene
terephthalate), poly vinyl compounds such as polyvinyl alcohols, polyvinyl
ethers,
and polyvinyl esters, polymers of acrylic and methacrylic acids, celluloses
and other
polysaccharides, and peptides or proteins, or copolymers or blends thereof.
Polymers may be selected with or modified to have the appropriate stability
and
degradation rates in vivo for different controlled drug delivery applications.
[0126] The
compositions described herein may include two or more species of
suspending particles.
Even further, compositions according to the present
description can include suspending particles that include one or more active
agents
incorporated into the suspending particles. Where active agent is incorporated
into
suspending particles, the suspending particles will be of a respirable size
and can
be formulated and produced using, for example, the methods and materials
described herein.
[0127]
Compositions formulated according to the present teachings can inhibit
degradation of active agent included therein. For example, in specific
embodiments,
the compositions described herein inhibit one or more of flocculation,
aggregation
and the solution mediated transformation of active agent material included in
the
compositions. The pharmaceutical compositions described herein are suited for
respiratory delivery via and MDI in a manner that achieves desirable delivered
dose
uniformity ("DDU") of each active agent included in a combination of two or
more
active agents, even with combinations including potent and highly potent
actives. As
is illustrated in detail in the Examples included herein, even when delivering
very low
doses of two or more active agents, compositions described herein can achieve
a
DDU of 30%, or better, for each active agent throughout emptying of an MDI
canister. In one such embodiment, compositions described herein achieve a DDU
of
25%, or better, for each active agent throughout emptying of an MDI canister.
In
yet another such embodiment, compositions described herein achieve a DDU for
the
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active agent of 20%, or better, for each active agent throughout emptying of
an
MDI canister.
[0128]
Pharmaceutical compositions described herein also serve to substantially
preserve FPF and FPD performance throughout emptying of an MDI canister, even
after being subjected to accelerated degradation conditions. For
instance,
compositions according to the present description maintain as much as 80%,
90%,
95%, or more, of the original FPF and FPD performance throughout emptying of
an
MDI canister, even after being subjected to accelerated degradation
conditions.
Compositions described herein provide the added benefit of achieving such
performance while being formulated using non-CFC propellants and eliminating
or
substantially avoiding pharmaceutical effects often experienced with
compositions
incorporating multiple active agents. In specific embodiments, the
compositions
described herein achieve desired one or all of a targeted DDU, FPF and FPD
performance while being formulated with suspension medium including only one
or
more non-CFC propellants and without the need to modify the characteristics of
the
non-CFC propellant, such as by the addition of, for example, one or more
cosolvent,
antisolvent, solubilizing agent, adjuvant or other propellant modifying
material.
[0129] In
one embodiment, a co-suspension composition deliverable from a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising glycopyrrolate, including
any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
glycopyrrolate of between about 15 pg and about 80 pg per actuation of the
metered
dose inhaler; a second species of active agent particles comprising
formoterol,
including any pharmaceutically acceptable salts, esters, isomers or solvates
thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; and a plurality of respirable suspending
particles
comprising perforated microstructures exhibiting a volume median optical
diameter
of between about 1.5 pm and about 10 pm, wherein the first and second species
of
active agent particles associate with the plurality of suspending particles to
form a
co-suspension. In one such embodiment, the ratio of the total mass of the
suspending particles to the total mass of the first and second species of
active agent
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particles is selected from between about 3:1 and about 15:1 and between about
2:1
and 8:1.
[0130] In
another embodiment, a co-suspension composition deliverable from a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising tiotropium, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
tiotropium of between about 5 pg and about 20 pg per actuation of the metered
dose
inhaler; a second species of active agent particles comprising formoterol,
including
any pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; and a plurality of respirable suspending
particles
comprising perforated microstructures exhibiting a volume median optical
diameter
of between about 1.5 pm and about 10 pm, wherein the first and second species
of
active agent particles associate with the plurality of suspending particles to
form a
co-suspension. In one such embodiment, the ratio of the total mass of the
suspending particles to the total mass of the first and second species of
active agent
particles is selected from between about 3:1 and about 15:1 and between about
2:1
and 8:1.
[0131] In
another embodiment, a co-suspension composition deliverable from a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
plurality of active agent particles comprising glycopyrrolate, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
glycopyrrolate of between about 15 pg and about 80 pg per actuation of the
metered
dose inhaler; and a plurality of respirable suspending
particles comprising
formoterol, including any pharmaceutically acceptable salts, esters, isomers
or
solvates thereof, wherein the plurality of suspending particles exhibit a
volume
median optical diameter of between about 1.5 pm and about 10 pm, are included
in
the suspension medium at a concentration sufficient to provide a delivered
dose of
formoterol of between about 2 pg and about 10 pg per actuation of the metered
dose
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inhaler, and associate with the plurality of active agent particles to form a
co-
suspension. In one such embodiment, the ratio of the total mass of the
suspending
particles to the total mass of the first and second species of active agent
particles is
selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.
[0132] In another embodiment, a co-suspension composition deliverable from
a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
plurality of active agent particles comprising tiotropium, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
tiotropium of between about 5 pg and about 20 pg per actuation of the metered
dose
inhaler; and a plurality of respirable suspending particles comprising
formoterol,
including any pharmaceutically acceptable salts, esters, isomers or solvates
thereof,
wherein the plurality of suspending particles exhibit a volume median optical
diameter of between about 1.5 pm and about 10 pm, are included in the
suspension
medium at a concentration sufficient to provide a delivered dose of formoterol
of
between about 2 pg and about 10 pg per actuation of the metered dose inhaler,
and
associate with the plurality of active agent particles to form a co-
suspension. In one
such embodiment, the ratio of the total mass of the suspending particles to
the total
mass of the first and second species of active agent particles is selected
from
between about 3:1 and about 15:1 and between about 2:1 and 8:1.
[0133] In another embodiment, a co-suspension composition deliverable from
a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising glycopyrrolate, including
any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
glycopyrrolate of between about 15 pg and about 80 pg per actuation of the
metered
dose inhaler; a second species of active agent particles comprising
formoterol,
including any pharmaceutically acceptable salts, esters, isomers or solvates
thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; a third species of active agent particles comprising
a
corticosteroid selected from beclomethasone, budesonide, ciclesonide,
flunisolide,
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fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone,
including any pharmaceutically acceptable salts, esters, isomers or solvates
thereof;
and a plurality of respirable suspending particles comprising perforated
microstructures exhibiting a volume median optical diameter of between about
1.5
pm and about 10 pm, wherein the first, second and third species of active
agent
particles associate with the plurality of suspending particles to form a co-
suspension.
In one such embodiment, at least 90% of the first, second, and third species
of active
agent particles by volume exhibit an optical diameter of less than 7 pm, and
the ratio
of the total mass of the suspending particles to the total mass of the first,
second,
and third species of active agent particles is selected from between about 3:1
and
about 15:1 and between about 2:1 and 8:1.
[0134] In another embodiment, a co-suspension composition deliverable from
a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising glycopyrrolate, including
any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
glycopyrrolate of between about 15 pg and about 80 pg per actuation of the
metered
dose inhaler; a second species of active agent particles comprising
formoterol,
including any pharmaceutically acceptable salts, esters, isomers or solvates
thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; a third species of active agent particles comprising
budesonide, including any pharmaceutically acceptable salts, esters, isomers
or
solvates thereof, suspended in the suspension medium at a concentration
sufficient
to provide a delivered dose of budesonide of between about 30 pg and about 50
pg
per actuation of the metered dose inhaler; and a plurality of respirable
suspending
particles comprising perforated microstructures exhibiting a volume median
optical
diameter of between about 1.5 pm and about 10 pm, wherein the first, second
and
third species of active agent particles associate with the plurality of
suspending
particles to form a co-suspension. In one such embodiment, at least 90% of the
first,
second, and third species of active agent particles by volume exhibit an
optical
diameter of less than 7 pm, and the ratio of the total mass of the suspending
particles to the total mass of the first, second, and third species of active
agent
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particles is selected from between about 3:1 and about 15:1 and between about
2:1
and 8:1.
[0135] In another embodiment, a co-suspension composition deliverable from
a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising tiotropium, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
tiotropium of between about 5 pg and about 20 pg per actuation of the metered
dose
inhaler; a second species of active agent particles comprising formoterol,
including
any pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; a third species of active agent particles comprising
budesonide, including any pharmaceutically acceptable salts, esters, isomers
or
solvates thereof suspended in the suspension medium at a concentration
sufficient
to provide a delivered dose of budesonide of between about 30 pg and about 50
pg
per actuation of the metered dose inhaler; and a plurality of respirable
suspending
particles comprising perforated microstructures exhibiting a volume median
optical
diameter of between about 1.5 pm and about 10 pm, wherein the first, second
and
third species of active agent particles associate with the plurality of
suspending
particles to form a co-suspension. In one such embodiment, at least 90% of the
first,
second, and third species of active agent particles by volume exhibit an
optical
diameter of less than 7 pm, and the ratio of the total mass of the suspending
particles to the total mass of the first, second, and third species of active
agent
particles is selected from between about 3:1 and about 15:1 and between about
2:1
and 8:1.
[0136] In another embodiment, a co-suspension composition deliverable from
a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising glycopyrrolate, including
any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
glycopyrrolate of between about 15 pg and about 80 pg per actuation of the
metered
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dose inhaler; a second species of active agent particles comprising
formoterol,
including any pharmaceutically acceptable salts, esters, isomers or solvates
thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; a third species of active agent particles comprising
mometasone, including any pharmaceutically acceptable salts, esters, isomers
or
solvates thereof, suspended in the suspension medium at a concentration
sufficient
to provide a delivered dose of mometasone of between about 20 pg and about 100
pg per actuation of the metered dose inhaler; and a plurality of respirable
suspending
particles comprising perforated microstructures exhibiting a volume median
optical
diameter of between about 1.5 pm and about 10 pm, wherein the first, second
and
third species of active agent particles associate with the plurality of
suspending
particles to form a co-suspension. In one such embodiment, at least 90% of the
first,
second, and third species of active agent particles by volume exhibit an
optical
diameter of less 7 pm, and the ratio of the total mass of the suspending
particles to
the total mass of the first, second, and third species of active agent
particles is
selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.
[0137] In another embodiment, a co-suspension composition deliverable from
a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising tiotropium, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
tiotropium of between about 5 pg and about 20 pg per actuation of the metered
dose
inhaler; a second species of active agent particles comprising formoterol,
including
any pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; a third species of active agent particles comprising
mometasone, including any pharmaceutically acceptable salts, esters, isomers
or
solvates thereof suspended in the suspension medium at a concentration
sufficient
to provide a delivered dose of mometasone of between about 20 pg and about 100
pg per actuation of the metered dose inhaler; and a plurality of respirable
suspending
particles comprising perforated microstructures exhibiting a volume median
optical
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diameter of between about 1.5 pm and about 10 pm, wherein the first, second
and
third species of active agent particles associate with the plurality of
suspending
particles to form a co-suspension. In one such embodiment, at least 90% of the
first,
second, and third species of agent particles by volume exhibit an optical
diameter of
less than 7 pm, and the ratio of the total mass of the suspending particles to
the total
mass of the first, second, and third species of active agent particles is
selected from
between about 3:1 and about 15:1 and between about 2:1 and 8:1.
[0138] In
another embodiment, a co-suspension composition deliverable from a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising glycopyrrolate, including
any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
glycopyrrolate of between about 15 pg and about 80 pg per actuation of the
metered
dose inhaler; a second species of active agent particles comprising
formoterol,
including any pharmaceutically acceptable salts, esters, isomers or solvates
thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; and a plurality of respirable suspending
particles
comprising perforated microstructures incorporating a corticosteroid selected
from
beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-
prednisolone, mometasone, prednisone and trimacinolone, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
wherein the
suspending particles exhibit a volume median optical diameter of between about
1.5
pm and about 10 pm and associate with the first and second species of active
agent
particles to form a co-suspension. In one such embodiment, at least 90% of the
first
and second species of active agent particles by volume exhibit an optical
diameter of
less than 7 pm, and the ratio of the total mass of the suspending particles to
the total
mass of the first and second species of active agent particles is selected
from
between about 3:1 and about 15:1 and between about 2:1 and 8:1.
[0139] In
another embodiment, a co-suspension composition deliverable from a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising glycopyrrolate, including
any
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pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
glycopyrrolate of between about 15 pg and about 80 pg per actuation of the
metered
dose inhaler; a second species of active agent particles comprising
formoterol,
including any pharmaceutically acceptable salts, esters, isomers or solvates
thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; and a plurality of respirable suspending
particles
comprising perforated microstructures incorporating budesonide, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
wherein the
suspending particles include sufficient budesonide to provide a delivered dose
of
budesonide of between about 30 pg and about 50 pg per actuation of the metered
dose inhaler, exhibit a volume median optical diameter of between about 1.5 pm
and
about 10 pm, and associate with the first and second species of active agent
particles to form a co-suspension. In one such embodiment, at least 90% of the
first
and second species of active agent particles by volume exhibit an optical
diameter of
less than 7 pm, and the ratio of the total mass of the suspending particles to
the total
mass of the first and second species of active agent particles is selected
from
between about 3:1 and about 15:1 and between about 2:1 and 8:1.
[0140] In
another embodiment, a co-suspension composition deliverable from a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising glycopyrrolate, including
any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
glycopyrrolate of between about 15 pg and about 80 pg per actuation of the
metered
dose inhaler; a second species of active agent particles comprising
formoterol,
including any pharmaceutically acceptable salts, esters, isomers or solvates
thereof
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; and a plurality of respirable suspending
particles
comprising perforated microstructures incorporating mometasone, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
wherein the
suspending particles include sufficient mometasone to provide a delivered dose
of
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mometasone of between about 20 pg and about 100 pg per actuation of the
metered
dose inhaler, exhibit a volume median optical diameter of between about 1.5 pm
and
about 10 pm, and associate with the first and second species of active agent
particles to form a co-suspension. In one such embodiment, at least 90% of the
first
and second species of active agent particles by volume exhibit an optical
diameter of
less than 7 pm, and the ratio of the total mass of the suspending particles to
the total
mass of the first and second species of active agent particles is selected
from
between about 3:1 and about 15:1 and between about 2:1 and 8:1.
[0141] In
another embodiment, a co-suspension composition deliverable from a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising tiotropium, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
tiotropium of between about 5 pg and about 20 pg per actuation of the metered
dose
inhaler; a second species of active agent particles comprising formoterol,
including
any pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; and a plurality of respirable suspending
particles
comprising perforated microstructures incorporating a corticosteroid selected
from
beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-
prednisolone, mometasone, prednisone and trimacinolone, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
wherein the
suspending particles exhibit a volume median optical diameter of between about
1.5
pm and about 10 pm and associate with the first and second species of active
agent
particles to form a co-suspension. In one such embodiment, at least 90% of the
first
and second species of active agent particles by volume exhibit an optical
diameter of
less than 7 pm, and the ratio of the total mass of the suspending particles to
the total
mass of the first and second species of active agent particles is selected
from
between about 3:1 and about 15:1 and between about 2:1 and 8:1.
[0142] In
another embodiment, a co-suspension composition deliverable from a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
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first species of active agent particles comprising tiotropium, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
tiotropium of between about 5 pg and about 20 pg per actuation of the metered
dose
inhaler; a second species of active agent particles comprising formoterol,
including
any pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; and a plurality of respirable suspending
particles
comprising perforated microstructures incorporating budesonide, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
wherein the
suspending particles include sufficient budesonide to provide a delivered dose
of
budesonide of between about 30 pg and about 50 pg per actuation of the metered
dose inhaler, exhibit a volume median optical diameter of between about 1.5 pm
and
about 10 pm, and associate with the first and second species of active agent
particles to form a co-suspension. In one such embodiment, at least 90% of the
first
and second species of active agent particles by volume exhibit an optical
diameter of
less than 7 pm, and the ratio of the total mass of the suspending particles to
the total
mass of the first and second species of active agent particles is selected
from
between about 3:1 and about 15:1 and between about 2:1 and 8:1.
[0143] In
another embodiment, a co-suspension composition deliverable from a
metered dose inhaler according to the present description includes the
following: a
suspension medium comprising a pharmaceutically acceptable HFA propellant; a
first species of active agent particles comprising tiotropium, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in
the suspension medium at a concentration sufficient to provide a delivered
dose of
tiotropium of between about 5 pg and about 20 pg per actuation of the metered
dose
inhaler; a second species of active agent particles comprising formoterol,
including
any pharmaceutically acceptable salts, esters, isomers or solvates thereof,
suspended in the suspension medium at a concentration sufficient to provide a
delivered dose of formoterol of between about 2 pg and about 10 pg per
actuation of
the metered dose inhaler; and a plurality of respirable suspending
particles
comprising perforated microstructures incorporating mometasone, including any
pharmaceutically acceptable salts, esters, isomers or solvates thereof,
wherein the
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suspending particles include sufficient mometasone to provide a delivered dose
of
mometasone of between about 20 pg and about 100 pg per actuation of the
metered
dose inhaler, exhibit a volume median optical diameter of between about 1.5 pm
and
about 10 pm, and associate with the first and second species of active agent
particles to form a co-suspension. In one such embodiment, at least 90% of the
first
and second species of active agent particles by volume exhibit an optical
diameter of
less than 7 pm, and the ratio of the total mass of the suspending particles to
the total
mass of the first and second species of active agent particles is selected
from
between about 3:1 and about 15:1 and between about 2:1 and 8:1.
Ill. Metered Dose Inhaler Systems
[0144] As described in relation to the methods provided herein, the co-
suspension compositions disclosed herein may be used in an MDI system. MDIs
are
configured to deliver a specific amount of a medicament in aerosol form. In
one
embodiment, an MDI system includes a pressurized, liquid phase formulation-
filled
canister disposed in an actuator formed with a mouthpiece. The MDI system may
include the formulations described herein, which include a suspension medium,
at
least one species of active agent particles and at least one species of
suspending
particles. The canister used in the MDI may be of any suitable configuration,
and in
one exemplary embodiment, the canister may have a volume ranging from about 5
mL to about 25 mL, such as, for example a canister having a 19 mL volume.
After
shaking the device, the mouthpiece is inserted into a patient's mouth between
the
lips and teeth. The patient typically exhales deeply to empty the lungs and
then
takes a slow deep breath while actuating the cartridge.
[0145] Inside an exemplary cartridge is a metering valve including a
metering
chamber capable of holding a defined volume of the formulation (e.g., 63 pl or
any
other suitable volume available in commercially available metering valves),
which is
released into an expansion chamber at the distal end of the valve stem when
actuated. The actuator retains the canister and may also include a port with
an
actuator nozzle for receiving the valve stem of the metering valve. When
actuated,
the specified volume of formulation travels to the expansion chamber, out the
actuator nozzle and into a high-velocity spray that is drawn into the lungs of
a
patient.
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IV. Methods
[0146]
Methods of formulating a pharmaceutical composition for respiratory
delivery of at least two active agents are provided herein. In one embodiment,
the
method involves the steps of providing a suspension medium, one or more
species
of active agent particles and one or more species of suspending particles, and
combining such constituents to form a composition wherein the active agent
particles
associate with the suspending particles and co-locate with the suspending
particles
within the suspension medium such that a co-suspension as described herein is
formed. In one such embodiment, the association of the active agent particles
and
the suspending particles is such that they do not separate due to their
different
buoyancies in a propellant. As will be appreciated, a method of formulating a
pharmaceutical composition as described herein can include providing two or
more
species of active agent particles in combination with one or more species of
suspending particles. In further embodiments, the method may include providing
two
or more species of suspending particles in combination with two or more
species of
active agent particles in a manner which results in a co-suspension. In still
other
embodiments, one or more species of active agent particles may be combined
with
one or more species of suspending particles, as described herein. In
particular
embodiments, the active agent material included in the active agent particles
is
selected from one or more of LABA, LAMA or corticosteroid active agents. In
certain
embodiments, the active agent particles consist essentially of active agent
material,
and are free of additional excipients, adjuvants, stabilizers, etc.
[0147] In
specific embodiments of methods for providing a stabilized composition
of a combination of two or more active agents, the present disclosure provides
methods for inhibiting the solution mediated transformation of the active
agents in a
pharmaceutical composition for pulmonary delivery. In
one embodiment, a
suspension medium as described herein, such as a suspension medium formed by
an HFA propellant, is obtained. Suspending particles are also obtained or
prepared
as described herein. Active agent particles are also obtained, and the
suspension
medium, suspending particles and active agent particles are combined to form a
co-
suspension wherein the active agent particles associate with suspending
particles
and co-locate with the suspending particles within the continuous phase formed
by
the suspension medium. When compared to active agent particles contained in
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same suspension medium in the absence of suspending particles, co-suspensions
according to the present description have been found to exhibit a higher
tolerance to
solution mediated phase transformation that leads to irreversible crystal
aggregation,
and thus may lead to improved stability and dosing uniformity.
[0148] In further embodiments, methods for forming stabilized compositions
including two or more active agents for pulmonary delivery include preserving
the
FPF and/or FPD of the composition throughout emptying of an MDI canister. In
specific embodiments of methods for preserving the FPF and/or FPD provided by
a
pharmaceutical composition for pulmonary delivery, a respirable co-suspension
as
described herein is provided which is capable of maintaining the FPD and/or
the FPF
to within 20%, 10%, or even 5% the initial FPD and/or FPF, respectively,
throughout emptying of an MDI canister. Such performance can be achieved where
two or more active agents are incorporated into the co-suspension and even
after
the co-suspension is subjected to accelerated degradation conditions. In one
embodiment, a suspension medium as described herein, such as a suspension
medium formed by an HFA propellant, is obtained. Suspending particles are also
obtained or prepared as described herein. Active agent particles are also
obtained,
and the suspension medium, suspending particles and active agent particles are
combined to form a co-suspension wherein the active agent particles associate
with
suspending particles and co-locate with the suspending particles within the
suspension medium. Even after exposure of such composition to one or more
temperature cycling events, the co-suspension maintains an FPD or FPF within
20%, 10%, or even 5% of the respective values measured prior to exposure
of
the composition to multiple temperature cycling events.
[0149] Methods for preparing an MDI for respiratory delivery of two or more
active agents are disclosed. In certain embodiments, such a method may include
loading a canister, as described herein, with active agent particles and
suspending
particles. An actuator valve can be attached to an end of the canister and the
canister sealed. The actuator valve may be adapted for dispensing a metered
amount of the active agents included in the co-suspension composition per
actuation
of the MDI. The canister can be charged with a pharmaceutically acceptable
suspension medium, such as a propellant as described herein, whereupon the
active
agent particles and suspending particles yield a stable co-suspension in the
suspension medium.
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[0150] In
methods involving respiratory delivery of two or more active agents
using compositions described herein, the compositions may be delivered by an
MDI.
Therefore, in particular embodiments of such methods, an MDI loaded with a
composition described herein is obtained, and two or more active agents are
administered to a patient via respiratory delivery through actuation of the
MDI. For
example, in one embodiment involving pulmonary delivery of two or more active
agents, after shaking the MDI device, the mouthpiece is inserted into a
patient's
mouth between the lips and teeth. The patient typically exhales deeply to
empty the
lungs and then takes a slow deep breath while actuating the cartridge of the
MDI.
When actuated, the specified volume of formulation travels to the expansion
chamber, out the actuator nozzle and into a high-velocity spray that is drawn
into the
lungs of a patient. In one embodiment the dose of each active agent delivered
throughout emptying of an MDI canister is not more than 30% greater than the
mean
delivered dose and is not less than 30% less than the mean delivered dose.
Therefore, methods of achieving a desired DDU of two or more active agents
delivered from an MDI are also provided. In such embodiments, the method may
include achieving a DDU for each of the two or more active agents delivered
from an
MDI selected from, for example, a DDU of 30%, or better, a DDU of 25%, or
better, and a DDU of 20%, or better throughout emptying of the MDI canister
from
which the co-suspension composition is delivered.
[0151]
Methods for treating patients suffering from an inflammatory or obstructive
pulmonary disease or condition are provided herein. In specific embodiments,
such
methods include pulmonary delivery of a pharmaceutical composition described
herein, and in certain such embodiments, pulmonary administration of the
pharmaceutical composition is accomplished by delivering the composition using
an
MDI. The disease or condition to be treated can be selected from any
inflammatory
or obstructive pulmonary disease or condition that responds to the
administration of,
for example, the active agents described herein. In some embodiments, the
combination of active agents includes at least one active agent selected from
LAMA,
LABA or corticosteroid active agents. In particular embodiments, the
pharmaceutical
compositions described herein may be used in treating a disease or disorder
selected from asthma, COPD, exacerbation of airways hyper reactivity
consequent
to other drug therapy, allergic rhinitis, sinusitis, pulmonary
vasoconstriction,
inflammation, allergies, impeded respiration, respiratory distress syndrome,
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pulmonary hypertension, pulmonary vasoconstriction, emphysema, and any other
respiratory disease, condition, trait, genotype or phenotype that can respond
to the
administration of combinations of active agents described herein. In
certain
embodiments, the pharmaceutical compositions described herein may be used in
treating pulmonary inflammation and obstruction associated with cystic
fibrosis.
[0152] Additionally, pharmaceutical compositions according to the present
description delivered from an MDI provide desirable pharmacodynamic (PD)
performance. In particular embodiments, pulmonary delivery of the
pharmaceutical
compositions described herein results in rapid, significant improvement in the
lung
capacity, which can be characterized by an improvement in the patient's forced
expiratory volume in one second (FEV1). For example, in particular
embodiments,
methods for achieving a clinically significant increase in FEVi are provided,
wherein
such methods include providing a co-suspension composition comprising two or
more active agents, wherein at least one of those active agents is selected
from a
LABA, LAMA or corticosteroid active agents, as described herein, and
administering
such composition to a patient experiencing pulmonary inflammation or
obstruction
via an MDI. In one such embodiment, the active agents included in the
composition
include a combination selected from one of a combination of LABA and LAMA
active
agents, a combination of LABA and corticosteroid active agents, a combination
of
LAMA and corticosteroid active agents, and a combination of LABA, LAMA and
corticosteroid active agents. For purposes of the present disclosure, a
clinically
significant increase in FEVi is any increase of 100 ml or greater, and in
certain
embodiments of the methods described herein, administration of compositions
according to the present description to patient results in a clinically
significant
increase in FEVi within 1 hour or less. In other such embodiments, methods for
administering a composition as described herein to a patient via an MDI result
in a
clinically significant increase in FEV1 within 0.5 hours or less.
[0153] In
further embodiments, methods are provided for achieving an increase in
FEVi greater than 100 ml. For example, in certain embodiments, the methods
described herein include methods for achieving an FEVi of 150 ml or greater
within a
period of time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours
or less.
In other embodiments, the methods described herein include methods for
achieving
an FEVi of 200 ml or greater within a period of time selected from 0.5 hours
or less,
1 hour or less, and 1.5 hours or less, and 2 hours or less. In yet other such
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embodiments, the methods described herein include methods for achieving an
FEVi
of 250 ml or greater within a period of time selected from 0.5 hours or less,
1 hour or
less, and 1.5 hours or less, and 2 hours or less. In still other such
embodiments, the
methods described herein include methods for achieving an FEVi of 300 ml or
greater within a period of time selected from 0.5 hours or less, 1 hour or
less, and
1.5 hours or less, and 2 hours or less. In yet other such embodiments, the
methods
described herein include methods for achieving an FEVi of 350 ml or greater
within a
period of time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours
or less,
and 2 hours or less. In certain such embodiments, the active agents included
in the
composition include a combination selected from one of a combination of LABA
and
LAMA active agents, a combination of LABA and corticosteroid active agents, a
combination of LAMA and corticosteroid active agents, and a combination of
LABA,
LAMA and corticosteroid active agents, wherein the composition is delivered to
the
patient via an MDI.
[0154] In still further embodiments, methods for achieving and maintaining
a
clinically significant increase in FEVi are provided. In particular
embodiments, upon
administration of a single dose of a combination of active agents formulated
in a
composition as described herein to a patient via an MDI, a clinically
significant
increase in FEVi is achieved in a period of time selected from 0.5 hours or
less, 1
hour or less, and 1.5 hours or less, and the clinically significant increase
in FEVi is
maintained for up 12 hours or more. In certain such embodiments, the increase
in
FEVi may be selected from an increase of 150 ml or greater, 200 ml or greater,
250
ml or greater, 300 ml or greater, and 350 ml or greater, and the increase in
FEVi
remains clinically significant for a time period selected from up to 4 hours,
up to 6
hours, up to 8 hours, up to 10 hours, and up to 12 hours, or more. In certain
such
embodiments, the active agents included in the composition include a
combination
selected from one of a combination of LABA and LAMA active agents, a
combination
of LABA and corticosteroid active agents, a combination of LAMA and
corticosteroid
active agents, and a combination of LABA, LAMA and corticosteroid active
agents,
wherein the composition is delivered to the patient via an MDI.
[0155] Compositions, systems and methods described herein are not only
suited
to achieving desirable pharmacodynamic performance in short periods of time,
but
will achieve such results in a high percentage of patients. For example,
methods are
provided herein for achieving a 10% or greater increase in FEVi in 50% or more
of
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patients experiencing pulmonary inflammation or obstruction. For
example, in
particular embodiments, methods for achieving a 10% or greater increase in
FEVi in
a patient include providing a co-suspension composition comprising a
combination of
active agents, wherein at least one active agent is selected from LABA, LAMA,
and
corticosteroid active agents as described herein, and administering such
composition
via an MDI to a patient experiencing pulmonary inflammation or obstruction. In
certain such embodiments, administration of the composition results in 10% or
greater increase in FEVi within a period of time selected from 0.5 hours or
less, 1
hour or less, 1.5 hours or less, and 2 hours in 50% or more of patients. In
other such
embodiments, administration of the composition results in 10% or greater
increase in
FEVi within a period of time selected from 0.5 hours or less, 1 hour or less,
1.5 hours
or less, and 2 or less hours in 60% or more of patients. In still other such
embodiments, administration of the composition results in 10% or greater
increase in
FEVi within a period of time selected from 0.5 hours or less, 1 hour or less,
1.5 hours
or less, and 2 hours or less in 70% or more of patients. In yet other such
embodiments, administration of the composition results in 10% or greater
increase in
FEVi within a period of time selected from 0.5 hours or less, 1 hour or less,
1.5 hours
or less, and 2 or less hours in 80% or more of patients. In
certain such
embodiments, the active agents included in the composition include a
combination
selected from one of a combination of LABA and LAMA active agents, a
combination
of LABA and corticosteroid active agents, a combination of LAMA and
corticosteroid
active agents, and a combination of LABA, LAMA and corticosteroid active
agents,
wherein the composition is delivered to the patient via an MDI.
[0156] In
specific embodiments, the methods described herein facilitate treatment
of patients experiencing pulmonary inflammation or obstruction, wherein such
methods include providing a co-suspension composition comprising a combination
of
active agents as described herein and administering such composition to a
patient
experiencing pulmonary inflammation or obstruction via an MDI, and
administration
of the composition via an MDI results in patients experiencing either an
increase
from baseline in FEVi of at least 200 ml or a 12%, or greater, increase from
baseline
in FEVi coupled with total increase in FEVi of at least 150 ml. In certain
such
embodiments, administration of the composition results in either an increase
from
baseline in FEVi of at least 200 ml or a 12%, or greater, increase from
baseline in
FEVi coupled with total increase in FEVi of at least 150 ml within a period of
time
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selected from 1 hour, or less, 1.5 hours or less, 2 hours, or less, and 2.5
hours, or
less, in 50% or more of patients. In other such embodiments, administration of
the
composition results in an increase from baseline in FEVi of at least 200 ml or
a 12%,
or greater, increase from baseline in FEVi coupled with total increase in FEVi
of at
least 150 ml within a period of time selected from 1 hour, or less, 1.5 hours,
or less,
2 hours, or less, and 2.5 hours, or less, in 60% or more of patients. In still
other such
embodiments, administration of the composition results in either an increase
from
baseline in FEVi of at least 200 ml or a 12%, or greater, increase from
baseline in
FEVi coupled with total increase in FEVi of at least 150 ml within a period of
time
selected from 1.5 hours, or less, 2 hours, or less, 2.5 hours, or less, and 3
hours, or
less, in 70% or more of patients. In yet other such embodiments,
administration of
the composition results in either an increase from baseline in FEVi of at
least 200 ml
or a 12%, or greater, increase from baseline in FEVi coupled with total
increase in
FEVi of at least 150 ml within a period of time selected from 1.5 hours, or
less, 2
hours, or less, 2.5 hours or less, and 3 hours, or less, in 80% or more of
patients. In
certain such embodiments, the active agents included in the composition
include a
combination selected from one of a combination of LABA and LAMA active agents,
a
combination of LABA and corticosteroid active agents, a combination of LAMA
and
corticosteroid active agents, and a combination of LABA, LAMA and
corticosteroid
active agents, wherein the composition is delivered to the patient via an MDI.
[0157] In some embodiments, the methods for achieving and maintaining a
clinically significant increase in FEVi described herein result in an increase
in FEVi
that represents a significant improvement in FEVi relative to the improvement
provided by compositions delivering only a single active agent. For purposes
of
comparing the FEVi performance of a composition described herein with one
delivering only a single active agent, a significant improvement in FEVi is an
improvement of 60 ml or greater. For example, in particular embodiments,
methods
for achieving a significant improvement in FEVi relative to the improvement
provided
by compositions delivering only a single active agent include providing a co-
suspension composition as described herein comprising a combination of active
agents, wherein at least one active agent is selected from LABA, LAMA, and
corticosteroid active agents as described herein, and administering such
composition
via an MDI to a patient experiencing pulmonary inflammation or obstruction. In
certain such embodiments, administration of the co-suspension composition
results
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in an improvement in FEVi AUC0_12 of at least 70 ml when compared to the FEVi
AUC0_12 achieved by a composition delivering a single active agent. In other
such
embodiments, administration of the co-suspension composition results in an
improvement in FEVi AUC0_12 of at least 80 ml when compared to the FEVi
AUC0_12
achieved by a composition delivering a single active agent. In
still other
embodiments, administration of the co-suspension composition results in an
improvement in FEVi AUC0_12 of at least 90 ml when compared to the FEVi
AUC0_12
achieved by a composition delivering a single active agent.
[0158] In
other embodiments, methods for achieving a significant improvement in
FEVi relative to the improvement provided by compositions delivering only a
single
active agent include providing a co-suspension composition as described herein
comprising a combination of active agents, wherein at least one active agent
is
selected from LABA, LAMA, and corticosteroid active agents as described
herein,
administering such composition via an MDI to a patient experiencing pulmonary
inflammation or obstruction, with such administration resulting in a
significant
improvement in the peak change in FEVi (Peak FEVi) when compared to the Peak
FEVi achieved by a composition delivering a single active agent. In certain
such
embodiments, administration of the co-suspension composition as described
herein
results in an improvement in Peak FEVi of at least 70 ml when compared to the
Peak FEVi achieved by a composition delivering a single active agent. In other
such
embodiments, administration of the co-suspension composition as described
herein
results in an improvement in Peak FEVi of at least 80 ml when compared to the
Peak FEVi achieved by a composition delivering a single active agent. In
further
such embodiments, administration of the co-suspension composition as described
herein results in an improvement in Peak FEVi of at least 90 ml when compared
to
the Peak FEVi achieved by a composition delivering a single active agent.
[0159]
Methods for providing a clinically significant increase in inspiratory
capacity (IC) in patients suffering from pulmonary inflammation or obstruction
are
also provided. As used herein, IC is defined as the maximal volume of gas that
can
be taken into the lungs in a full inhalation following a normal expiration,
and a
clinically significant increase in IC is any increase of 70 ml or greater. For
example,
in particular embodiments, methods for improving IC as described herein
include
providing a co-suspension composition as described herein comprising a
combination of active agents, wherein at least one active agent is selected
from
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LABA, LAMA, and corticosteroid active agents as described herein, and
administering such composition via an MDI to a patient experiencing pulmonary
inflammation or obstruction, wherein administration of the composition results
in an
increase in IC of 70 ml or greater. In certain such embodiments,
administration of
the composition according to the present description results in an increase in
IC of
100 ml or greater. In other such embodiments, administration of the
composition
according to the present description results in an increase in IC of 200 ml or
greater.
In still other such embodiments, administration of composition according to
the
present description results in an increase in IC of 300 ml or greater, and in
still other
embodiments, administration of composition according to the present
description
results in an increase in IC of 350 ml or greater. In specific such
embodiments, the
increase in IC is experienced rapidly. For example, in each of the methods
described, a clinically significant increase in IC or an increase in IC
selected from
100 ml or greater, 200 ml or greater, 300 ml or greater, or 350 ml or greater
can be
experienced in a patient within a time selected from 1 hour or less and 2
hours or
less.
[0160] The methods for increasing IC described herein are not only useful
for
quickly achieving clinically significant increases in IC in a short period of
time, but
they are useful for maintaining a clinically significant increase in IC over
time. For
example, as is highlighted by the clinical results presented in Example 12,
the
clinically significant increases in IC provided by the methods described
herein are
experienced by patients quickly after administration, the increases in IC
remain
clinically significant for a period of up to 12 hours or more post-
administration, and
the increases in IC remain clinically significant even after chronic dosing
(e.g.,
multiple consecutive dosing days).
[0161] Additionally, compositions according to the present description
provide
increases in IC that are significantly greater than increases in IC provided
by
compositions delivering only a single active agent. In embodiments of the
methods
described herein for increasing IC, administration of a co-suspension
composition as
described herein provides an increase in IC that is at least 70 ml greater
than the
increase in IC provided by a composition delivering only a single active
agent. In
one such embodiment, the increase in IC provided by administering a co-
suspension
composition described herein is at least 100 ml greater than the increase in
IC
provided by a composition delivering only a single active agent. In another
such
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embodiment, the increase in IC provided by administering a co-suspension
composition described herein is at least 125 ml greater than the increase in
IC
provided by a composition delivering only a single active agent
[0162] In some embodiments, the methods described herein for achieving
desired
pharmacodynamic effects are characterized by delivery of relatively low
amounts of
active agents. In certain such embodiments, for example, the methods described
herein for achieving clinically significant increases in FEVi include
administering a
co-suspension as described herein comprising a combination of glycopyrrolate
and
formoterol active agents, wherein the co-suspension is administered to a
patient via
a metered dose inhaler up to two times daily and with each administration a
total
delivered dose of glycopyrrolate of no more than 150 pg and a total delivered
dose of
formoterol of no more than 12 ug are administered to the patient. In other
such
embodiments, the methods described herein for achieving clinically significant
increases in FEVi include administering a co-suspension as described herein
comprising a combination of glycopyrrolate and formoterol active agents,
wherein the
co-suspension is administered to a patient via a metered dose inhaler up to
two
times daily and with each administration a total delivered dose of
glycopyrrolate of no
more than 100 pg and a total delivered dose of formoterol of no more than 12
ug are
administered to the patient. In other such embodiments, the methods described
herein for achieving clinically significant increases in FEVi include
administering a
co-suspension as described herein comprising a combination of glycopyrrolate
and
formoterol active agents, wherein the co-suspension is administered to a
patient via
a metered dose inhaler up to two times daily and with each administration a
total
delivered dose of glycopyrrolate of no more than 80 pg and a total delivered
dose of
formoterol of no more than 12 ug are administered to the patient. In still
other
embodiments, the methods described herein for achieving clinically significant
increases in FEVi include administering a co-suspension as described herein
comprising a combination of glycopyrrolate and formoterol active agents,
wherein the
co-suspension is administered to a patient via a metered dose inhaler up to
two
times daily and with each administration a total delivered dose of
glycopyrrolate of no
more than 50 pg and a total delivered dose of formoterol of no more than 12 ug
are
administered to the patient.
[0163] In some embodiments, the methods for achieving clinically
significant
increases in IC described herein include administering a co-suspension
composition
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as described herein to a patient via a metered dose inhaler, wherein the co-
suspension includes glycopyrrolate and formoterol active agents, the co-
suspension
is administered to a patient via a metered dose inhaler up to two times daily,
and
with each administration total delivered doses of no more than 150 pg
glycopyrrolate
and 12 ug formoterol are administered to the patient. In certain such
embodiments,
for example, the methods described herein for achieving clinically significant
increases in IC include administering a co-suspension as described herein
comprising a combination of glycopyrrolate and formoterol active agents,
wherein the
co-suspension is administered to a patient via a metered dose inhaler up to
two
times daily and with each administration a total delivered dose of
glycopyrrolate of no
more than 100 pg and a total delivered dose of formoterol of no more than 12
ug are
administered to the patient. In other such embodiments, the methods described
herein for achieving clinically significant increases in IC include
administering a co-
suspension as described herein comprising a combination of glycopyrrolate and
formoterol active agents, wherein the co-suspension is administered to a
patient via
a metered dose inhaler up to two times daily and with each administration a
total
delivered dose of glycopyrrolate of no more than 80 pg and a total delivered
dose of
formoterol of no more than 12 ug are administered to the patient. In still
other
embodiments, the methods described herein for achieving clinically significant
increases in IC include administering a co-suspension as described herein
comprising a combination of glycopyrrolate and formoterol active agents,
wherein the
co-suspension is administered to a patient via a metered dose inhaler up to
two
times daily and with each administration a total delivered dose of
glycopyrrolate of no
more than 50 pg and a total delivered dose of formoterol of no more than 12 ug
are
administered to the patient.
[0164] The
compositions provided and delivered in the methods described herein
may include a co-suspension composition including any combination of active
agents
as described herein. For
example, in particular embodiments, the methods
described herein for achieving a clinically significant increase in FEVi or IC
include
providing a co-suspension composition comprising two or more active agents,
wherein at least one of those active agents is selected from a LABA, LAMA or
corticosteroid active agents as described herein, and administering such
composition
to a patient experiencing pulmonary inflammation or obstruction via an MDI. In
one
such embodiment, the active agents included in the co-suspension composition
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include a combination selected from one of a combination of LABA and LAMA
active
agents, a combination of LABA and corticosteroid active agents, a combination
of
LAMA and corticosteroid active agents, and a combination of LABA, LAMA and
corticosteroid active agents. In specific embodiments of the methods described
herein, the co-suspension composition provided and administered can be any of
the
specific co-suspension compositions detailed herein.
[0165] The
specific examples included herein are for illustrative purposes only
and are not to be considered as limiting to this disclosure.
Moreover, the
compositions, systems and methods disclosed herein have been described in
relation to certain embodiments thereof, and many details have been set forth
for
purposes of illustration, it will be apparent to those skilled in the art that
the invention
is susceptible to additional embodiments and that certain of the details
described
herein may be varied without departing from the basic principles of the
invention.
Any active agents and reagents used in the following examples are either
commercially available or can be prepared according to standard literature
procedures by those skilled in the art of organic synthesis. The entire
contents of all
publications, patents, and patent applications referenced herein are hereby
incorporated herein by reference.
Example 1
[0166] An
exemplary co-suspension composition as described herein was
prepared and evaluated. The composition included a combination of
glycopyrrolate
(GP) and formoterol fumarate (FF) active agents. GP was present in the
propellant
as micronized, crystalline active agent particles. It was co-suspended with
spray
dried suspending particles that included FF disposed within the material
forming the
suspending particle. To achieve this, FF was dissolved in the feedstock used
to
manufacture the lipid-based suspending particles.
[0167] GP
active agent particles were formed by micronizing glycopyrrolate using
a jet mill. The particle size distribution of the glycopyrrolate active agent
particles
was determined by laser diffraction using a laser diffraction particle size
analyzer,
Fraunhofer diffraction mode, equipped with a dry powder dispenser (e.g.,
Sympatec
GmbH, Clausthal-Zellerfeld, Germany). 50% by volume of the active agent
particles
exhibited an optical diameter smaller than 1.7 pm, and 90% by volume exhibited
an
optical diameter smaller than 3.5 pm.
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[0168] FF-containing suspending particles were manufactured as follows: 654
mL of a fluorocarbon-in-water emulsion of PFOB (perfluorooctyl bromide)
stabilized
by a phospholipid was prepared; 26.5 g of the phospholipid, DSPC (1,2-
disteroyl-sn-
glycero-3-phosphocholine), and 2.4 g of calcium chloride were homogenized in
276
mL of hot water (80 C) using a high shear mixer; and 142 mL of PFOB were added
slowly during homogenization. The resulting coarse emulsion was then further
homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, CA)
at pressures of up to 170 MPa for 5 passes. 552 mg FF was dissolved in 273 ml
of
warm water (50 C) and most of the solution was combined with the emulsion
using a
high shear mixer. The emulsion was spray dried in nitrogen using the following
spray drying conditions: inlet temperature 95 C; outlet temperature 68 C;
emulsion
feed rate 2.4 ml/min; and total gas flow 498 l/min. The final mass fraction of
formoterol in the spray dried powder was 2%.
[0169] A second lot of FF-containing suspending particles was manufactured
in a
similar fashion. The mass fraction of FF in the spray dried powder was 1`)/0
for this
lot. A third lot of suspending particles was manufactured without FF.
[0170] The particle size distribution of the suspending particles (VMD) was
determined by laser diffraction. For both lots of FF containing suspending
particles,
50% by volume were smaller than 3.5 pm and the Geometric Standard Deviation of
the distribution was 1.7. For the suspending particles without FF, 50% by
volume
were smaller than 3.2 pm and the Geometric Standard Deviation of the
distribution
was 1.8.
[0171] MDIs containing FF, GP or both were prepared by weighing the target
masses of active agent particles and suspending particles into fluorinated
ethylene
polymer (FEP) coated aluminum canisters (Presspart, Blackburn, UK) with a 19
mL
volume. The canisters were crimp sealed with 63 pl valves (# BK 357, Bespak,
King's Lynn, UK) and filled with 12.4 g of HFA 134a (1,1,1,2-
tetrafluoroethane)
(Ineos Fluor, Lyndhurst, UK) by overpressure through the valve stem. The
resulting
suspension concentrations and the target delivered dose assuming 20% actuator
deposition are given in Table la for three different configurations
(configurations 1A
through 1C). After injecting the propellant, the canisters were sonicated for
15
seconds and agitated on a wrist action shaker for 30 minutes. The canisters
were
fitted with polypropylene actuators with a 0.3 mm orifice (# BK 636, Bespak,
King's
Lynn, UK).
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Table la: Configurations of the glycopyrrolate - formoterol fumarate
combination co-
suspensions of Example 1
GP Suspending Suspending Suspending Ex
actuator
Particle 1 Particle 2 Particle to dose
Active
Cs FF Cs GP
# Cs [mg/ml] Particle FF
[pg]
[mg/ml] content [mg/ml] [pg]
Ratio
1A 1.9% 3.2- 6.7
1B 0.48 1 (:)/0 6.4- 13.3 24 3.2
1C 1.9% 3.2 3.2 13.3
[0172] The
filled MDIs were stored valve down at two different conditions:
refrigerated at 5 C without overwrap and controlled room temperature at 25
C/60%
RH with a foil overwrap. Aerosol performance and delivered dose uniformity
tests
were carried out at different time points. Aerosol performance was assessed
after
manufacturing in accordance with USP <601> (United States Pharmacopoeia
Monograph 601). A Next Generation Impactor (NG!) operated at a flow rate of 30
l/min was used for determination of particle size distribution. Sample
canisters were
seated into an actuator with two waste actuations and two additional waste
priming
actuations. Five actuations were collected in the NG1 with a USP throat
attached.
The valve, actuator, throat, NG1 cups, stages, and filter were rinsed with
volumetrically dispensed solvent. The sample solutions were assayed using a
drug-
specific chromatographic method. The fine particle fraction was defined using
the
sum of stages 3 through filter. Delivered dose uniformity through use testing
was
performed using a Dose Uniformity Sampling Apparatus as described by USP
<601>. Inhalers were seated and primed as described before. Two actuations
were
collected and assayed at beginning, middle and end of use.
[0173] No
trends in aerosol performance or delivered dose uniformity were
observed for the duration of the study (3 months) or as a function of storage
temperature. Hence, all aerosol performance test results were pooled. Table lb
lists the average performance of the different configuration. The fine
particle dose is
the sum of collected mass on stages 3 to filter of the impactor, normalized by
the
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metered dose. The average aerosol performance for all three configurations was
equivalent.
Table lb: Average aerosol performance for co-suspensions in Example 1
MMAD in pm FPD in %
#
FF GP FF GP
1A 2.8 3.4 52 44
1B 2.9 3.6 51 45
2.9 3.6 51 45
[0174]
Dose content uniformity was tested through canister life for both actives of
the combination product. Figures 1 and 2 show the
ex-actuator dose for
configuration 1A and 1B, respectively, normalized by the actual metered doses
of the
canister. Assuming an actuator deposition of 20% the target ex-actuator doses
for
both actives were 80%. The individual FF and GP doses are represented by dots
and triangles, respectively. The closed line denotes the mean of the
formoterol
doses, and the broken line denotes the mean of the glycopyrrolate doses.
Figures 3
and 4 show the ratio of the normalized ex actuator doses for configuration 1A
and
1B, respectively. The result indicates that the dose ratio remained constant
through
canister life. Furthermore the variability of the dose ratio is much lower
than that of
the individual doses, indicating that a co-suspension with a consistent
carrier to
active ratio was formed and maintained through container life.
[0175] The
results show that, when formulated according to the disclosure
provided herein, combination product co-suspensions are formed with suspending
particles containing one of the active pharmaceutical ingredients, in this
case FF.
Suspending particle to active agent particle ratios can be adjusted to achieve
targeted dose content uniformity while maintaining similar aerosol
performance.
Example 2
[0176]
MDIs containing FF, GP or both were prepared at target concentrations of
2.4 and 18 pg per actuation for FF and GP respectively. GP active agent was
micronized and had a d10, d50, d90 and span of 0.6, 1.7, 3.6 and 1.9 pm
respectively
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as measured by laser diffraction as described Example 1. FF was incorporated
into
spray dried suspending particles and prepared as described in Example 1, with
a
composition of 2% FF, 91.5% DSPC and 6.5% CaCl2. The GP, FF and GP + FF
MDIs were prepared by weighing the target masses of active agent particles and
suspending particles into fluorinated ethylene polymer (FEP) coated aluminum
canisters (Presspart, Blackburn, UK) with a 19 mL volume. The canisters were
crimp sealed with 50 pl valves (# BK 357, Bespak, King's Lynn, UK) and filled
with
10.2 g of HFA 134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) by
overpressure through the valve stem. After injecting the propellant, the
canisters
were sonicated for 15 seconds and agitated on a wrist action shaker for 30
minutes.
The canisters were fitted with polypropylene actuators with a 0.3 mm orifice
(# BK
636, Bespak, King's Lynn, UK).
[0177] Long term aerosol stability and delivery characteristics of the MDI
compositions were assessed. In particular the aerosol particle size
distribution and
delivered dose characteristics of such compositions were evaluated as in
accordance with USP <601> as described in Example 1, under various conditions
and, in some instances, for periods of time extending up to 12 months. For
example,
as is shown in Figure 5, the delivered dose uniformity provided by the
compositions
prepared according to Example 1 was substantially preserved, even after 12
months
storage of such compositions at 5 C or after 4.5 months at 25 C and 60 %
relative
humidity (RH) for samples stored inside aluminum foil pouches to minimize
water
ingress into the MDI canister (i.e., "protected storage").
[0178] The aerosol performance of such compositions was also evaluated
throughout unprotected storage conditions extending up to 12 months and
protected
storage conditions extending up to 6 months. As is shown in Figure 6, the GP
and
FF particle size distributions provided by this co-suspension composition were
substantially preserved after 12 months of protected storage at 5 C and six
months
of unprotected storage conditions at 25 C and 60% RH. As is shown in Figure 7,
even under stressed conditions (40 C, 75% RH), the compositions showed no
noticeable degradation in the particle size distribution of GP and FF
delivered from
the metered dose inhalers after six months.
[0179] In order to evaluate whether the combination of GP and FF within a
single
formulation would result in the degradation of the aerosol properties relative
to
compositions including a single active agent, the aerosol properties of co-
suspension
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compositions were assessed relative to suspension compositions including only
a
single active agent.
[0180] As
can be seen in Figure 8, the aerosol performance of the combination
co-suspension composition including both GP and FF active agent was no
different
than the aerosol performance achieved by suspension compositions including
either
GP or FF alone demonstrating that the aerosol properties of the individual
active
agents are substantially the same when achieved from the single component or
dual
combination co-suspensions.
Example 3
[0181] The
pharmacokinetics and safety of a combination co-suspension metered
dose inhaler containing glycopyrrolate and formoterol fumarate were evaluated
in a
clinical trial. The clinical trial was a single-center, randomized, double-
blind, single
dose, four-period, four-treatment crossover study used to evaluate four
inhaled
treatments administered by MDI. The four treatments included a Formoterol
Fumarate (FF) Inhalation Aerosol, a Glycopyrrolate (GP) Inhalation Aerosol, a
GP +
FF Inhalation Aerosol, and consecutive delivery of the GP Inhalation Aerosol
followed immediately by delivery of the FF Inhalation Aerosol. The
GP + FF
Inhalation Aerosol as well as the FF Inhalation Aerosol and GP Inhalation
Aerosol
were prepared as described in Example 2. The GP+FF Inhalation Aerosol was also
labeled the "fixed" combination of GP and FF, while the treatment calling for
consecutive delivery of the GP Inhalation Aerosol followed immediately by
delivery of
the FF Inhalation Aerosol was labeled the "loose" combination of GP and FF.
[0182]
Subjects were randomized in to the study and assigned one of four
treatment sequences, with each treatment sequence including all four study
treatments. Each subject received four single dose treatments separated by 7
to 21
days. Sixteen subjects were enrolled and analyzed for safety. Three subjects
were
excluded from the PK analysis as a result of not receiving one or more of the
four
treatments, and an additional two subjects were excluded from the PK analysis
as
non-evaluable due to dosing errors arising from poor inhalation technique.
[0183] The
GP + FF Inhalation Aerosol was administered to provide each subject
a 72 pg dose of GP and a 9.6 pg dose of FF (four actuations, 18 pg GP and 2.4
pg
FF per actuation). The GP Inhalation Aerosol was administered to provide each
subject a 72 pg dose of GP (four actuations, 18 pg GP per actuation). The FF
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Inhalation Aerosol was administered to provide each subject a 9.6 pg dose of
FF
(four actuations, 2.4 pg FF per actuation). For blinding purposes each of the
preceding three treatments were preceded by four actuations of placebo MDI.
The
loose combination of GP Inhalation Aerosol followed by FF Inhalation Aerosol
was
administered to provide each subject a 72 pg dose of GP and a 9.6 pg dose of
FF
(four actuations, 18 pg GP per actuation followed by four additional
actuations, 2.4
pg FF per actuation).
[0184] Both the loose and fixed combinations of GP and FF were safe and
well-
tolerated, with the fixed combination providing a safety profile similar to
that
observed for the other three treatments evaluated in the trial. Blood samples
were
collected pre-dose and at 2, 5, 15, and 30 minutes, as well as 1, 2, 4, 6, 8,
and 12
hours post-dose for determining the plasma concentrations of GP and FF that
were
used to calculate various PK parameters. Plasma concentration time profiles
for
both GP and FF in the 12 hour period immediately following dosing are provided
in
Figure 9. As can be seen in Figure 9, administration of GP and FF from the
fixed
combination resulted in plasma concentrations of GP and FF following
administration
comparable to those resulting from administration of the loose combination of
GP
and FF. As was noted for the in-vitro delivered dose and particle size
distribution
performance described in Example 2, no combination effect was observed in-vivo
for
the fixed combination GP + FF Inhalation Aerosol.
Example 4
[0185] An exemplary dual co-suspension composition according to the present
description was produced and metered dose inhalers incorporating the
composition
were prepared. The composition included a combination of glycopyrrolate (GP)
and
formoterol fumarate (FF), with each being provided as a micronized,
crystalline
material. A combination crystalline co-suspension MDI was manufactured by semi-
automated suspension filling. The dual co-suspension consisted of a
combination of
two microcrystalline active pharmaceutical ingredients (also referred to as
"APIs" or
"API" in the singular), GP and FF, co-suspended with suspending particles in
HFA
134a propellant. The dual co-suspension was formulated to provide a delivered
dose of 18 pg GP per actuation and 4.8 pg FF per actuation. In preparing the
dual
co-suspension compositions, in certain compositions, the FF API material used
was
denoted as "coarse", while in other compositions, the FF API material used was
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denoted as "fine." Whether the co-suspension compositions incorporated course
or
fine FF, the compositions were formulated to provide a delivered FF dose of
4.8 pg
per actuation. The particle size characteristics for the course FF, fine FF
and GP
API materials used in formulation the co-suspension compositions described in
this
Example are detailed in Table 2. In addition to the dual co-suspension
compositions,
a monotherapy co-suspension composition incorporating only FF active agent
material was formulated. The FF monotherapy co-suspension utilized coarse FF
API. A monotherapy MDI was manufactured using such FF monotherapy co-
suspension, and the FF monotherapy MDI was formulated and manufactured
provide a delivered dose of 4.8 pg FF per actuation.
[0186] Suspending particles were manufactured via spray dried emulsion at a
feed stock concentration of 80 mg/mL with a composition of 93.44% DSPC (1,2-
Distearoyl-sn-Glycero-3-Phosphocholine) and 6.56% anhydrous calcium chloride
(equivalent to a 2:1 DSPC:CaCl2 mole/mole ratio). During the emulsion prep,
DSPC
and CaCl2 was dispersed with a high shear mixer at 8000-10000 rpm in a vessel
containing heated water (80 3 C) with PFOB slowly added during the process.
The
emulsion was then processed with 6 passes in a high pressure homogenizer
(10000-
25000 psi). The emulsion was then spray dried via a spray dryer fitted with a
0.42"
atomizer nozzle with a set atomizer gas flow of 18 SCFM. The drying gas flow
rate
was set to 72 SCFM with an inlet temperature of 135 C, outlet temperature 70
C,
and an emulsion flow rate of 58 mL/min.
[0187] For the MDI manufacturing, a drug addition vessel (DAV) was prepared
for
suspension filling in the following manner: first adding half of suspending
particle
quantity, next filling microcrystalline materials, and lastly adding the
remaining half of
suspending particles to the top. Materials were added to the vessel in a
humidity
controlled environment of <10% RH. The DAV was then connected to a 4 L
suspension vessel and flushed with HFA 134a propellant and then mixed with
gently
to form a slurry. The slurry is then transferred back to the suspension mixing
vessel
and diluted with additional HFA-134a to form the final suspension at target
concentration stirring gently with an impeller. The temperature inside the
vessel was
maintained at 21-23 C throughout the entire batch production. After
recirculation for
30 min the suspension was filled into 14 mL fluorinated ethylene polymer (FEP)
coated aluminum canisters (Presspart, Blackburn, UK) through 50 pl valves
(Bespak,
King's Lynn, UK). Sample canisters were the selected at random for total
canister
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analysis to ensure correct formulation quantities. The optical diameter and
particle
size distribution of two lots of micronized formoterol particles was
determined by
laser diffraction as described in Example 1. . Table 2 lists the d10, d50 and
d90 values
for the different lots of micronized material used. d10, d50 and d90 denote
the particle
size at which the cumulative volume distribution reported by the particle
sizing
instrument reaches 10%, 50% and 90%, respectively.
[0188] The particle size distributions provided by both dual co-suspension
formulations prepared in accordance with this Example 4 were compared to the
particle size distribution provided by a co-suspension compositions prepared
according to Example 1. The results of this comparison are provided in Table
3,
where "(YoFPF FF" and "(YoFPF GP" represent the fine particle mass of the
specified
active agent on Stages 3 through filter of an NGI, divided by actuator mass,
and
multiplied by 100.
Table 2: Particle Size Distributions for micronized Formoterol Fumarate and
Glycopyrrolate used to prepare Dual Co-Suspensions
Designation d10 (pm) d50 (pm) c190 (pm) Span
Coarse FF API 0.6 1.9 4.4 2.0
Fine FF API 0.5 1.3 2.3 1.5
GP API 0.5 1.3 3.0 1.9
Table 3: Particle Size Distributions for Different, Exemplary GP/FF Co-
suspensions
MMAD MMAD
(YoFPF MMAD (YoFPF
(YoFPF FF
FF GP GP DSPC DSPC
Dual Co-
Suspension 1 3.4 59% 2.9 65% 2.9 64%
(FF coarse)
Dual Co-
Suspension 2 2.7 62% 3.0 62% 3.1 62%
(FF fine)
Spray-dried FF
2.7 66% 2.9 65% not
tested not tested
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[0189] The aerosol performance of the dual co-suspension compositions
prepared according to this Example was evaluated and compared to the co-
suspension composition prepared according to Example 1, with aerosol
performance
being assessed as described in Example 1. The results of such comparisons are
provided in Figure 10 through Figure 12. As is easily appreciated by reference
to
these figures, regardless of whether the crystalline formoterol material used
in
providing the dual co-suspension was fine or coarse, the FF and GP particle
size
distributions for the dual co-suspension compositions were substantially the
same as
those achieved by the co-suspension composition prepared according to Example
1.
[0190] In addition, the delivered dose uniformity for GP and FF provided by
the
dual co-suspension compositions as described in this Example was assessed in
as
described in Example 1. The results of this assessment are illustrated in
Figure 13.
The dual co-suspension formulations provided desirable DDU characteristics for
both
GP and FF as all actuations delivered the expected dose within 25% of the
mean.
Example 5
[0191] The formulation of a dual co-suspension composition of salmeterol
xinafoate (SX) active agent particles and fluticasone propionate (FP) active
agent
particles is described. Both FP and SX are present in the propellant as a
micronized, crystalline particles. The two species of micronized active agent
particles
are co-suspended with spray dried suspending particles.
[0192] Micronized SX (4-hydroxy-al -[[[6-(4-phenylbutoxy)hexyl]amino]
methyl]-
1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate) was received by the
manufacturer (Inke SA, Germany) and used as active agent particles. The
particle
size distribution of the SX was determined by laser diffraction. 50% by volume
of the
micronized particles exhibited an optical diameter smaller than 2 pm, and 90%
by
volume exhibited an optical diameter smaller than 3.9 pm.
[0193] Micronized FP (S-(fluoromethy1)6a,9-difluoro-1113-17-dihydroxy-16a-
methyl-
3-oxoandrosta-1,4-diene-1713-carbothioate, 17-propionate) was received as
micronized by the manufacturer (Hovione FarmaCiencia SA, Loures Portugal) and
used as active agent particles. The particle size distribution of the FP was
determined by laser diffraction. 50% by volume of the micronized particles
exhibited
an optical diameter smaller than 2.6 pm, and 90% by volume exhibited an
optical
diameter smaller than 6.6 pm.
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[0194] Suspending particles were manufactured as follows: 150 mL of a
fluorocarbon-in-water emulsion of PFOB (perfluorooctyl bromide) stabilized by
a
phospholipid was prepared; 12.3 g of the phospholipid, DSPC (1,2-disteroyl-sn-
glycero-3-phosphocholine) and 1.2 g of calcium chloride were homogenized in
100
mL of hot water (70 C) using a high shear mixer; and 65 mL of PFOB were added
slowly during homogenization. The resulting coarse emulsion was then further
homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, CA)
at pressures of up to 140 MPa for 3 passes.
[0195] The emulsion was spray dried in nitrogen using the following spray
drying
conditions: Inlet temperature 90 C; outlet temperature 69 C; emulsion feed
rate 2.4
ml/min; and total gas flow 498 l/min. The particle size distribution of the
suspending
particles, VMD, was determined by laser diffraction. 50% by volume of the
suspending particles were smaller than 2.7 pm, the Geometric Standard
Deviation of
the distribution was 2Ø Additionally, the aerodynamic particle size
distribution of the
suspending particles was determined with a time-of-flight particle sizer. 50%
by
volume of the suspending particles had an aerodynamic particle diameter
smaller
than 1.6 pm. The large difference between aerodynamic particle diameter and
optical particle diameter indicates that the suspending particles had a low
particle
density < 0.5 kg/I. This was verified by electron microscopy, which confirmed
that
the suspending particles exhibited a hollow, thin-walled morphology.
[0196] MDIs were prepared by weighing the target masses of micronized FP,
SX,
and suspending particles into fluorinated ethylene polymer (FEP) coated
aluminum
canisters (Presspart, Blackburn, UK) with a 19 mL volume. The canisters were
crimp sealed with 63 pl valves (# BK 357, Bespak, King's Lynn, UK) and filled
with
ml of HFA 134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) by
overpressure through the valve stem. After injecting the propellant, the
canisters
were sonicated for 15 seconds and agitated on a wrist action shaker for 30
minutes.
The canisters were fitted with polypropylene actuators with a 0.3 mm orifice
(# BK
636, Bespak, King's Lynn, UK). Aerosol performance was assessed shortly after
manufacturing in accordance with USP 601, as described in Example 1. Results
are
reported below in Table 4.
Table 4: Results for a co-suspension of Fluticasone Propionate (FP) and
Salmeterol
Xinafoate (SX) of Example 5
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Suspending Target Target FP SX FP SX FP SX
particle
Delivered Delivered DDU DDU FPF FPF MMAD MMAD
conc. Dose FP Dose SX
5.9 mg/mL 12 pg 25 pg 6.1%
6.1% 27% 49% 4.1 pm 3.4 pm
RSD* RSD*
*no trend observed
[0197] The
delivered dose uniformity through use was tested and all individual
delivered doses were within 20% of mean, at 6.1% relative standard deviation
(also
referred to as "RSD"). Visual observation of the co-suspension was conducted
in
glass vials and no sedimentation of active agent particles was observed. The
vials
were left to settle for 24 hours without agitation. The suspension flocculated
slowly
and formed a homogeneous, single cream layer.
Example 6
[0198] The
formulation of a combination co-suspension composition of salmeterol
xinafoate (SX) active agent particles and fluticasone propionate (FP)
suspending
particles is described. SX is present in the propellant as a micronized,
crystalline
particle. It
is co-suspended with spray dried suspending particles that have
micronized FP disposed into the material forming the suspending particles. To
achieve this, FP crystals are suspended in the feedstock used to manufacture
the
lipid-based suspending particles. The FP and SX used to form the active agent
particles and suspending particles referenced in this example were as
described in
Example 5.
[0199] FP-
containing suspending particles were manufactured as follows: 200
mL of a fluorocarbon-in-water emulsion of PFOB stabilized by a phospholipid
was
prepared; 3.3g of the phospholipid (DSPC) and 0.8g of micronized FP were
dispersed and 0.3g of calcium chloride dihydrate was dissolved in 100mL of
warm
water (70 C) using a high shear mixer; and 44mL of PFOB was added slowly
during
dispersion. The resulting coarse emulsion was then further homogenized using a
high pressure homogenizer at 140 MPa for 3 passes. The homogenization reduced
the particle size of the suspended FP crystals. The emulsion was spray dried
in
nitrogen using the following spray drying conditions: inlet temperature 95 C;
outlet
temperature 72 C; emulsion feed rate 2.4 ml/min; and total gas flow 525 l/min.
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[0200] MDIs were prepared by weighing the target masses of micronized SX
active agent particles and FP-containing suspending particles into fluorinated
ethylene polymer (FEP) coated aluminum canisters (Presspart, Blackburn, UK)
with
a 19 mL volume. The canisters were crimp sealed with 63 pl valves (# BK 357,
Bespak, King's Lynn, UK) and filled with 10 ml of HFA 134a (1,1,1,2-
tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) by overpressure through the
valve
stem. After injecting the propellant, the canisters were sonicated for 15
seconds and
agitated on a wrist action shaker for 30 minutes. The canisters were fitted
with
polypropylene actuators with a 0.3 mm orifice (# BK 636, Bespak, King's Lynn,
UK).
Aerosol performance was assessed shortly after manufacturing in accordance
with
USP 601 as previously described in Example 1. Results are reported below in
Table
5.
Table 5: Results for a Co-suspension of Salmeterol Xinafoate (SX) Active Agent
Particles with Fluticasone Propionate-containing Suspending Particles.
FP- Target Target FP SX FP SX FP SX
Suspending Delivered Delivered DDU DDU FPF FPF MMAD MMAD
conc. Dose FP Dose SX
4.2 mg/mL 60 pg 13 pg 9.0% 13% 55%
51% 2.8 pm 3.0 pm
RSD* RSD*
*with a slight upward trend
[0201] The delivered dose uniformity through use was tested and all
individual
delivered doses were within 25% of mean, at 9.0% RSD for FP and 13% RSD for
SX. Visual observation of the co-suspension was conducted in glass vials and
no
sedimentation of active agent particles was observed. The vials were left to
settle for
24 hours without agitation. The suspension flocculated slowly and formed a
homogeneous, single cream layer, showing no indication of separation of SX and
suspending particles.
Example 7
[0202] The formulation of a dual co-suspension composition including
budesonide
active agent particles and mometasone furoate active agent particles is
described.
Budesonide (BD) and mometasone furoate (MF) were present in the propellant as
a
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micronized, crystalline particles and are co-suspended with spray dried
suspending
particles.
[0203] BD, 16,17-(butylidenebis(oxy))-11,21-dihydroxy-, (1143,16-a)-pregna-
1,4-
diene-3,20-dione, was received micronized by the manufacturer (AARTI, Mumbai,
India) and used as active agent particles. The particle size distribution of
the BD
was determined by laser diffraction. 50% by volume of the micronized particles
exhibited an optical diameter smaller than 1.9 pm, and 90% by volume exhibited
an
optical diameter smaller than 4.3 pm.
[0204] MF, 9a,21-d ichloro-11[3,17-d ihydroxy-16a-methylpregna-1,4-d
iene-3,20-
dione 17-(2-furoate), was received micronized by the manufacturer (AARTI,
Mumbai,
India) and used as active agent particles. The particle size distribution of
the MF
was determined by laser diffraction. 50% by volume of the micronized particles
exhibited an optical diameter smaller than 1.6 pm, and 90% by volume exhibited
an
optical diameter smaller than 3.5 pm.
[0205] Suspending particles were manufactured as follows: 500 mL of a
fluorocarbon-in-water emulsion of PFOB (perfluorooctyl bromide) stabilized by
a
phospholipid was prepared; 18.7 g of the phospholipid, DSPC (1,2-disteroyl-sn-
glycero-3-phosphocholine) and 1.3 g of calcium chloride were homogenized in
400
mL of hot water (75 C) using a high shear mixer; and 100 mL of PFOB were added
slowly during homogenization. The resulting coarse emulsion was then further
homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, CA)
at pressures of up to 170 MPa for 5 passes. The emulsion was spray dried in
nitrogen using the following spray drying conditions: inlet temperature 95 C;
outlet
temperature 72 C; emulsion feed rate 2.4 ml/min; and total gas flow 498 l/min.
[0206] MDIs were prepared by weighing the target masses of micronized
active
and suspending particles into coated glass vials with a 15 mL volume. The
canisters
were crimp sealed with 63 pl valves (Valois, Les Vaudreuil, France) and filled
with
9.2 g of HFA 134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) by
overpressure through the valve stem. After injecting the propellant, the
canisters
were sonicated for 15 seconds and agitated on a wrist action shaker for 30
minutes.
The suspension concentrations were 0.8 mg/ml for BD active agent particles,
1.1
mg/ml for MF active agent particles, and 6 mg/ml for the suspending particles.
The
suspending particle to active agent particle ratio was 7.5 for BD and 5.5 for
MF.
Target ex actuator doses were 40 pg for BD and 55 pg for MF.
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[0207] Visual observation of the co-suspended configurations showed no
sedimentation of active agent particles. The vials were left to settle for 16
hours
without agitation. No active agent particles were visible at the bottom of the
co-
suspension vials. The results showed that crystalline budesonide and
mometasone
furoate material forming the different species of active agent particles
associated
with the suspending particles, formed a co-suspension in the configurations
disclosed herein. The association between active agent particles and
suspending
particles was strong enough to overcome buoyancy forces as settling of the
active
agent particles was successfully inhibited.
Example 8
[0208] Dual co-suspension compositions were prepared with suspending
particles
including either mometasone furoate (MF) or budesonide (BD), and MD's
incorporating the composition were prepared. The co-suspension composition
included a combination of crystalline glycopyrrolate (GP) and formoterol
fumarate
(FF) active agent particles co-suspended with suspending particles including
either
MF or BD. Each of the APIs were provided as a micronized, crystalline
material.
[0209] Suspending particles containing 50% (w/w) of either BD or MF were
manufactured as follows: high shear homogenization of a dispersion containing
2.8
g of DSPC (1,2-Distearoyl-sn-Glycero-3-Phosphocholine), and 0.26 g of calcium
chloride in 400 mL of hot water (75 C) using a high shear mixer was performed
while 56.6 g of PFOB were added slowly. Micronized MF or BD (in 1:1 weight
proportion to DSPC) was added to the resulting coarse emulsion, which was
further
homogenized using a high pressure homogenizer (Model 03, Avestin, Ottawa, CA)
at pressures of up to 170 MPa for 3 to 5 passes. The emulsion was spray dried
using the following spray drying conditions: inlet temperature 90-95 C;
outlet
temperature 95-72 C; emulsion feed rate 2-8 mL/min; total dry nitrogen flow
525-
850 L/min. The particle size distribution of the resulting powders was
determined by
laser diffraction, 50% by volume of the suspending particles were smaller than
1.8
pm, the span of the distribution was 1.6 pm.
[0210] Canisters containing either 50% (w/w) MF or BD containing suspending
particles were filled with HFA 134a propellant, targeting a 50 or 100
pg/actuation of
MF or BD, respectively. Their aerosol particle size distributions were
determined
according to the methods described in Example 1, and results are shown in
Table 6.
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A comparable series of canisters containing MF or BD containing suspending
particles in combination with GP and FF active agent particles were produced.
Sufficient micronized GP and FF API material was added to such canisters in
amounts sufficient to provide targeted delivered doses of 36 pg/actuation and
6
pg/actuation for GP and FF, respectively. Additional placebo suspending
particles
prepared as described herein but free of any active agent (also referred to as
"placebo" suspending particles) were added to certain to reach a total co-
suspension
concentration of 5.5 mg/ml.
[0211] The aerosol particle size distributions provided by the co-
suspension
compositions prepared according to this Example were determined as described
in
Example 1, with the results are shown in Table 7. The mass mean aerodynamic
diameter of the corticosteroid in the single component suspensions is
equivalent to
the one obtained in the triple combination formulations prepared with two
different
species of active agent particles co-suspended with BD or MF containing
suspending
particles. As was true of the co-suspension compositions containing a
combination
of two different active agents, the triple co-suspension compositions prepared
according to the present description avoided a combination effect.
Table 6: Suspension MDIs in HFA 134a propellant containing corticosteroid
suspending particles. Aerosol properties, mass aerodynamic diameter and fine
particle fraction determined by drug specific cascade impaction.
Suspension. MMAD FPF
Concentration
(mg/ml) (pm) (0/0)
Mometasone
5.5 2.88 61.0
Furoate
Budesonide
5.6 3.20 61.7
Table 7: Triple combination suspension MDIs in HFA 134a propellant including
corticosteroid containing suspending particles (Mometasone Furoate or
Budesonide), a LAMA (Glycopyrrolate) and a LABA (Formoterol Fumarate). Aerosol
properties, mass mean aerodynamic diameter and fine particle fraction
determined
by drug specific cascade impaction.
Suspension
MMAD FPF
Concentration Drug
(pm) (%)
(mg/ml)
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Triple A 2.3 Formoterol 3.96 44.4
Glycopyrrolate 3.71 49.0
Mometasone 2.90 61.6
Triple B* 5.6 Formoterol 3.52 44.4
Glycopyrrolate 3.34 49.0
Mometasone 2.54 61.6
Triple C 5.5 Formoterol 3.89 47.1
Glycopyrrolate 3.74 50.0
Budesonide 3.12 63.1
*with added placebo suspending particles
Example 9
[0212] A
triple co-suspension composition according to the present description
was produced and MDIs incorporating the composition were prepared. The
composition included a combination of glycopyrrolate (GP), formoterol fumarate
(FF),
and mometasone furoate (MF) active agent particles, with each being provided
as a
micronized, crystalline API material.
[0213] A
triple co-suspension MDI was manufactured by semi-automated
suspension filling. The triple co-suspension consisted of a combination of
three
microcrystalline active pharmaceutical ingredients forming three different
species of
active agent particles: MF (corticosteroid); GP (LAMA); and FF (LABA). These
three
different species of active agent particles were co-suspended with suspending
particles in HFA 134a propellant. The triple co-suspension was formulated to
the
following delivered dose targets: 50 pg per actuation MF; 36 pg per actuation
GP;
and 4.8 pg per actuation FF. In addition to the triple co-suspension, a
monotherapy
co-suspension including only MF was produced. The monotherapy MF co-
suspension included MF active agent particles co-suspended in the propellant
with
suspending particles as described in this Example, and was formulated to
provide a
target delivered dose of 50 pg per actuation MF.
[0214]
Suspending particles were manufactured via spray dried emulsion at a
feed stock concentration of 80 mg/mL with a composition of 93.44% DSPC (1,2-
Distearoyl-sn-Glycero-3-Phosphocholine) and 6.56% anhydrous calcium chloride
(equivalent to a 2:1 DSPC:CaCl2 mole/mole ratio). During the emulsion prep,
DSPC
and CaCl2 were dispersed with a high shear mixer at 8000-10000 rpm in a vessel
containing heated water (80 3 C) with PFOB slowly added during the process.
The
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emulsion was then processed with 5 passes in a high pressure homogenizer
(10000-
25000 psi). The emulsion was then spray dried via a spray dryer fitted with a
0.42"
atomizer nozzle with a set atomizer gas flow of 18 SCFM. The drying gas flow
rate
was set to 72 SCFM with an inlet temperature of 135 C, outlet temperature 70
C,
and an emulsion flow rate of 58 mL/min.
[0215] For MDI manufacturing, a drug addition vessel (DAV) was prepared for
suspension filling in the following manner: first adding half of suspending
particle
quantity, next filling microcrystalline materials, and lastly adding the
remaining half of
suspending particles to the top. Materials were added to the vessel in a
humidity
controlled environment of <10% RH. The DAV was then connected to a 4 L
suspension vessel and flushed with HFA 134a propellant and then mixed with a
magnetic stir bar. The temperature inside the vessel was maintained at 21-23
C
throughout the entire batch production. After recirculation of the batch for
30 min
canisters were filled with the suspension mixture through 50 1.11_ EPDM
valves.
Sample canisters were the selected at random for Total Canister Analysis to
ensure
correct formulation quantities. The freshly manufactured triple co-suspension
MDI
batch was then placed on one week quarantine before initial product
performance
analysis. The mometasone furoate only MDI was manufactured by suspension
filling
in the same manner.
[0216] The primary particle size distribution of all microcrystalline APIs
was
determined by laser diffraction as described in Example 1, results are shown
in
Table 9. Aerodynamic particle size distribution and mass mean aerodynamic
diameter of all components upon actuation of the suspension MDIs was
determined
by drug specific cascade impaction as described in Example 1 and are shown in
Table 9.
Table 9: Triple microcrystalline Co-Suspension in HFA 134a propellant MDI.
Primary
particle size distribution determined by laser diffraction (Sympatec).
x10 x90
Materials x50 (pm) Span
(pm) (pm)
Micronized Mometasone
0.4 1.1 2.8 2.2
Furoate (MF)
Micron ized
0.5 1.3 3.0 1.8
Glycopyrrolate (GP)
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1 Micronized Formoterol 1
0.6 1.9 4.1 1.8 1
Fumarate Dihydrate (FF)
Table 10: Triple co-suspension MDIs in HFA 134a propellant containing
microcrystalline Corticosteroid (Mometasone Furoate), LABA (Formoterol
Fumarate)
and a LAMA (Glycopyrrolate). Aerosol properties, mass mean aerodynamic
diameter
and fine particle fraction were determined by drug specific cascade impaction
(NGI).
Suspension MMAD FPF
Concentration Drug
(mg/ml) (pm) (%)
Triple Mometasone 3.18 62.6
(Corticosteroid, 6 Formoterol 3.50 59.5
LABA, LAMA) Glycopyrrolate 2.97 64.1
Mono Mometasone 3.36 58.9
(Corticosteroid) 6
[0217] Aerosol performance and delivered dose uniformity achieved by the
triple
co-suspensions prepared according to this Example were evaluated according to
the
description provided in Example 1. Figure 14 illustrates the GP, FF and MF DDU
achieved from two canisters containing MF only and two canisters containing
MF,
GP and FF prepared according to this Example. The DDU of MF delivered from the
MF monotherapy configuration is equivalent to the one achieved with the triple
co-
suspension composition. The aerosol performance of the triple co-suspension
composition prepared according to this example was also assessed relative to
formulations containing a combination of only two active agents, FF and GP.
The
aerodynamic particle size distribution of FF and GP are equivalent whether
delivered
from the compositions containing two active agents or three active agents as
shown
in Figures 15 and 16, respectively.
[0218] As was true of the co-suspension compositions containing a
combination
of two different active agents, the triple co-suspension compositions prepared
according to the present description avoided a combination effect.
Example 10
[0219] Exemplary triple co-suspension compositions according to the present
description were produced and metered dose inhalers incorporated in the
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composition were prepared. The triple co-suspensions included glycopyrrolate
(GP)
or tiotropium bromide (TB) in combination with formoterol fumarate (FF), and
mometasone furoate (MF) active agents, with each API being used as micronized,
crystalline material.
[0220] Two separate suspension MDI batches containing three active
pharmaceutical ingredients (APIs), a corticosteroid, a LAMA and a LABA were
prepared. The APIs were provided as microcrystalline materials that served as
the
active agent particles co-suspended with suspending particles prepared as
described herein. The triple co-suspension compositions prepared as described
in
this Example were prepared by adding the active agent particles and suspending
particles to an HFA 134a propellant.
[0221] The first triple co-suspension batch (Triple GFM) was formulated to
the
following delivered dose targets: 40 pg per actuation MF; 13 pg per actuation
GP;
and 4.8 pg per actuation FF. The active agent particles were co-suspended with
suspending particles manufactured using an emulsion composed of 93.46% DSPC
(1,2-Distearoyl-sn-Glycero-3-Phosphocholine) and 6.54% anhydrous calcium
chloride spray dried with an 80 mg/mL feed concentration. The DSPC:CaCl2 molar
ratio of the suspending particles was 2:1. The suspending particles were
combined
with the active agent particles in propellant for a formulation target of 6
mg/ml
suspending particle concentration. The primary particle sizes of the
microcrystalline
active agent particles, determined by Sympatec laser diffraction measurements
as
described in Example 1, are displayed below in Table 11.
[0222] The second triple co-suspension batch (TFM) was prepared using a
different LAMA API, anhydrous tiotropium bromide (TB) to replace GP. The
second
triple co-suspension was formulated to the following delivered dose targets:
50 pg
per actuation MF; 9 pg per actuation TB; and 4.8 pg per actuation FF. The
suspending particles were prepared as described in relation to the Triple GFM
co-
suspension, and the active agent particles were co-suspended with the
suspending
particles at a targeted suspension concentration of 6 mg/ml. The primary
particle
sizes of the microcrystalline active agent particles, determined by Sympatec
laser
diffraction measurements as described in Example 1, are displayed below in
Table
12.
[0223] MDIs were prepared using the Triple GFM and Triple TFM co-suspension
compositions, and the aerosol properties, fine particle fraction, and mass
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aerodynamic diameter were determined as described in Example 1. Table 13 sets
out the MMAD and FPF performance for Triple GFM and Triple TFM, while the
desirable aerosol properties achieved by the Triple GFM and Triple TFM co-
suspensions are shown in Figure 17 (showing the aerodynamic particle size
distribution of GP and TB obtained from Triple GFM and Triple TFM,
respectively).
Table 11: Triple GFM primary particle size distribution determined by laser
diffraction
(Sympatec).
Materials du, (pm) d50 (pm) dso (pm) Span
Micronized Mometasone
0.4 1.0 2.3 1.9
Furoate
Micronized
0.5 1.4 3.4 2.1
Glycopyrrolate
Micronized Formoterol
0.5 1.4 2.7 1.9
Fumarate Dihydrate
Table 12: Triple TFM primary particle size distribution determined by laser
diffraction
(Sympatec).
Materials du, (pm) d50 (pm) dso
(pm) Span
Micronized Mometasone
0.4 1.1 2.8 2.2
Furoate
Micronized Tiotropium
0.5 1.3 3.9 2.7
Bromide Anhydrous
Micronized Formoterol
0.6 1.9 4.1 1.9
Fumarate Dihydrate
Table 13: Triple GFM and Triple TFM aerosol properties, mass mean aerodynamic
diameter and fine particle fraction determined by drug specific cascade
impaction
Suspension MMAD FPF
Concentration Drug
(pm) (0/0)
(mg/ml)
Formoterol 2.80 65.3
Triple GFM 6 Glycopyrrolate 2.90 49.5
Mometasone 3.10 49.2
Formoterol 3.82 42.4
Triple TFM 6 Tiotropium 3.79 42.0
Mometasone 4.00 43.6
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Example 11
[0224]
Exemplary dual co-suspension compositions according to the present
description were produced and MDIs incorporating the dual co-suspension
compositions were prepared. The
compositions included a combination of
glycopyrrolate (GP) and formoterol fumarate (FF), with each being provided as
a
micronized, crystalline material with particle size distribution as shown in
Table 14.
The microcrystalline GP and FF materials provided two species of active agent
particles, while suspending particles were prepared as described in Example 4.
In
preparing the dual co-suspensions described in this Example, the GP active
agent
particles, FF active agent particles, and suspending particles were combined
in an
HFA 134a propellant.
[0225] The
dual co-suspensions described in this example were prepared by first
dispensing the appropriate quantities of GP and FF active agent particles and
suspending particles into a drug addition vessel (DAV) inside a humidity
controlled
chamber (RH < 5%). The DAV is then sealed under a nitrogen atmosphere and
connected to the suspension vessel containing 12 kg of HFA-134a. A slurry was
then formed by adding 0.5-1 kg of HFA-134a into the DAV, which is then removed
from the suspension vessel and gently swirled. The slurry is then transferred
back to
the suspension mixing vessel and diluted with additional HFA-134a to form the
final
suspension at target concentration stirring gently with an impeller. The
suspension
is then recirculated via a pump to the filling system for a minimum time prior
to
initiation of filling. Mixing and recirculation continue throughout the
filling process.
Valves are placed onto MDI canisters and then purged of air either by a vacuum
crimping process, or an HFA-134a purging process, followed by valve crimping.
The
crimped canisters are then filled through-the-valve with the appropriate
quantity of
suspension, adjusted by the metering cylinder.
Table 14: Glycopyrrolate and Formoterol Fumarate particle size distributions.
Designation dio (pm) d50 (pm) clso (pm) Span
FF API 0.6 1.9 4.1 1.8
GP API 0.5 1.3 3.0 1.9
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[0226] The
suspension for pressure filling is prepared by first dispensing the
appropriate quantities of micronized glycopyrrolate and formoterol fumarate
crystals
and suspending particles to a drug addition vessel (DAV), inside a humidity
controlled chamber (RH < 5%). In the current example the suspending particle
carrier was added in three equal portions intercalating the addition of GP and
FF
after the first and second addition respectively. The DAV is then sealed under
a
nitrogen atmosphere and connected to the suspension vessel containing 12 kg of
HFA-134a. A slurry was then formed by adding 0.5-1 kg of HFA-134a into the
DAV,
which is then removed from the suspension vessel and gently swirled. The
slurry is
then transferred back to the suspension mixing vessel and diluted with
additional
HFA-134a to form the final suspension at target concentration stirring gently
with an
impeller. The suspension is then recirculated via a pump to the filling system
for a
minimum time prior to initiation of filling.
Mixing and recirculation continue
throughout the filling process. Valves are placed onto canisters and then
purged of
air either by a vacuum crimping process, or an HFA-134a purging process
followed
by valve crimping. The crimped canisters are then filled through-the-valve
with the
appropriate quantity of suspension, adjusted by the metering cylinder.
[0227]
MD's containing the dual co-suspensions described in this Example were
prepared to contain two different doses GP and FF. Specifically, a first run
of dual
co-suspension compositions were prepared to provide 18 pg per actuation GP and
4.8 pg per actuation FF ("low dose"), and a second run of dual co-suspension
compositions were prepared to provide 36 pg per actuation GP and 4.8 pg per
actuation FF ("high dose"). In addition to the dual co-suspensions
compositions,
monotherapy FF and GP co-suspension compositions were prepared. The
monotherapy co-suspension compositions were prepared as described for the dual
co-suspensions, except that they included only one species of active agent
particles
(either GP or FF). The monotherapy co-suspensions were formulated and
monotherapy MD's prepared to provide the following targeted delivered doses:
18 pg
per actuation of GP, and 0.5, 1.0, 3.6 or 4.8 pg per actuation of FF. The
compositions and MD's providing 0.5 pg FF and 1 pg FF per actuation are
referred
to as "ultra low" dose.
[0228] The
drug specific aerodynamic size distributions achieved with MD's
containing the co-suspension compositions prepared according to this Example
were
determined as described in Example 1. The proportionality of the aerodynamic
size
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distributions of GP obtained from the low and high dose dual co-suspensions as
well
as the equivalency between the dual and monotherapy co-suspensions is
demonstrated in Figure 18. In
the same manner, the proportionality of the
aerodynamic size distributions of FF obtained from the dual and monotherapy co-
suspensions, including the ultralow, low, and high dose compositions is
demonstrated in Figure 19.
[0229] The
delivered dose uniformity of the ultra low dose FF monotherapy MDIs
was also measured as described in Example 1. The DDU for the 1 pg/actuation
and
0.5 pg/actuation compositions and systems are shown in Figure 20. Desirable
dose
delivery uniformity is achieved even for ultralow doses.
Example 12
[0230] The
safety, efficacy and PK performance of combination co-suspension
compositions as described herein delivered via a metered dose inhaler (MDI)
were
evaluated in a clinical trial. The combination co-suspension compositions
contained
both glycopyrrolate and formoterol fumarate. The clinical trial was a
randomized,
double-blind, customized, unbalanced, incomplete block, crossover, multi-
center
study conducted in patients with moderate to very severe Chronic Obstructive
Pulmonary Disease (COPD). Two different combination co-suspension
compositions as described herein were compared to a placebo and four active
comparator compositions delivering only one of the two active agents included
in the
combination compositions.
[0231] The
two combination co-suspension compositions administered in the
clinical trial included both Glycopyrrolate (GP) and Formoterol Fumarate (FF)
active
agents delivered as a fixed combination. The combination co-suspensions were
prepared generally as described in Example 4, with the GP and FF active agent
particles provided as micronized, crystalline GP and FF material, the
suspending
particles being spray dried particles comprising DSPC and CaCl2, and the
suspension medium being formed by HFA 134a. The combination co-suspension
compositions were prepared for delivery to patients via an MDI as described
herein
and were tailored to facilitate administration of two different doses of the
GP and FF
active agents. The first co-suspension combination composition was formulated
to
deliver 36 pg GP and 4.8 pg FF to a patient per actuation of the MDI and was
used
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to dose 72 pg GP and 9.6 pg FF to patients twice daily (two actuations of the
MDI
administered twice daily). This first composition and treatment is also
referred to in
this example and the accompanying figures as "GP/FF 72/9.6" and the "GP/FF
72/9.6 treatment." The second co-suspension combination composition was
formulated to deliver 18 pg GP and 4.8 pg FF to a patient per actuation of the
MDI
and was used to dose 36 pg GP and 9.6 pg FF to patients twice daily (two
actuations
of the MDI administered twice daily). This second composition and treatment is
also
referred to in this example and the accompanying figures as "GP/FF 36/9.6" and
the
"GP/FF 36/9.6 treatment."
[0232] The GP/FF 72/9.6 and GP/FF 36/9.6 treatments were compared against a
placebo and five different active compositions containing one of FF, GP or
tiotropium
as a single active agent. The first composition was an active control, Spiriva
Handihaler (tiotropium bromide inhalation powder). Spiriva is a dry powder
inhaler
(DPI) product and was administered to patients once daily, with each DPI
capsule
including and 18 pg dose of tiotropium. The next composition, Foradil
Aerolizer
(formoterol fumarate inhalation powder), was also an active control. Foradil
is also a
DPI product, but it was administered to patients twice daily, and each DPI
capsule
included a 12 pg dose of FF. The
third composition was a co-suspension
composition including only GP as the active agent. The monotherapy GP co-
suspension composition (GP 36) was manufactured for pulmonary delivery via an
MDI and was administered twice daily, with each administration delivering a 36
pg
dose of GP to the patient. The remaining two compositions were two different
monotherapy co-suspension compositions including only FF as the active
ingredient
(FF 9.6 and FF 7.2). The monotherapy FF co-suspension compositions were
manufactured for pulmonary delivery via an MDI and were administered twice-
daily,
with each administration delivering either a 9.6 pg dose of FF (FF 9.6) or a
7.2 pg
dose of FF (FF 7.2) to the patient. The GP and FF monotherapy co-suspension
compositions were formulated using micronized, crystalline GP or FF material
as
active agent particles, spray dried particles comprising DSPC and CaCl2 as the
suspending particles, and HFA 134a as the suspension medium.
[0233] 118
patients were randomized into the study and administered study
compositions over 7 day periods. On Day 7 of treatment, improvement in FEVi
was
assessed in each patient over a period of 12 hours post administration of each
of the
study compositions, and the area under the curve of the improvement in FEVi
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relative to baseline provided by each of the study compositions over the
twelve-hour
period (AUC0_12) was calculated. The AUC0_12 on treatment day 7 (Day 7) was
used
as the primary endpoint for the study. Secondary endpoints included the peak
change in FEVi post administration of each of the study compositions (Peak
FEVi)
on Day 1 and Day 7, the trough FEVi experienced by patients after chronic
dosing
for 7 days but prior to dosing on treatment Day 7 (Morning Trough FEVi) and
safety
assessments. The two GP/FF co-suspension compositions were safe and well-
tolerated.
[0234] The percentage of subjects experiencing an improvement in FEVi of
12% from baseline on treatment day 1 (Day 1) and the rate at which such
improvement was experienced is represented in Figure 21. As can be seen in
Figure 21, the cumulative response and rate of onset provided by the GP/FF
72/9.6
and GP/FF 36/9.6 treatments was greater than the cumulative response and rate
of
onset provided by Spiriva. Relative to the comparator compositions having only
a
single active agent, the GP/FF 72/9.6 and GP/FF 36/9.6 treatments provided
greater
changes from baseline in FEVi at Day 7 (shown in Figure 22 ¨ Figure 24).
[0235] Both GP/FF 72/9.6 and GP/FF 36/9.6 were superior to all the
comparators
for the primary endpoint. Figure 25 shows the improvement in FEVi AUC0_12 on
Day
7 achieved by GP/FF 72/9.6, GP/FF 36/9.6, and each of the active comparators
relative to placebo. As is shown in Figure 25, GP/FF 72/9.6 and GP/FF 36/9.6
provided markedly better improvement in FEVi AUC0_12 on Day 7 relative to the
comparator compositions, with the improvement in FEVi AUC0_12 on Day 7
provided
by GP/FF 72/9.6 and GP/FF 36/9.6 being at least 80 ml greater than that
provided by
each of the comparator compositions. The difference in FEVi AUC0_12 on Day 7
shown in Figure 26 further highlights, for example, the improvement in FEVi
AUC0-12
on Day 7 provided by the GP/FF 36/9.6 composition relative to the GP 36, FF
9.6,
Spiriva, and Foradil comparators.
[0236] Using the improvement in FEVi AUC0_12 provided by the GP/FF 72/9.6
treatment as a reference point, Figure 32 presents the percent improvement in
FEVi
AUC0_12 on Day 7 provided by GP/FF 36/9.6 and each of the comparators in all
patients, patients with moderate COPD, and patients with severe to very severe
COPD. The results shown in Figure 32 illustrate that the response in patients
was
consistent regardless of the severity of COPD.
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[0237] GP/FF 72/9.6 and GP/FF 36/9.6 were also superior to all other
comparators for the secondary endpoints of the study. The Peak FEVi shown in
Figure 27 represents a change from baseline provided by each of the active
study
compositions relative to placebo on Day 1 and Day 7 of administration. As
shown in
Figure 27, GP/FF 72/9.6 and GP/FF 36/9.6 provided superior Peak FEVi on both
Day 1 and Day 7. Figure 28 highlights the improvement in Peak FEVi relative to
Spiriva and Foradil provided by GP/FF 72/9.6 and GP/FF 36/9.6 on Day 1 and Day
7. Figure 29 illustrates the improvement in Morning Trough FEVi provided by
GP/FF
72/9.6, GP/FF 36/9.6, and each of the active comparators relative to placebo.
As
can be appreciated by reference to Figure 29, superior increases in FEVi
provided
by the two combination co-suspensions are better maintained over time, with
the
GP/FF 72/9.6 and GP/FF 36/9.6 compositions providing an approximately 50%
improvement in Morning Trough FEVi relative to the other active comparators.
[0238] Figure 30 shows the difference between the increase in pre-dose FEVi
on
Day 7 provided by GP/FF 72/9.6 and GP/FF 36/9.6 and the increase in pre-dose
FEVi on Day 7 provided by the GP 36, FF 9.6, Spiriva and Foradil comparators.
As
can be easily appreciated by reference to FIG. 30, realtive to the GP 36, FF
9.6,
Spiriva and Foradil comparators, the GP/FF 36/9.6 treatment provided
significantly
greater improvements in pre-dose FEVi on Day 7.
[0239] In addition to the specified secondary endpoints for the study,
improvements in inspiratory capacity (IC) were assessed. Both GP/FF 72/9.6,
GP/FF 36/9.6 provided greater increases in IC relative to each of the
comparators at
Day 1 and on Day 7. For patients receiving GP/FF 72/9.6, GP/FF 36/9.6, and
Spiriva, Figure 31 illustrates the peak improvement in IC experienced on Day 1
(Day
1 Peak), the improvement in IC retained in patients prior to administration of
the
specified test compositions on Day 7 (Day 7 Pre), and the peak improvement in
IC
experienced in patients on Day 7 after administration of the specified
compositions
(Day 7 Peak).
87
