Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITION AND METHOD FOR INHALATION
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent
Application Serial No.
62/682,109, filed on June 7, 2018, the entire contents of which are
incorporated herein by
reference.
TECHNICAL FIELD
[0002] Compositions and methods for treating pulmonary arterial hypertension
are disclosed.
BACKGROUND
[0003] Pulmonary arterial hypertension (PAH) is a complex, multifactorial,
progressive
syndrome characterized by persistent elevation of pulmonary artery pressure
and pulmonary
vascular resistance (PVR) that leads to increase in right ventricular
afterload and eventually
culminates in right heart failure. Right ventricular failure limits cardiac
output during exertion.
The most common symptom at presentation is breathlessness, fatigue, angina,
syncope, and
abdominal distension, with impaired exercise capacity as a hallmark of the
disease.
[0004] The symptoms of PAH are non-specific. The symptoms at rest are reported
only in
very advanced cases due to the non-specific nature of the symptoms, there is a
substantial delay
of more than 2 years in the diagnosis of pulmonary hypertension (PH).
Unfortunately
approximately 70% of the patients with PH are diagnosed when they have reached
an advanced
stage of disease (World Health Organization (WHO) Functional Class III and
IV). Early
identification and treatment of pulmonary hypertension (PH) is generally
suggested because
advanced disease may be less responsive to therapy. Treatment begins with a
baseline
assessment of disease severity, followed by primary therapy.
10005] Assessing patients with pulmonary hypertension involves evaluating the
severity of
their disease using a range of clinical assessments, exercise tests, detection
of specific
biochemical markers, and echocardiographic and hemodynamic assessments. The
clinical
assessment of the patient has a pivotal role in the choice of the initial
treatment, the evaluation
of the response to therapy, and the possible escalation of therapy if needed.
[0006] PAH is classified into five groups (1-5) depending on the severity of
the disease. In
group 1, for example, the disease is heritable and commonly induced by drugs
and toxins. PAH
includes idiopathic pulmonary arterial hypertension (IPAH, formerly called
primary
pulmonary hypertension), hereditary PAH, or PAH due to diseases such as
connective tissue
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diseases, HIV infection, portal hypertension, congenital heart disease,
schistosomiasis, and
drug or toxin exposure (e.g. anorexigens). Estimated prevalence PAH is 15-50
cases per
million, in the USA and Europe. However, the prevalence of PAH in certain at-
risk groups is
substantially higher. For example, in HIV-infected patients the prevalence of
PAH is 0.5%, in
patients with collagen vascular disorders it has been reported to be 7-12%,
and in patients with
sickle cell disease the prevalence is around 2-3.75%. In patients with
hepatosplenic
schistosomiasis 5% may have PAH. It is estimated that 10% of adults with
congenital heart
disease (CHD) may also have PAH. PAH in the newborn, known as persistent
pulmonary
hypertension of the newborn has been estimated to occur in 0.2% of live-born
term infants.
100071 Group 2 patients develop PH due to left heart disease from, inter alia,
left ventricular
systolic dysfunction, left ventricular diastolic dysfunction, valvular
disease, or
congenital/acquired left heart inflow/outflow tract obstruction, and
congenital
cardiomyopathi es. In group 3, the PH is due to chronic lung disease and/or
hypoxia exhibiting
chronic obstructive pulmonary disease, interstitial lung disease, other
pulmonary diseases with
mixed restrictive and obstructive pattern, sleep-disordered breathing,
alveolar hypoventilation
disorders, chronic exposure to high altitude and developmental lung diseases.
In group 4. PH
is due to chronic thromboembolic pulmonary hypertension and group 5 patients
exhibit PH due
to unclear multifactorial mechanisms, including hematologic disorders such as
chronic
hemolytic anemia, myeloproliferative disorders, splenectoiny, systemic
disorders such as
sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis; metabolic
disorders,
including glycogen storage disease, Gaucher's disease and thyroid disorders;
and other
disorders such as tumor/mass obstruction, fibrosing mediastinitis, chronic
renal failure,
segmental PH.
[0008] Primary therapy is directed at the underlying cause of the PH and is
warranted in
nearly all patients with PH. The disease severity should be reassessed
following primary
therapy, in order to determine whether advanced therapy is indicated. Advanced
therapy is
directed at the pulmonary hypertension itself, rather than the underlying
cause of the PH.
Advanced therapy is widely accepted for many patients with group 1 pulmonary
arterial
hypertension (PAH). In contrast, it should only be administered on a case-by-
case basis for
patients with group 3 PH, group 4 PH, or group 5 PH, after carefully weighing
the risks versus
the benefits. Advanced therapy should not be administered to most patients
with group 2 PH.
[0009] Until 2001, the only drug available to treat PAH was epoprostenol
(Flolan,
GlaxoSmithKline Pharmaceuticals), and it was mostly used as a bridge to
transplantation. Since
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then, other therapies have evolved, and as a result the prognosis of patients
with PAH has
significantly improved.
[0010] The clinical assessment of the patient has a pivotal role in the choice
of the initial
treatment, the evaluation of the response to therapy, and the possible
escalation of therapy if
needed. As mentioned above, diagnosing patients with pulmonary hypertension
involves
evaluating the severity of their disease using a range of clinical
assessments, exercise tests,
identification of biochemical markers, echocardiographic and hemodynamic
assessments.
[0011] The clinical severity of PAH is classified according to a system
originally developed
for heart failure by the New York Heart Association (NYHA) and then modified
by WHO for
patients with PH. This functional classification (I-IV) system links symptoms
with activity
limitations, and allows clinicians to quickly predict disease progression and
prognosis, as well
as the need for specific treatment regimens, irrespective of the underlying
etiology of PAH.
Class I patients exhibit PH, but without resulting limitation of physical
activity, and ordinary
physical activity does not cause dyspnea or fatigue, chest pain, or near
syncope. Class 1,1
patients exhibit pulmonary hypertension resulting in slight limitation of
physical activity. They
are comfortable at rest and ordinary physical activity causes undue dyspnea or
fatigue, chest
pain, or near syncope. Class ftl are patients with pulmonary hypertension
resulting in marked
limitation of physical activity, they are comfortable at rest and less than
ordinary activity causes
undue dyspnea or fat4-?,ae, chest pain, or near syncope. Class IV are patients
with pulmonary
hypertension with inability to carry out any physical activity without
symptoms. These patients
manifest signs of right heart failure. Dyspnea andlor fatigue may even be
present at rest, and
discomfort is increased by any physical activity.
[0012] The pathogenesis of PH is complex and many biochemical pathways and
cell types
have been identified or proposed as contributing to this vasoconstriction and
vascular
remodeling. These include altered synthesis of nitric oxide (NO), prostacyclin
(PGI) and
endothelin (ET-1), impaired potassium channel and growth factor receptor
function, altered
serotonin transporter regulation, increased oxidant stress, and enhanced
matrix production of
vasoactive factors, calcium signaling molecules, inflammatory mediators,
growth factors, bone
morphogenetic protein receptor 2 (BMPR2) mutations. However, the relative
importance of
each of these processes is unknown.
[0013] Clinical and preclinical studies strongly suggest that the pulmonary
vascular
endothelium plays a critical role and interactions between pulmonary
endothelial cells with
pulmonary arterial smooth muscle cells, and pulmonary pericytes plays a
critical role in either
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initiation and/or perpetuation of the characteristic progressive pulmonary
arterial obstruction
in PAH. Pulmonary vascular endothelium is a critical local source of several
key mediators for
vascular remodeling, including growth factors (fibroblast growth factor [FGF]-
2, serotonin [5-
HT], angiotensin II, and vasoactive peptides (NO, PGI2, ET-1), cytokines (IL-
1, IL-6,
macrophage migration inhibitory factor [MIF1), and chemokines (monocyte
chemoattractant
protein [MCP1-1), adipokines (leptin). Endothelial dysfunction, is believed to
occur early in
disease and this leads to chronically impaired production of vasodilator and
antiproliferative
agents such as NO and prostacyclin, along with overexpression of
vasoconstrictor and
proliferative substances such as thromboxane A2 and endothelin-1 Paracrine
overproduction
of ET-1, 5-HT, angiotensin II, and FGF-2 contributes to an increased pulmonary
vascular cell
proliferation, survival, migration, and differentiation. Many of these
abnormalities both elevate
vascular tone and promote endothelial and smooth muscle cell proliferation
followed by
structural changes or remodeling of the pulmonary vascular bed, which in turn
results in an
increase in pulmonary vascular resistance. In addition, in the adventitia
there is increased
production of extracellular matrix including collagen, elastin, fibronectin,
and tenascin.
[0014] Over the past two decades, three main mechanistic pathways, namely the
endothelin,
nitric oxide and prostacyclin (prostaglandin (PG) 12) pathways are targeted
for PAH-specific
therapies. The PAH-specific drug classes include the endothelin receptor
antagonists,
phosphodiesterase type-5 inhibitors (PDE-5i), including bosentan, sitaxsentan
and ambrisentan
and others such as sildenafil, tadalafil, or soluble guanylate cyclase
stimulators and prostanoids.
These "targeted" therapies have led to both short- and long-term benefits to
many patients. All
of the currently approved PAH drugs belong to one of these classes. These
agents have received
their initial regulatory approval as monotherapy for the primary indication by
improving six-
minute walk distance (6MWD). Additional endpoints such as functional class,
hemodynamics,
and clinical worsening of PAH have also been included in most of these Phase
III trials. In
these registration trials, drugs in these classes have been universally shown
to improve exercise
capacity and haemodynamics of patients with PAH, In addition, some of these
drugs were
shown to be associated with improvements in outcome for patients with PAH
compared with
historical data.
[0015] All of the currently approved PAH drugs belong to one of these classes,
including,
protenoids, for example, epoprostenol (Flo'an and Veletri0 intravenous
infusions),
treprostinil (Remodulin0 subcutaneous/IV infusion); Tyvaso0 (inhaled X4 time.
day) , Iloprost
0 (inhaled 6-9 times/day). These agents have received their initial regulatory
approval as
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monotherapy for the primary indication by improving six-minute walk distance
(6MWD).
Additional endpoints such as functional class, hemodynamics, and clinical
worsening of PAH
have also been included in most of these Phase III trials. in these
registration trials, drugs in
these classes have been universally shown to improve exercise capacity and
haemodynamics
of patients with PAI-I. In addition, some of these drugs were shown to be
associated with
improvements in outcome for patients with PAH compared with historical data.
[0016] Parenteral prostacyclin analogs have been the most widely studied.
Intravenous
epoprostenol was the first US Food and Drug Administration (FDA)-approved
treatment for
PAH (approved in 1995). However, due to its extremely short half-life (3-5
min), epoprostenol
needs to be delivered as a continuous intravenous infusion through an
indwelling catheter, with
the risk of rebound PAH and acute right heart failure in case of infusion
interruption.
Furthermore, due to the inherent chemical instability of epoprostenol at room
temperature and
neutral pH (room temperature stability <8 hours), ice packs are needed to slow
decomposition
throughout the infusion period. A thermostable epoprostenol preparation for
infusion
(Veletri0), which does not require cooling, has been approved for use by the
FDA. However,
serious adverse events related to the delivery system include pump
malfunction, local site
infection, catheter obstruction, and sepsis continues to be a barrier for its
use.
[0017] Treprostinil, is a longer-acting tricyclic benzidine analogue of
epoprostenol with a
terminal elimination half-life of approximately 2 to 4 hours and a
distribution half-life of
approximately 40 minutes. Unlike epoprostenol, Treprostinil is chemically
stable at room
temperature allowing it to be administered at ambient temperature and
overcomes some of the
limitations associated with epoprostenol therapy. Treprostinil causes
vasodilation of
pulmonary and systemic arterial vascular beds, and inhibits platelet
aggregation by binding to
prostacyclin IP receptors located on the surface of vascular smooth muscle
cells and platelets.
Treprostinil (Remodulin0) was first approved by the FDA in 2002 for adults
with WHO group
1 PAH and functional class II to class IV status for continuous subcutaneous
infusion and is
marketed by United Therapeutics (Silver Spring, MD). In a pivotal 12 week
randomized,
controlled trial of 470 patients, subcutaneous Treprostinil significantly
improved exercise
capacity compared with placebo. The most common adverse events noted in
subcutaneous
infusion of Treprostinil-treated patients were infusion site pain.
[0018] Currently, an oral, extended release tablet of treprostinil diolamine
(Orenitran0) is
also available. However, with orally delivered medications, the absorption of
treprostinil may
be inconsistent particularly taken with food. The pharmacological and
physiochemical
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properties of treprostinil make this drug amenable to intermittent
administration via the inhaled
route. Tyvasot and Iloprost (Ventavislt) are solutions for inhalation, which
need to be
administered using a special nebulizer for a prolonged period of time and
often times in a
physician's office. Using Tyvaso0 inhalation system [Opti- Neb ultrasonic
nebulizer
(NebuTec, Elsenfeld, Germany)]. The inhalation system is complex to assemble
and use,
cumbersome to administer the dose (patient need to reset the device 3 times
during a treatment
session after every 3 breaths) and was found to have high error rates in human
factor study.
There is a distinct risk of under dosing as patient need to take 9 breaths
within a specified 90
second time limit. Additionally, breath counter mechanism is triggered by time
(time related)
and not by inspiration or expiration flow or effort (breath related) and thus
patient can overdose
or under dose themselves by taking more or less than prescribed breaths (dose)
in the 90
seconds time limit. The system also requires 4 different cleaning schedule
(daily, weekly,
monthly and yearly). Accordingly, new methods of PAR treatment are needed to
facilitate the
administration of these products to a patient.
[0019] Drug delivery to lung tissue has been achieved using a variety of
devices for
inhalation, including, nebulizers and inhalers, such as metered dose inhalers
and dry powder
inhalers to treat local disease or disorders. Dry powder inhalers used to
deliver medicaments
to the lungs contain a dose system of a powder formulation usually either in
bulk supply or
quantified into individual doses stored in unit dose compartments such as hard
gelatin capsules
or blister packs. Bulk containers are equipped with a measuring system
operated by the patient
in order to isolate a single dose from the powder immediately before
inhalation.
[0020] Dosing reproducibility with inhalers requires that the drug formulation
is uniform and
that the dose be delivered to a subject with consistency and reproducible
results. Therefore, the
dosing system ideally should operate to completely discharge all of the
formulation effectively
during an inspiratory maneuver when the patient is taking his/her dose.
However, complete
powder discharge from the inhaler is not required as long as reproducible
dosing can be
achieved. Flow properties of the powder formulation, and long term physical
and mechanical
stability in this respect, are more critical for bulk containers than they are
for single unit dose
compartments. Good moisture protection for preventing product degradation can
be achieved
more easily for unit dose compartments such as blisters. However, the
materials used to
manufacture the blisters allow air into the drug compartment and subsequently,
the formulation
loses viability with prolonged storage, particularly if the formulation to be
delivered is
hygroscopic. The ambient air permeating through the blisters carries in
humidity that
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destabilizes the active ingredient. Additionally, dry powder inhalers which
use blisters to
deliver a medicament by inhalation can suffer with inconsistency of dose
delivery to the lungs
due to variations in geometry of the air conduit architecture resulting from
puncturing films or
peeling films of the blisters.
[0021] Dry powder inhalers such as those described in U.S. Patents No.
7,305,986, 7,464,706,
8,499,757 and 8,636,001, which disclosures are incorporated herein by
reference in their
entirety, can generate primary drug particles, or suitable inhalation plumes
during an
inspiratory maneuver by deagglomerating the powder formulation within a
capsule or cartridge
comprising a single dose. The amount of fine powder discharged from the
inhaler's mouthpiece
during inhalation is largely dependent on, for example, the inter-particulate
forces in the
powder formulation and the efficiency of the inhaler to separate those
particles so that they are
suitable for inhalation. The benefits of delivering drugs via the pulmonary
circulation are
numerous and include rapid entry into the arterial circulation, avoidance of
drug degradation
by liver metabolism, and ease of use without discomfort.
[0022] Some dry powder inhaler products developed for pulmonary delivery have
met with
some success to date. However, due to lack of practicality and/or cost of
manufacture, there is
room for improvement. Some of the persistent problems observed with prior art
inhalers,
include lack of device ruggedness, inconsistency in dosing, inconvenience of
the equipment,
poor deagglomeration, problems with delivery in light of divorce from
propellant use, high
manufacturing costs, and/or lack of patient compliance. Therefore, the
inventors have
identified the need to design and manufacture new formulations and inhalers
with consistent
improved powder delivery properties, easy to use, and having discrete
configurations which
would allow for better patient compliance.
SUMMARY
[0023] The present disclosure is directed to compositions and methods for
using the
compositions in the treatment of pulmonary hypertension. In embodiments
herewith, a
composition is provided in a dry powder inhaler comprising a replaceable
cartridge comprising
a dry powder for inhalation for delivery to the lungs for local or systemic
delivery into the
pulmonary circulation. The dry powder inhaler is a breath-powered inhaler
which is compact,
reusable or disposable, has various shapes and sizes, and comprises a system
of airflow conduit
pathways for the effective and rapid delivery of powder medicament to the
lungs and the
systemic circulation.
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[0024] In a particular embodiment, the method of treating pulmonary arterial
hypertension
utilizes a drug delivery system which is designed for drug delivery to the
lungs, including by
inhalation, for rapid delivery and onset of action of the active agent being
delivered to target
tissues using the arterial circulation in the lungs. In this method, the
active agent can reach its
target site in a therapeutically effective manner.
[0025] In one embodiment, the method comprises administering a stable
pharmaceutical
composition comprising, one or more active agents, including, a vasodilator,
including,
sildenafil, tadalafil, vardenafil, a prostaglandin or an analog thereof, for
example, treprostinil
or a pharmaceutically acceptable salt thereof, including treprostinil sodium,
for treating PAH
and delivering the treprostinil into the systemic circulation of a subject by
pulmonary inhalation
using a dry powder inhaler. In one embodiment, the method comprises providing
to a patient
in need of treatment a dry powder inhaler comprising treprostinil in a stable
dry powder
formulation, and administering the active agent by oral inhalation.
[0026] In one embodiment, the drug delivery system comprises a dry powder
inhaler
comprising a diketopiperazine-based drug formulation for delivering small
molecules, for
example, a prostaglandin, or analogs thereof including, tresprostinil and
protein-based products
for treating PAH. The method provides advantages over typical methods of drug
delivery, such
as, oral tablet and subcutaneous and intravenous injectable/infusion drug
products that are
sensitive to degradation and/or enzymatic deactivation.
[0027] In certain embodiments disclosed herein, a method for providing a
prostaglandin
formulation to a patient in need thereof is disclosed, the method comprising,
selecting a patient
to be treated for PAH patient, and administering to the patient a dry powder
formulation
comprising treprostinil; wherein the treprostinil is combined with a
diketopiperazine to produce
a pharmaceutical formulation or composition suitable for pulmonary inhalation,
and delivering
the trepostinil formulation using a breath-powered dry powder inhaler. In this
and other
embodiments, the dry powder formulations is provided in a reconfigurable
cartridge
comprising from about 1 ug to about 200 ug of treprostinil in the dry powder
formulation per
dose. In certain embodiments, the dry powder formulation can comprise from
about 10 ug to
about 300 ug of treprostinil per dose in a cartridge or capsule. In one
embodiment, a cartridge
for single use can comprise from about 10 ug to about 90 ug of treprostinil
for at least one
inhalation. In some embodiments, the dry powder formulation is delivered using
at least one
inhalation per use. In this and other embodiments, the dry powder formulation
is delivered to
a patient in less than 10 seconds, or less than 8 seconds or less than 6
seconds per inhalation or
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breath. In one embodiment, the pharmaceutical dry powder composition comprises
microcrystalline particles of fumaryl diketopiperazine wherein the particles
have a specific
surface area ranging from about 59 m2/g to about 63 m2/g and have a pore size
ranging from
about 23 nm to about 30 nm.
[0028] Also disclosed herein is a method of treating a pulmonary arterial
hypertension disease
or disorder comprising, selecting a patient to be treated with pulmonary
arterial hypertension,
or a patient with PAH which exhibits a condition treatable with an active
agent, including
treprostinil, epoprostenol, bosentan, ambrisentan, macisentan, sildenafil,
tadalafil, riociguat
and the like, or combinations thereof, which patients are typically treated
only by oral or
injectable administration; replacing the aforementioned therapy with an
inhalation therapy
comprising providing the patient with an inhaler comprising the active agent
in a stable dry
powder composition for treating the disease or disorder; wherein the stable
dry powder
composition comprises the active agent and a diketopiperazine; and
administering the stable
dry powder composition to the patient by pulmonary inhalation; thereby
treating the disease or
condition.
[0029] In an exemplary embodiment, the formulation for treating pulmonary
arterial
hypertension comprises treprostinil in an amount up to 200 [ig per dose, for
example, amounts
of 1 fig, 5 [ig, 10 fig, 15 [ig, 20 fig, 30 fig, 60 fig, 90 fig, 100 fig, 120
fig, 150 fig, 180 fig, or
200 fig, and one or more pharmaceutically acceptable carriers and/or
excipients per dose are to
be administered to a subject. In this embodiment, the pharmaceutically
acceptable carrier
and/or excipient can be formulated for oral inhalation and can form particles,
for example, a
diketopiperazine, including, fumaryl diketopiperazine, sugars such as
mannitol, xylitol,
sorbitol, and trehalose; amino acids, including, glycine, leucine, isoleucine,
methionine;
surfactants, including, polysorbate 80; cationic salts, including, monovalent,
divalent and
trivalent salts, including, sodium chloride, potassium chloride, magnesium
chloride, and zinc
chloride; buffers such as citrates and tartrates, or combination of one or
more carriers and/or
excipients and the like. In a particular embodiment, the formulation comprises
a dry powder
comprising treprostinil, a sugar and an amino acid, wherein the sugar is
mannitol or trehalose;
and the amino acid is leucine or isoleucine and a cationic salt. In certain
embodiments, the
formulation can further comprise sodium chloride, potassium chloride,
magnesium chloride or
zinc chloride, sodium citrate, sodium tartrate, or combinations thereof
[0030] In an exemplary embodiment, the treprostinil dose is administered using
a dry powder
inhaler for oral inhalation. In this embodiment, a treprostinil inhalation
powder dose is
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provided to a patient suffering with pulmonary arterial hypertension and in
need of treatment;
wherein the a dry powder inhaler comprises a container including, a cartridge,
and the
container or cartridge comprises the dry powder comprising treprostinil is
administered in
multiple daily doses for a period of six months and the treprostinil is
administered by oral
inhalation at an earlier time in the course of the disease to patients with
Functional Class II as
a first line monotherapy.
[0031] In one embodiment, a method for treating pulmonary arterial
hypertension is provided
comprising providing a patient in need of treatment a monotherapy using an
inhalable dry
powder comprising treprostinil and a pharmaceutically acceptable carrier,
and/or excipient by
oral inhalation using a dry powder inhaler and a container comprising the
inhalable dry powder
and administering the dry powder formulation to the patient. In some
embodiments, the
treprostinil formulation comprises fumaryl diketopiperazine particles.
[0032] In one embodiment, a method for treating pulmonary arterial
hypertension is provided
comprising providing a patient in need of treatment a combination therapy
using an inhalable
dry powder comprising treprostinil and fumaryl diketopiperazine, and
administering separately
in combination with orally administered drugs selected from prostacyclin
analogues,
endothelin receptor antagonists (ERAs), including bosentran, ambrisentran and
macitentan,
soluble guanine cyclase agonists/stimulators such as riociguat, and PDE-5
inhibitors, including
sildenafil, vardenafil and tadalafil.
[0033] In another embodiment, a dry powder comprising treprostinil and fumaryl
diketopiperazine can also be administered as a part of up-front combination
therapy with an
oral agent. In an alternate embodiment, an inhalable treprostinil composition
comprising a
dose of fumaryl diketopiperazine and treprostinil powder, wherein treprostinil
is in an amount
from about 1 [ig to about 200 pg administered in combination with an oral
agent such as a
PDE-5 inhibitor, or an endothelin receptor antagonist and/or the combination
therapy may also
be administered to replace continuously parenteral infusion of prostacyclin
analogs in patients
with severe disease and classified in WHO Functional class IV.
Phosphodiesterase inhibitors,
including PDE-5 inhibitors can also be formulated for inhalation alone, or in
combination with
the treprostinil and can be administered subsequently if administered alone,
as a combination
therapy.
[0034] In another embodiment, the inhalation system comprises a breath-powered
dry powder
inhaler, a container or cartridge containing a dry powder, for delivering an
active agent to the
pulmonary tract and lungs, including a medicament, wherein the medicament can
comprise,
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for example, an inhalable drug formulation for pulmonary delivery such as a
composition
comprising a diketopiperazine in a crystalline powder form that self-assembles
in a suspension,
an amorphous powder form, and/or a microcrystalline powder form comprising
crystallites that
do not self-assemble in suspension, or combinations thereof, and an active
agent, including,
treprostinil, sildenafil, vardenafil, tadalafil, or combinations thereof
[0035] In alternate embodiments, the dry powder for inhalation may be
formulated with other
carriers and/or excipients other than diketopiperazines, for example a sugar,
including
trehalose; buffers, including sodium citrate; salts, including, sodium
chloride and zinc chloride,
and one or more active agents, including, treprostinil, vardenafil, and
sildenafil.
[0036] In embodiments herewith, the method of treating PAH comprises,
administering to a
patient with moderate to severe PAH a dry powder formulation comprising
treprostinil and a
pharmaceutically acceptable carrier and/or excipient in an amount up to 200 ug
of treprostinil
using a dry powder inhaler comprising a movable member for loading a container
comprising
the pharmaceutical composition and the movable member can configure a
container to attain a
dosing configuration from a container loading configuration so that inhaler
creates an airflow
through the inhaler during an inhalation maneuver to allow the contents of the
container to
enter the airflow path and greater than 60% of a dry powder dose in the
container is delivered
to the lungs in a single inhalation.
[0037] In some embodiments, the treatment regimen with an inhalation dry
powder depends
on the patient's need and can be one inhalation to replace each of a
nebulization session
performed with standard therapy, including, at least one to four inhalations
per day depending
on the severity of disease.
DETAILED DESCRIPTION
[0038] In embodiments disclosed herein, dry powder compositions and dry powder
inhalers
comprising a container or a cartridge for delivering dry powders including
pharmaceutical
medicaments to a subject by oral inhalation are described. In one embodiment,
the dry powder
inhaler is a breath-powered, dry powder inhaler, and the container or
cartridge is designed to
contain an inhalable dry powder, including but not limited to pharmaceutical
formulations
comprising an active ingredient, including a pharmaceutically active
substance, and optionally,
a pharmaceutically acceptable carrier. In particular, the dry powder inhalers
are for the
treatment of pulmonary arterial hypertension.
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[0039] The dry powder inhalers are provided in various embodiments of shapes
and sizes,
and can be reusable, easy to use, inexpensive to manufacture and/or produced
in high volumes
in simple steps using plastics or other acceptable materials. Various
embodiments of the dry
powder inhalers are provided herein and in general, the inhalation systems
comprise inhalers,
powder-filled cartridges, and empty cartridges. The present inhalation systems
can be designed
to be used with any type of dry powder. In one embodiment, the dry powder is a
relatively
cohesive powder which requires optimal deagglomeration conditions. In one
embodiment, the
inhalation system provides a re-useable, miniature breath-powered inhaler in
combination with
single-use cartridges containing pre-metered doses of a dry powder
formulation. The inhaler
can deliver a dry powder dose in a single inhalation to a patient in treating
pulmonary arterial
hypertension in less than 10 seconds. In particular embodiments, oral
inhalation can deliver
greater than 60% of a powder dose in less than 6 seconds, in less than 4
seconds and in less
than 2 seconds.
[0040] As used herein the term "a unit dose inhaler" refers to an inhaler that
is adapted to
receive a single enclosure, cartridge or container comprising a dry powder
formulation and
delivers a single dose of a dry powder formulation by inhalation from a single
container to a
user. It should be understood that in some instances multiple unit doses will
be required to
provide a user with a specified dosage.
[0041] As used herein a "cartridge" is an enclosure configured to hold or
contain a dry powder
formulation, a powder containing enclosure, which has a cup or container and a
lid. The
cartridge is made of rigid materials, and the cup or container is moveable
relative to the lid in
a translational motion or vice versa.
[0042] As used herein a "powder mass" is referred to an agglomeration of
powder particles
or agglomerate having irregular geometries such as width, diameter, and
length.
[0043] As used herein a "unit dose" refers to a pre-metered dry powder
formulation for
inhalation. Alternatively, a unit dose can be a single enclosure including a
container having a
single dose or multiple doses of formulation that can be delivered by
inhalation as metered
single amounts. A unit dose enclosure/cartridge/container contains a single
dose. Alternatively
it can comprise multiple individually accessible compartments, each containing
a unit dose.
[0044] As used herein, the term "about" is used to indicate that a value
includes the standard
deviation of error for the device or method being employed to determine the
value.
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[0045] As used herein, the term "microparticle" refers to a particle with a
diameter of about
0.5 to about 1000 p.m, irrespective of the precise exterior or interior
structure. Microparticles
having a diameter of between about 0.5 and about 10 microns can reach the
lungs, successfully
passing most of the natural barriers. A diameter of less than about 10 microns
is required to
navigate the turn of the throat and a diameter of about 0.5 p.m or greater is
required to avoid
being exhaled. To reach the deep lung (or alveolar region) where most
efficient absorption is
believed to occur, it is preferred to maximize the proportion of particles
contained in the
"respirable fraction" (RF), generally accepted to be those particles with an
aerodynamic
diameter of about 0.5 to about 6 p.m, though some references use somewhat
different ranges,
as measured using standard techniques, for example, with an Anderson Cascade
Impactor.
Other impactors can be used to measure aerodynamic particle size such as the
NEXT
GENERATION IMPACTORTm (NGITM, MSP Corporation), for which the respirable
fraction
is defined by similar aerodynamic size, for example < 6.4 pm. In some
embodiments, a laser
diffraction apparatus is used to determine particle size, for example, the
laser diffraction
apparatus disclosed in U.S. Patents No. 8,508732, which disclosure is
incorporated herein in
its entirety for its relevant teachings related to laser diffraction, wherein
the volumetric median
geometric diameter (VMGD) of the particles is measured to assess performance
of the
inhalation system. For example, in various embodiments cartridge emptying of?
80%, 85%,
or 90% and a VMGD of the emitted particles of <12.5 p.m, <7.0 p.m, or <4.8 pm
can indicate
progressively better aerodynamic performance.
[0046] Respirable fraction on fill (RF/fill) represents the percentage (%) of
powder in a dose
that is emitted from an inhaler upon discharge of the powder content filled
for use as the dose,
and that is suitable for respiration, i.e., the percent of particles from the
filled dose that are
emitted with sizes suitable for pulmonary delivery, which is a measure of
microparticle
aerodynamic performance. As described herein, a RF/fill value of 40% or
greater than 40%
reflects acceptable aerodynamic performance characteristics. In certain
embodiments disclosed
herein, the respirable fraction on fill can be greater than 50%. In an
exemplary embodiment, a
respirable fraction on fill can be up to about 80%, wherein about 80% of the
fill is emitted with
particle sizes <5.8 p.m as measured using standard techniques.
[0047] As used herein, the term "dry powder" refers to a fine particulate
composition that is
not suspended or dissolved in a propellant, or other liquid. It is not meant
to necessarily imply
a complete absence of all water molecules.
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[0048] As used herein, "amorphous powder" refers to dry powders lacking a
definite
repeating form, shape, or structure, including all non-crystalline powders.
[0049] The present disclosure also provides improved powders comprising
microcrystalline
particles, compositions, methods of making the particles, and therapeutic
methods that allow
for improved delivery of drugs to the lungs for treating diseases and
disorders in a subject.
Embodiments disclosed herein achieve improved delivery by providing
crystalline
diketopiperazine compositions comprising microcrystalline diketopiperazine
particles having
high capacity for drug adsorption yielding powders having high drug content of
one or more
active agents. Powders made with the present microcrystalline particles can
deliver increased
drug content in lesser amounts of powder dose, which can facilitate drug
delivery to a patient.
The powders can be made by various methods including, methods utilizing
surfactant-free
solutions or solutions comprising surfactants depending on the starting
materials.
[0050] In alternate embodiments disclosed herein, the drug delivery system can
comprise a
dry powder for inhalation comprising a plurality of substantially uniform,
microcrystalline
particles, wherein the microcrystalline particles can have a substantially
hollow spherical
structure and comprise a shell which can be porous comprising crystallites of
a
diketopiperazine that do not self-assemble in a suspension or in solution. In
certain
embodiments, the microcrystalline particles can be substantially hollow
spherical and
substantially solid particles comprising crystallites of the diketopiperazine
depending on the
drug and/or drug content provided and other factors in the process of making
the powders. In
one embodiment, the microcrystalline particles comprise particles that are
relatively porous,
having average pore volumes of about 0.43 cm3/g, ranging from about 0.4 cm3/g
to about 0.45
cm3/g, and average pore size ranging from about 23 nm to about 30 nm, or from
about 23.8 nm
to 26.2 nm as determined by BJH adsorption.
[0051] Certain embodiments disclosed herein comprise dry powders comprising a
plurality
of substantially uniform, microcrystalline particles, wherein the particles
have a substantially
spherical structure comprising a shell which can be porous, and the particles
comprise
crystallites of a diketopiperazine that do not self-assemble in suspension or
solution, and have
a volumetric median geometric diameter less than 5 um; or less than 2.5 um and
comprise an
active agent.
[0052] In a particular embodiment herein, up to about 92% of the
microcrystalline particles
have a volumetric median geometric diameter of 5.8 um. In one embodiment, the
particle's
shell is constructed from interlocking diketopiperazine microcrystals having
one or more drugs
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adsorbed on their surfaces. In some embodiments, the particles can entrap the
drug in their
interior void volume and/or combinations of the drug adsorbed to the
crystallites' surface and
drug entrapped in the interior void volume of the spheres.
[0053] In certain embodiments, a diketopiperazine composition comprising a
plurality of
substantially uniformly formed, microcrystalline particles is provided,
wherein the particles
have a substantially hollow spherical structure and comprise a shell
comprising crystallites of
a diketopiperazine that do not self-assemble; wherein the particles are formed
by a method
comprising the step of combining diketopiperazine having a trans isomer
content ranging from
about 45% to 65% in a solution and a solution of acetic acid without the
presence of a surfactant
and concurrently homogenizing in a high shear mixer at high pressures of up to
2,000 psi to
form a precipitate; washing the precipitate in suspension with deionized
water; concentrating
the suspension and drying the suspension in a spray drying apparatus. The
microcrystalline
particles can be pre-formed without for later used, or combined with an active
agent in
suspension prior to spray drying.
[0054] The method can further comprise the steps of adding with mixing a
solution
comprising an active agent or an active ingredient such as a drug or bioactive
agent along with
other pharmaceutically acceptable carriers and/or excipients prior to the
spray drying step so
that the active agent or active ingredient is adsorbed and/or entrapped on or
within the particles.
Particles made by this process can be in the submicron size range prior to
spray-drying.
[0055] In certain embodiments, a diketopiperazine composition comprising a
plurality of
substantially uniformly formed, microcrystalline particles is provided,
wherein the particles
have a substantially hollow spherical structure and comprise a shell
comprising crystallites of
a diketopiperazine that do not self-assemble, and the particles have a
volumetric mean
geometric diameter less than equal to 5 p.m; wherein the particles are formed
by a method
comprising the step of combining diketopiperazine in a solution and a solution
of acetic acid
without the presence of a surfactant and concurrently homogenizing in a high
shear mixer at
high pressures of up to 2,000 psi to form a precipitate; washing the
precipitate in suspension
with deionized water; concentrating the suspension and drying the suspension
in a spray drying
apparatus.
[0056] The method can further comprise the steps of adding with mixing a
solution
comprising an active agent or an active ingredient such as a drug or bioactive
agent prior to the
spray drying step so that the active agent or active ingredient is adsorbed
and/or entrapped on
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or within the particles. Particles made by this process can be in the
submicron size range prior
to spray-drying.
[0057] In certain embodiments, a diketopiperazine composition comprising a
plurality of
substantially uniformly formed, microcrystalline particles is provided,
wherein the
microcrystalline particles have a substantially hollow spherical structure and
comprise a shell
comprising crystallites of a diketopiperazine that do not self-assemble, and
the particles have
a volumetric mean geometric diameter less than equal to 5 p.m; wherein the
particles are formed
by a method comprising the step of combining diketopiperazine in a solution
and a solution of
acetic acid without the presence of a surfactant and without the presence of
an active agent,
and concurrently homogenizing in a high shear mixer at high pressures of up to
2,000 psi to
form a precipitate; washing the precipitate in suspension with deionized
water; concentrating
the suspension and drying the suspension in a spray drying apparatus.
[0058] In certain embodiments wherein the starting material comprising the
active ingredient
is an extract exhibiting a high degree of viscocity, or a substance having a
honey like viscous
appearance, the microcrystalline particles are formed as above and by washing
them in water
using tangential flow filtration prior to combining with the extract or
viscous material. After
washing in water, the resultant particle suspension is lyophilized to remove
the water and re-
suspended in an alcohol solution, including ethanol or methanol prior to
adding the active
ingredient as a solid, or in a suspension, or in solution. In one embodiment,
optionally, the
method of making the composition comprises the step of adding any additional
excipient,
including one or more, amino acid, such as leucine, isoleucine, norleucine,
methionine or one
or more phospholipids, for example, 1,2-dipalmitoyl-sn-glycero-3-
phosphocholine (DPPC) or
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), concurrently with the
active ingredient
or subsequent to adding the active ingredient, and prior to spray drying. In
certain
embodiments, forming the composition comprises the step wherein the extract
comprising
desired active agents is optionally filtered or winterized to separate and
remove layers of
unwanted materials such as lipids to increase its solubility.
[0059] The method can further comprise the steps of adding a solution with
mixing to the
mixture, and wherein the mixing can optionally be performed with or without
homogenization
in a high shear mixer, wherein the solution comprises an active agent or an
active ingredient
such as a drug or bioactive agent prior to the spray drying step so that the
active agent or active
ingredient is adsorbed and/or entrapped within or on the surface of the
particles. Particles made
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by this process can be in the submicron size range prior to spray-drying, or
the particles can be
formed from the solution during spray-drying.
[0060] In some embodiments herewith, the drug content can be delivered on
crystalline
powders using FDKP and which are lyophilized or sprayed dried at contents to
about 10%, or
about 20%, or about 30% or higher. In embodiments using microcrystalline
particles formed
from FDKP, or FDKP disodium salt, and wherein the particles do not self-
assemble and
comprise submicron size particles, drug content can typically be greater than
0.01 % (w/w). In
one embodiment, the drug content to be delivered with the microcrystalline
particles of from
about 0.01 % (w/w) to about 75 % (w/w); from about 1 % to about 50 % (w/w),
from about 10
% (w/w) to about 25 % (w/w), or from about 10 % to about 20% (w/w), or from 5%
to about
30%, or greater than 25% depending on the drug to be delivered. An example
embodiment
wherein the drug is a peptide such as insulin, the present microparticles
typically comprise
approximately 10 % to 45% (w/w), or from about 10 % to about 20% (w/w)
insulin. In certain
embodiments, the drug content of the particles can vary depending on the form
and size of the
drug to be delivered.
[0061] In an exemplary embodiment, the composition comprises a dry powder
comprising
microcrystalline particles of fumaryl diketopiperazine, wherein the
treprostinil is adsorbed to
the particles and wherein the content of the treprostinil in the composition
comprises up to
about 20% (w/w) and ranges from about 0.5% to about 10% (w/w), or from about
1% to about
5% (w/w) of the dry powder. In one embodiment, the composition herein can
comprise other
excipients suitable for inhalation such as amino acids including methionine,
isoleucine and
leucine. In this embodiment, the treprostinil composition can be used in the
prevention and
treatment of pulmonary hypertension by self-administering an effective dose
comprising about
1 mg to 15 mg of a dry powder composition comprising microcrystalline
particles of fumaryl
diketopiperazine and treprostinil in a single inhalation. In a particular
embodiment, the
treprostinil content in the formulation can be from about 1 [ig to about 200
fig. In one
embodiment, the dry powder content of the cartridges comprising treprostinil
can be 20 fig, 30
fig, 60 fig, 90 fig, 120 fig, 150 fig, 180 fig, or 200 fig.
[0062] In alternate embodiments, the pharmaceutically acceptable carrier for
making dry
powders can comprise any carriers or excipients useful for making dry powders
and which are
suitable for pulmonary delivery. Example of pharmaceutically suitable carriers
and excipients
include, sugars, including saccharides and polysaccharides, such as lactose,
mannose, sucrose,
mannitol, trehalose; citrates, amino acids such as glycine, L-leucine,
isoleucine, trileucine,
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tartrates, methionine, vitamin A, vitamin E, zinc citrate, sodium citrate,
trisodium citrate,
sodium tartrate, sodium chloride, zinc chloride, zinc tartrate,
polyvinylpyrrolidone, polysorbate
80, phospholipids including diphosphotidylcholine and the like.
[0063] In one embodiment, a method of self-administering a dry powder
formulation to one's
lung(s) with a dry powder inhalation system is also provided. The method
comprises: obtaining
a dry powder inhaler in a closed position and having a mouthpiece; obtaining a
cartridge
comprising a pre-metered dose of a dry powder formulation in a containment
configuration;
opening the dry powder inhaler to install the cartridge; closing the inhaler
to effectuate
movement of the cartridge to a dose position; placing the mouthpiece in one's
mouth, and
inhaling once deeply to deliver the dry powder formulation.
[0064] In still yet a further embodiment, a method of treating obesity,
hyperglycemia, insulin
resistance, pulmonary hypertention, anaphylaxis, and/or diabetes is disclosed.
The method
comprises the administration of an inhalable dry powder composition or
formulation
comprising, for example, a diketopiperazine having the formula 2,5-diketo-3,6-
di(4-X-
aminobutyl)piperazine, wherein X is selected from the group consisting of
succinyl, glutaryl,
maleyl, and fumaryl. In this embodiment, the dry powder composition can
comprise a
diketopiperazine salt. In still yet another embodiment, there is provided a
dry powder
composition or formulation, wherein the diketopiperazine is 2,5-diketo-3,6-di-
(4-fumaryl-
aminobutyl)piperazine, with or without a pharmaceutically acceptable carrier,
or excipient.
[0065] An inhalation system for delivering a dry powder formulation to a
patient's lung(s) is
provided, the system comprising a dry powder inhaler configured to have flow
conduits with a
total resistance to flow in a dosing configuration ranging in value from 0.065
to about 0.200
(\ikPa)/liter per minute. The dry powder inhaler can be provided comprising a
dry powder
formulation for single use that can be discarded after use, or with individual
doses that are
replaceable in a multiple use inhaler and the individual dose enclosures or
containers can be
discarded after use.
[0066] In one embodiment, a dry powder inhalation kit is provided comprising a
dry powder
inhaler as described above, one or more medicament cartridges comprising a dry
powder
formulation for treating a disorder or disease such as respiratory tract and
lung disease,
including pulmonary arterial hypertension, cystic fibrosis, respiratory
infections, cancer, and
other systemic diseases, including, endocrine disease, including, diabetes and
obesity.
[0067] Methods of treating a disease or disorder in a patient with the dry
powder inhaler
embodiments disclosed herewith is also provided. The method of treatment
comprises
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providing to a patient in need of treatment a dry powder inhaler comprising a
cartridge
containing a dose of an inhalable formulation comprising an active ingredient
selected from
the group as described above and a pharmaceutical acceptable carrier and/or
excipient; and
having the patient inhale through the dry powder inhaler deeply for about 3 to
4 seconds to
deliver the dose. In the method, the patient can resume normal breathing
pattern thereafter.
[0068] The following examples illustrate some of the processes for making dry
powders
suitable for using with the inhalers described herein and data obtained from
experiments using
the dry powders.
Example 1
[0069] Preparation of surfactant-free dry powder comprising FDKP
microcrystalline
powder for use with inhalers: In an example embodiment, surfactant free dry-
powders
comprising FDKP microcrystalline particles were prepared. Using a dual-feed
high shear
mixer, approximately equal masses of acetic acid solution (Table 1) and FDKP
solution (Table
2) held at about 25 C 5 C were fed at 2000 psi throught a 0.001-in2 orifice
to form a
precipitate by homogenization. The precipitate was collected in deionized (DI)
water of about
equal temperature. The wt% content of FDKP microcrystallites in the suspension
is about 2 ¨
3.5%. The suspension FDKP concentration can be assayed for solids content by
an oven drying
method. The FDKP microcrystallite suspension can be optionally washed by
tangential flow
filtration using deionized water. The FDKP microcrystallites can be optionally
isolated by
filtration, centrifugation, spray drying or lyophilization.
Table 1. Composition of Acetic Acid Solution
Component Component Range (wt. %)
Acetic Acid 10.5 ¨ 13.0
Deionized Water 87.0- 89.5
Table 2. Composition of FDKP Solution
Component Component Range (wt. %)
FDKP 2.5 ¨ 6.25
30% NH4OH Solution 1.6¨ 1.75
Deionized Water 92 ¨ 95.9
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[0070] Dry powders (A, B, C and D) comprising microcrystalline particles made
by the
methods described above were tested for various characteristics, including
surface area, water
content and porosity measurements. Four different powders were used in this
experiments.
All powders tested had a residual water content of 0.4%. Table 2a demonstrates
data obtained
from the experiments.
Table 2a
Surface Area Pore Volume Pore Size
BJH Adsorption BJH Adsorption
BET Surface
Powder ID cumulative volume of average pore
Area (m2/g)
pores (cm3/g) diameter
(4V/A) (nm)
A 61.3 0.43 25.1
62.3 0.43 24.4
63.0 0.42 23.8
59.0 0.44 26.2
[0071] The data in Table 2a show that the surface area of sprayed-dried, bulk
dry powder
comprising the microcrystalline particles of the samples tested ranged from 59
m2/g to 63 m2/g.
The porosity data indicate that the microcrystalline particles are relatively
porous, having
average pore volumes of about 0.43 cm3/g and average pore size ranging from
about 23.8 nm
to 26.2 nm as determined by BJH adsorption. The porosimetry data indicate that
these particles
differ from prior art FDKP microparticles which have been shown to have an
average pore
volume of about 0.36 cm3/g and average pore size from about 20 nm to about
22.6 nm.
Example 2
[0072] Preparation of dry powder comprising microcrystalline FDKP particles
containing
treprostinil. A solution containing 0.2 ¨ 1.0 wt% treprostinil in ethyl
alcohol was added to a
suspension of FDKP microcrystallites obtained as described in Example 1. The
mixture was
spray dried using a Buchi B290 spray-dryer equipped with a high efficiency
cyclone. Nitrogen
was used as the process gas (60 mm). Mixture were dried using 10-12% pump
capacity, 90-
100% aspiration rate, and an inlet temperature of 170 ¨ 190 C. The weight %
concentration
of treprostinil in the resultant powder was 0.5 ¨ 10%. Delivery efficiencies
of these powders
after discharge from a dry powder inhaler ranged between approximately 50% and
70%.
Example 3
[0073] Use of treprostinil-fumaryl diketopiperazine composition in healthy
subjects. This
study was an open-label, single ascending dose study in 36 healthy normal
volunteers that were
sequentially assigned to 6 cohorts receiving single doses of TreT (30, 60, 90,
120, 150, and
180 fig). The safety and tolerability of the dry powder compositions
comprising treprostinil
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was evaluated in each sequential cohort prior to escalating the dose for the
next cohort using a
dry powder inhaler system comprising a cartridge dose in a single inhalation.
Blood samples
were obtained before administration of the composition and at selected times
through 480
minutes post-dose. Blood samples were analyzed for treprostinil using a
validated analytical
method and PK parameters were calculated using non-compartmental methods.
[0074] A total of 36 individuals were randomized and dosed. There were no
severe adverse
events, serious adverse events, or deaths during this study. No adverse events
led to a subject's
early termination. The most frequently reported adverse events were cough
(n=11, 30.6%) and
headache (n=8, 22%). Bioanalysis data confirmed that the treprostinil plasma
concentrations
and exposure for treprostinil, achieved clinically relevant concentrations
comparable to those
observed in historical Tyvaso0 single dose clinical studies. Cmax and AUC for
treprostinil,
increased in a linear manner with increasing dose. Overall, treprostinil was
safe and well-
tolerated and produced clinically relevant concentrations of treprostinil when
inhaled as a dry
powder.
[0075] The preceding disclosures are illustrative embodiments. It should be
appreciated by
those of skill in the art that the devices, techniques and methods disclosed
herein elucidate
representative embodiments that function well in the practice of the present
disclosure.
However, those of skill in the art should, in light of the present disclosure,
appreciate that many
changes can be made in the specific embodiments that are disclosed and still
obtain a like or
similar result without departing from the spirit and scope of the invention.
[0076] Unless otherwise indicated, all numbers expressing quantities of
ingredients,
properties such as molecular weight, reaction conditions, and so forth used in
the specification
and claims are to be understood as being modified in all instances by the term
"about."
Accordingly, unless indicated to the contrary, the numerical parameters set
forth in the
following specification and attached claims are approximations that may vary
depending upon
the desired properties sought to be obtained. At the very least, and not as an
attempt to limit
the application of the doctrine of equivalents to the scope of the claims,
each numerical
parameter should at least be construed in light of the number of reported
significant digits and
by applying ordinary rounding techniques. Notwithstanding that the numerical
ranges and
parameters setting forth the broad scope are approximations, the numerical
values set forth in
the specific examples are reported as precisely as possible. Any numerical
value, however,
inherently contains certain errors necessarily resulting from the standard
deviation found in
their respective testing measurements.
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[0077] The terms "a" and "an" and "the" and similar referents used in the
context of describing
the invention (especially in the context of the following claims) are to be
construed to cover
both the singular and the plural, unless otherwise indicated herein or clearly
contradicted by
context. Recitation of ranges of values herein is merely intended to serve as
a shorthand
method of referring individually to each separate value falling within the
range. Unless
otherwise indicated herein, each individual value is incorporated into the
specification as if it
were individually recited herein. All methods described herein can be
performed in any
suitable order unless otherwise indicated herein or otherwise clearly
contradicted by context.
The use of any and all examples, or exemplary language (e.g. "such as")
provided herein is
intended merely to better illuminate the invention and does not pose a
limitation on the scope
otherwise claimed. No language in the specification should be construed as
indicating any
non-claimed element essential to the practice of the invention.
[0078] The use of the term "or" in the claims is used to mean "and/or" unless
explicitly
indicated to refer to alternatives only or the alternatives are mutually
exclusive, although the
disclosure supports a definition that refers to only alternatives and
"and/or."
[0079] Groupings of alternative elements or embodiments disclosed herein are
not to be
construed as limitations. Each group member may be referred to and claimed
individually or
in any combination with other members of the group or other elements found
herein. It is
anticipated that one or more members of a group may be included in, or deleted
from, a group
for reasons of convenience and/or patentability. When any such inclusion or
deletion occurs,
the specification is herein deemed to contain the group as modified thus
fulfilling the written
description of all Markush groups used in the appended claims.
[0080] Preferred embodiments are described herein, including the best mode
known to the
inventors for carrying out the invention. Of course, variations on those
preferred embodiments
will become apparent to those of ordinary skill in the art upon reading the
foregoing description.
The inventor expects those of ordinary skill in the art to employ such
variations as appropriate,
and the inventors intend for the invention to be practiced otherwise than
specifically described
herein. Accordingly, this invention includes all modifications and equivalents
of the subject
matter recited in the claims appended hereto as permitted by applicable law.
Moreover, any
combination of the above-described elements in all possible variations thereof
is encompassed
by the invention unless otherwise indicated herein or otherwise clearly
contradicted by context.
[0081] Specific embodiments disclosed herein may be further limited in the
claims using
consisting of or consisting essentially of language. When used in the claims,
whether as filed
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CA 03102967 2020-12-07
WO 2019/237028
PCT/US2019/036095
or added per amendment, the transition term "consisting of" excludes any
element, step, or
ingredient not specified in the claims. The transition term "consisting
essentially of" limits the
scope of a claim to the specified materials or steps and those that do not
materially affect the
basic and novel characteristic(s). Embodiments so claimed are inherently or
expressly
described and enabled herein.
[0082] Furthermore, numerous references have been made to patents and printed
publications
throughout this specification. Each of the above cited references and printed
publications are
herein individually incorporated by reference in their entirety.
[0083] Further, it is to be understood that the embodiments disclosed herein
are illustrative
of the principles of the present invention. Other modifications that may be
employed are within
the scope of the invention. Thus, by way of example, but not of limitation,
alternative
configurations may be utilized in accordance with the teachings herein.
Accordingly, the
present invention is not limited to that precisely as shown and described.
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