U.S. patent application number 16/011830 was filed with the patent office on 2018-10-25 for method of treating hypertension.
The applicant listed for this patent is Cipla Limited. Invention is credited to Kalpana Joshi, Geena Malhotra.
Application Number | 20180303835 16/011830 |
Document ID | / |
Family ID | 58800031 |
Filed Date | 2018-10-25 |
United States Patent
Application |
20180303835 |
Kind Code |
A1 |
Malhotra; Geena ; et
al. |
October 25, 2018 |
METHOD OF TREATING HYPERTENSION
Abstract
Disclosed herein are compositions and methods for the treatment
of pulmonary hypertension, including pulmonary arterial
hypertension. The methods include administering to a patient in
need thereof an effective amount of anagrelide or derivative
thereof. The compositions include an effective amount of anagrelide
or derivative thereof, in some instances combined with one or more
additional agents for the treatment of pulmonary hypertension.
Inventors: |
Malhotra; Geena; (Mumbai,
IN) ; Joshi; Kalpana; (Maharashtra, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cipla Limited |
Mumbai |
|
IN |
|
|
Family ID: |
58800031 |
Appl. No.: |
16/011830 |
Filed: |
June 19, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15361020 |
Nov 24, 2016 |
10022377 |
|
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16011830 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2018 20130101;
A61K 9/2054 20130101; A61K 31/519 20130101; A61K 9/2027
20130101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 9/20 20060101 A61K009/20 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 2, 2015 |
IN |
4548/MUM/2015 |
Claims
1-21. (canceled)
22. A pharmaceutical composition comprising anagrelide or
derivative thereof, in an amount effective to treat pulmonary
arterial hypertension, and a further agent selected from the group
consisting of a PDE-5 inhibitor, a calcium channel blocker, a
prostacyclin pathway agonist, an endothelin receptor antagonist, a
guanylate cyclase stimulator, an anti-coagulants, and combinations
thereof.
23. The pharmaceutical composition according to claim 22, wherein
the further agent comprises a PDE-5 inhibitor comprising avanafil,
lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil,
udenafil, zaprinast, or icariin.
24. The pharmaceutical composition according to claim 22, wherein
the further agent comprises a calcium channel blocker comprising
amlodipine, nifefipine, or diltiazem.
25. The pharmaceutical composition according to claim 22, wherein
the further agent comprises a prostacyclin pathway agonist
comprising epoprostenol, treprostinil, iloprost, or selexipag.
26. The pharmaceutical composition according to claim 22, wherein
the further agent comprises an endothelin receptor antagonist
comprising bosentan, macitentan, ambrisentan, or sitaxsentan.
27. The pharmaceutical composition according to claim 22, wherein
the further agent comprises a guanylate cyclase stimulator.
28. The pharmaceutical composition according to claim 22, wherein
the further agent comprises an anti-coagulant.
29. A kit comprising a pharmaceutical composition comprising
anagrelide or derivative thereof, in an amount effective to treat
pulmonary arterial hypertension, and a further agent selected from
the group consisting of a PDE-5 inhibitor, a calcium channel
blocker, a prostacyclin pathway agonist, an endothelin receptor
antagonist, a guanylate cyclase stimulator, an anti-coagulants, and
combinations thereof.
30. The kit according to claim 29, wherein the further agent is
provided in a separate composition from the anagrelide.
31. The kit according to claim 29, wherein the further agent
comprises a PDE-5 inhibitor comprising avanafil, lodenafil,
mirodenafil, sildenafil, tadalafil, vardenafil, udenafil,
zaprinast, or icariin.
32. The kit according to claim 29, wherein the further agent
comprises a calcium channel blocker comprising amlodipine,
nifefipine, or diltiazem.
33. The kit according to claim 29, wherein the further agent
comprises a prostacyclin pathway agonist comprising epoprostenol,
treprostinil, iloprost, or selexipag.
34. The kit according to claim 29, wherein the further agent
comprises an endothelin receptor antagonist comprising bosentan,
macitentan, ambrisentan, or sitaxsentan.
35. The kit according to claim 29, wherein the further agent
comprises a guanylate cyclase stimulator.
36. The kit according to claim 29, wherein the further agent
comprises an anti-coagulant.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of Indian Application
4548/MUM/2015, filed on Dec. 2, 2015, the content of which are
incorporated herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a method of treatment of
pulmonary hypertension, including pulmonary arterial hypertension,
by administering a platelet-aggregation inhibitor agent either
alone or optionally in combination with one or more other agents.
In particular, the present invention pertains to methods for the
treatment of pulmonary arterial hypertension in humans by
administering anagrelide or derivative thereof, alone or in
combination with one or more drugs.
BACKGROUND
[0003] Pulmonary arterial hypertension (PAH), one of the five types
of pulmonary hypertension (PH), is a life-threatening disease
characterized by pulmonary vascular remodeling that leads to
increased pulmonary vascular resistance and pulmonary arterial
pressure, most often resulting in right-side heart failure. It is a
progressive condition characterized by elevated pulmonary arterial
pressures leading to right ventricular (RV) failure. It is defined
at cardiac catheterization as a mean pulmonary artery pressure of
25 mm Hg or more. The most common symptom associated is
breathlessness, with impaired exercise capacity as a hallmark of
the disease.
[0004] PAH is associated with significant morbidity and mortality.
It is caused by complex pathways that culminate in structural and
functional alterations of the pulmonary circulation and increases
in pulmonary vascular resistance and pressure. Many mechanisms can
lead to elevation of pulmonary pressures. In PAH, progressive
narrowing of the pulmonary arterial bed results from an imbalance
of vasoactive mediators, including prostacyclin, nitric oxide, and
endothelin-1. This leads to an increased right ventricular
afterload, right heart failure, and premature death. Diverse
genetic, pathological, or environmental triggers stimulate PAH
pathogenesis culminating in vasoconstriction, cell proliferation,
vascular remodeling, and thrombosis. Current concepts suggest that
PAH pathogenesis involves three primary processes:
vasoconstriction, cellular proliferation/vascular remodeling, and
thrombosis.
[0005] The molecular mechanism underlying PAH pathophysiology is
not known yet, but it is believed that the endothelial dysfunction
results in a decrease in the synthesis of endothelium-derived
vasodilators such as nitric oxide and prostacyclin. Moreover,
stimulation of the synthesis of vasoconstrictors such as
thromboxane and vascular endothelial growth factor (VEGF) results
in a severe vasoconstriction and smooth muscle and adventitial
hypertrophy characteristic of patients with PAH.
[0006] Better understanding of disease mechanisms led to subsequent
classification of conditions with shared clinical and
pathophysiological characteristics: [0007] Group 1: Pulmonary
arterial hypertension (PAH), which can be idiopathic (IPAH) or
associated with other conditions, notably systemic sclerosis and
congenital heart disease [0008] Group 2: Pulmonary hypertension
owing to left heart disease (PH-LHD) [0009] Group 3: Pulmonary
hypertension owing to lung disease or hypoxia (PH-Lung), or both
[0010] Group 4: Chronic thromboembolic pulmonary hypertension
(CTEPH) [0011] Group 5: Unclear or multifactorial mechanisms.
[0012] Between 11% and 40% of patients with Idiopathic pulmonary
arterial hypertension [IPAH] and 70% of patients with a family
history of PAH carry a mutation in the gene encoding bone
morphogenetic receptor-2 (BMPR2). However, penetrance is low,
carriers have a 20% lifetime risk of developing pulmonary
hypertension. Therefore, "multiple hits" are probably needed for
the development of PAH. In pulmonary hypertension associated with
left heart disease (PH-LHD), raised left atrial pressures result in
secondary elevation of pulmonary pressure. In pulmonary
hypertension owing to lung disease or hypoxia (PH-Lung), raised
pulmonary arterial pressures result from mechanisms such as
vascular destruction and hypoxic vasoconstriction. In chronic
thromboembolic pulmonary hypertension [CTEPH], mechanical
obstruction of the pulmonary vascular bed, is the primary process.
Incidences are estimated to be 1-3.3 per million per year for IPAH
and 1.75-3.7 per million per year for CTEPH; the prevalence of PAH
is estimated at 15-52 per million. Pulmonary hypertension is more
common in severe respiratory and cardiac disease, occurring in
18-50% of patients assessed for transplantation or lung volume
reduction surgery, and in 7-83% of those with diastolic heart
failure.
[0013] While there is currently no cure for PAH significant
advances in the understanding of the pathophysiology of PAH have
led to the development of several therapeutic targets. Besides
conservative therapeutic strategies such as anticoagulation and
diuretics, the current treatment paradigm for PAH targets the
mediators of the three main biologic pathways that are critical for
its pathogenesis and progression: (1) endothelin receptor
antagonists inhibit the upregulated endothelin pathway by blocking
the biologic activity of endothelin-1; (2) phosphodiesterase-5
inhibitors prevent breakdown and increase the endogenous
availability of cyclic guanosine monophosphate, which signals the
vasorelaxing effects of the down regulated mediator nitric oxide;
and (3) prostacyclin derivatives provide an exogenous supply of the
deficient mediator prostacyclin.
[0014] There are various drugs approved for the treatment of PAH:
inotropic agents such as digoxin aids in the treatment by improving
the heart's pumping ability. Nifedipine (Procardia) and Diltiazem
(Cardizem) act as vasodilators and lowers pulmonary blood pressure
and may improve the pumping ability of the right side of the
heart.
[0015] Bosentan (Tracleer), ambrisentan (Letairis), macitentan
(Opsumit), etc. are dual endothelin receptor antagonist that help
to block the action of endothelin, a substance that causes
narrowing of lung blood vessels. There are others which dilate the
pulmonary arteries and prevent blood clot formation. Examples of
such drugs are Epoprostenol (Veletri, Flolan), treprostinil sodium
(Remodulin, Tyvaso), iloprost (Ventavis); PDE 5 inhibitors such as
Sildenafil (Revatio), tadalafil (Adcirca), relax pulmonary smooth
muscle cells, which leads to dilation of the pulmonary
arteries.
[0016] In addition to these established current therapeutic
options, a large number of potential therapeutic targets are being
investigated. These novel therapeutic targets include soluble
guanylyl cyclase, phosphodiesterases, tetrahydrobiopterin,
5-hydroxytryptamine (serotonin) receptor 2B, vasoactive intestinal
peptide, receptor tyrosine kinases, adrenomedullin, rho kinase,
elastases, endogenous steroids, endothelial progenitor cells,
immune cells, bone morphogenetic protein and its receptors,
potassium channels, metabolic pathways, and nuclear factor of
activated T cells.
[0017] Despite a certain success achieved in recent years, many
patients with PAH are not adequately managed with existing
therapies.
[0018] Anagrelide is commercialized under the brand name
AGRYLIN.RTM. 0.5 mg Capsules. It is indicated for the treatment of
patients with thrombocythemia, secondary to myeloproliferative
neoplasms, to reduce the elevated platelet count and the risk of
thrombosis and to ameliorate associated symptoms including
thrombo-hemorrhagic events. The recommended starting dosage of
AGRYLIN.RTM. is 0.5 mg four times daily or 1 mg twice daily in
adults and 0.5 mg daily as starting dose in pediatric population.
Clinically, AGRYLIN (anagrelide hydrochloride capsules) was found
to be an effective, highly specific platelet-reducing agent.
Anagrelide's effects on platelets are fully reversible. Moreover,
it has no clinically significant effect on the other formed
elements in the blood. These findings were demonstrated both
preclinically and clinically.
[0019] Preclinical pharmacology data that are available demonstrate
anagrelide's specificity toward platelets. While anagrelide was
found to be a potent inhibitor of platelet aggregation, it had no
significant effect on other cellular components of the blood.
Additional significant pharmacologic effects attributed to
anagrelide administration are hypotension and positive inotropic
activity.
[0020] Two major metabolites, one active and one inactive, have
been identified. The active metabolite, BCH24426 or 3-hydroxy
anagrelide, shows similar potency and efficacy as anagrelide in the
platelet lowering effect. Exposure as measured by plasma AUC is
approximately 2-fold higher for 3-hydroxy anagrelide (BCH24426)
compared to anagrelide. The inactive metabolite, RL603 or
5,6-dichloro-3,4-dihydroquinazolin-2-ylamine, does not participate
in the overall effect of AGRYLIN.
[0021] It is an object of the invention to provide a novel
therapeutic method for the treatment of pulmonary hypertension,
including pulmonary arterial hypertension.
[0022] It is an object of the invention to provide novel
compositions for the treatment of pulmonary hypertension, including
pulmonary arterial hypertension.
[0023] It is an object of the invention to provide a novel
therapeutic method for the treatment of pulmonary hypertension,
including pulmonary arterial hypertension, using platelet reducing
agents.
[0024] It is an object of the invention to provide novel
compositions for the treatment of pulmonary hypertension, including
pulmonary arterial hypertension, containing platelet reducing
agents.
[0025] It is an object of the invention to provide a novel
therapeutic method for the treatment of pulmonary hypertension,
including pulmonary arterial hypertension, using anagrelide or
derivative thereof.
[0026] It is an object of the invention to provide novel
compositions for the treatment of hypertension, including pulmonary
arterial hypertension, containing anagrelide or a derivative
thereof.
SUMMARY
[0027] Disclosed herein are methods for treating pulmonary
hypertension, for instance, pulmonary arterial hypertension, in
patients in need thereof. In some instances, the methods include at
least partial reduction of the symptoms associated with pulmonary
hypertension, and in some instances include completed elimination
of the symptoms associated with pulmonary hypertension. The methods
include the use of anagrelide or a derivative thereof for the
treatment of pulmonary hypertension. Also disclosed herein are
compositions for the treatment of hypertension, wherein the
compositions include anagrelide or a derivative thereof.
[0028] The details of one or more embodiments are set forth in the
descriptions below. Other features, objects, and advantages will be
apparent from the description and from the claims.
DETAILED DESCRIPTION
[0029] Before the present methods and systems are disclosed and
described, it is to be understood that the methods and systems are
not limited to specific synthetic methods, specific components, or
to particular compositions. It is also to be understood that the
terminology used herein is for the purpose of describing particular
embodiments only and is not intended to be limiting.
[0030] As used in the specification and the appended claims, the
singular forms "a," "an" and "the" include plural referents unless
the context clearly dictates otherwise. Ranges may be expressed
herein as from "about" one particular value, and/or to "about"
another particular value. When such a range is expressed, another
embodiment includes from the one particular value and/or to the
other particular value. Similarly, when values are expressed as
approximations, by use of the antecedent "about," it will be
understood that the particular value forms another embodiment. It
will be further understood that the endpoints of each of the ranges
are significant both in relation to the other endpoint, and
independently of the other endpoint.
[0031] "Optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances where it does not.
[0032] Throughout the description and claims of this specification,
the word "comprise" and variations of the word, such as
"comprising" and "comprises," means "including but not limited to,"
and is not intended to exclude, for example, other additives,
components, integers or steps. "Exemplary" means "an example of"
and is not intended to convey an indication of a preferred or ideal
embodiment. "Such as" is not used in a restrictive sense, but for
explanatory purposes.
[0033] Disclosed are components that can be used to perform the
disclosed methods and systems. These and other components are
disclosed herein, and it is understood that when combinations,
subsets, interactions, groups, etc. of these components are
disclosed that while specific reference of each various individual
and collective combinations and permutation of these may not be
explicitly disclosed, each is specifically contemplated and
described herein, for all methods and systems. This applies to all
aspects of this application including, but not limited to, steps in
disclosed methods. Thus, if there are a variety of additional steps
that can be performed it is understood that each of these
additional steps can be performed with any specific embodiment or
combination of embodiments of the disclosed methods.
[0034] Anagrelide is a selective inhibitor of phosphodiesterase 3A
(PDE3A). Anagrelide works by inhibiting PDE3 found in platelets and
as a result raises cAMP levels, which in turn may explain the
inhibitory effect on platelet aggregation. Platelet aggregation is
inhibited in humans at doses higher than those required to reduce
platelet count. PDE3 is clinically significant because of its role
in regulating heart muscle, vascular smooth muscle and platelet
aggregation. PDE3A is mainly implicated in cardiovascular function
and fertility. PDE3A is one of the therapeutic targets of PAH as
well since it hydrolyzes cAMP and cGMP into AMP and GMP,
respectively and thereby implicated in vasoconstriction of
pulmonary artery smooth muscle cells.
[0035] The present inventors have found that the PDE3A antagonistic
activity of anagrelide exhibits a significant role in the treatment
of PAH.
[0036] As a result of its high expression in both the vasculature
and the airways, PDE3 was identified as a potential therapeutic
target in cardiovascular disease and asthma, and indeed, PDE3
inhibitors have subsequently been shown to relax vascular and
airway smooth muscle, inhibit platelet aggregation and induce
lipolysis.
[0037] The term "combination" as used herein, defines either a
fixed combination in one dosage unit form, a non-fixed combination
or a kit containing individual parts for combined
administration.
[0038] The term "treating" or "treatment" as used herein comprises
a treatment relieving, reducing or alleviating at least one symptom
in a subject or effecting a delay of progression of a disease. For
example, treatment can be the diminishment of one or several
symptoms of a disorder or complete eradication of pulmonary
arterial hypertension. Within the meaning of the present invention,
the term "treat" also includes to arrest, delay the onset (i.e.,
the period prior to clinical manifestation of a disease) and/or
reduce the risk of developing or worsening a disease.
[0039] The term "anagrelide" refers to a compound having the
formula:
##STR00001##
or a pharmaceutically acceptable salt thereof. Unless specified to
the contrary, the term "anagrelide" embraces both the free base and
pharmaceutically acceptable salts thereof. An anagrelide derivative
includes active metabolites of anagrelide, as well as compounds
that convert in vivo either to anagrelide or an active metabolite
thereof. In some instance, the anagrelide derivative can be a
compound of Formula (1):
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein R is
hydrogen, C(O)R.sup.1, C(O)OR.sup.1, or PO.sub.3X.sub.2; R.sup.1 is
optionally substituted C.sub.1-8alkyl, optionally substituted
C.sub.1-8alkaryl, optionally substituted C.sub.3-8cycloalkyl,
optionally substituted C.sub.2-12heterocyclyl, optionally
substituted C.sub.2-12heteroaryl; X is independently selected from
hydrogen, pharmaceutically acceptable cation, or R.sup.1 (as
defined above). Unless specified to the contrary, the term
"anagrelide derivative" embraces both the free base and
pharmaceutically acceptable salts thereof.
[0040] Pharmaceutically acceptable salts are salts that retain the
desired biological activity of the parent compound and do not
impart undesirable toxicological effects. Examples of such salts
are acid addition salts formed with inorganic acids, for example,
hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids
and the like; salts formed with organic acids such as acetic,
oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric,
malic, methanesulfonic, ptoluenesulfonic, napthalenesulfonic, and
polygalacturonic acids, and the like; salts formed from elemental
anions such as chloride, bromide, and iodide; salts formed from
metal hydroxides, for example, sodium hydroxide, potassium
hydroxide, calcium hydroxide, lithium hydroxide, and magnesium
hydroxide; salts formed from metal carbonates, for example, sodium
carbonate, potassium carbonate, calcium carbonate, and magnesium
carbonate; salts formed from metal bicarbonates, for example,
sodium bicarbonate and potassium bicarbonate; salts formed from
metal sulfates, for example, sodium sulfate and potassium sulfate;
and salts formed from metal nitrates, for example, sodium nitrate
and potassium nitrate. Pharmaceutically acceptable and
non-pharmaceutically acceptable salts may be prepared using
procedures well known in the art, for example, by reacting a
sufficiently basic compound such as an amine with a suitable acid
comprising a physiologically acceptable anion. Alkali metal (for
example, sodium, potassium, or lithium) or alkaline earth metal
(for example, calcium) salts of carboxylic acids can also be made.
Pharmaceutically acceptable cations include the cationic component
of the acids listed above. Pharmaceutically acceptable anions
include the anionic component of the bases listed above. In some
preferred embodiments, anagrelide (or a derivative thereof) is
formulated as the hydrochloride salt.
[0041] Pulmonary hypertension can be classified as either primary
or secondary. When the arterial hypertension is not accompanied or
caused by another underlying heart or lung disease or condition, it
is called primary pulmonary arterial hypertension. When the
arterial hypertension is triggered by another disease state, it is
designated secondary arterial pulmonary hypertension. Exemplary
conditions which can cause secondary pulmonary hypertension include
congenital heart defects, ventricular or atrial septal
defects/holes, which are in some cases called Eisenmenger complex,
as well as valve conditions such as stenosis.
[0042] Pulmonary hypertension can be associated with left heart
disease, or right heart disease. In some embodiments, anagrelide
(or a derivative thereof) can be used to treat pulmonary
hypertension associated with left heart disease, whereas in other
embodiments, anagrelide (or a derivative thereof) can be used to
treat pulmonary hypertension associated with right heart disease.
In further embodiments, anagrelide (or a derivative thereof) can be
used to treat pulmonary hypertension associated with both right and
left heart disease.
[0043] Pulmonary hypertension can be characterized by a pulmonary
blood pressure greater than about 25 mm Hg at rest, and 30 mm Hg
during exercise. Normal pulmonary arterial pressure is about 8-20
mm Hg at rest. In certain embodiments, anagrelide (or a derivative
thereof) can be used to treat patients having a resting pulmonary
arterial pressure of at least 25 mm Hg, at least 30 mm Hg, at least
35 mm Hg, at least 40 mm Hg, at least 45 mm Hg, at least 50 mm Hg,
at least 55 mm Hg, or at least 60 mm Hg.
[0044] The dosage and dosage regimen may be calculated per kg body
weight.
[0045] The dosage regimen may vary from a day to a month.
Accordingly, the initial dosage and maintenance doses may be
specified. For instance, an initial dosage may be administered over
the course of 1, 3, 5, 7, 10, 14, 21 or 28 days, followed by a
maintenance dosage which is administered for the duration of the
treatment.
[0046] Preferably, the composition as contemplated by the invention
may be administered at least once, twice or thrice a day in the
dosing range from 0.05 to 20 mg or from 1 to 15 mg or as per the
requirement of the patient to be treated.
[0047] Preferably, anagrelide (or a derivative thereof) may be
provided in the form of a pharmaceutical composition such as but
not limited to, unit dosage forms including tablets, capsules
(filled with powders, pellets, beads, mini-tablets, pills,
micro-pellets, small tablet units, multiple unit pellet systems
(MUPS), disintegrating tablets, dispersible tablets, granules, and
microspheres, multiparticulates), sachets (filled with powders,
pellets, beads, mini-tablets, pills, micro-pellets, small tablet
units, MUPS, disintegrating tablets, dispersible tablets, granules,
and microspheres, multiparticulates), powders for reconstitution,
transdermal patches and sprinkles, however, other dosage forms such
as controlled release formulations, lyophilized formulations,
modified release formulations, delayed release formulations,
extended release formulations, pulsatile release formulations, dual
release formulations and the like. Liquid or semisolid dosage form
(liquids, suspensions, solutions, dispersions, ointments, creams,
emulsions, microemulsions, sprays, patches, spot-on), injection
preparations, parenteral, topical, inhalations, buccal, nasal etc.
may also be envisaged under the ambit of the invention.
[0048] In some instances, anagrelide (or a derivative thereof) can
be administered by inhalation, for instance as a powder or
aerosolizable formulation.
[0049] The bioavailability of the drug in a composition, depends on
various attributes of the drug as well as the other inactive
ingredients in the formulation. The particle size of the drug is
one of such attribute that may affect the bioavailability of the
drug, when administered to a patient. The particle size may thus be
adjusted as per the requirements of the invention.
[0050] The inventors of the present invention have also found that
the solubility properties of anagrelide (or a derivative thereof)
may be improved by nanosizing thus leading to better
bioavailability and dose reduction of the drug.
[0051] In one embodiment, anagrelide (or a derivative thereof) may
be present in the form of nanoparticles which have an average
particle size of less than 2000 nm, less than 1500 nm, less than
1000 nm, less than 750 nm, or less than 500 nm.
[0052] Suitable excipients may be used for formulating the dosage
forms according to the present invention such as, but not limited
to, surface stabilizers or surfactants, viscosity modifying agents,
polymers including extended release polymers, stabilizers,
disintegrants or super disintegrants, diluents, plasticizers,
binders, glidants, lubricants, sweeteners, flavoring agents,
anti-caking agents, opacifiers, anti-microbial agents, antifoaming
agents, emulsifiers, buffering agents, coloring agents, carriers,
fillers, anti-adherents, solvents, taste-masking agents,
preservatives, antioxidants, texture enhancers, channeling agents,
coating agents or combinations thereof.
[0053] Preferably, the composition as contemplated by the invention
may be administered at least once, twice or thrice a day, in a
dosing range of 0.05 to 20 mg or from 1 to 15 mg or as per the
requirement of the patient to be treated. On administration,
anagrelide prodrugs (i.e., compounds of Formula (1) in which R is
not hydrogen) hydrolyzes to the active moiety, 3-hydroxyanagrelide.
The dose calculation is done taking the above into consideration,
and the anagrelide prodrug is administered as a weight equivalent
to the parent 3-hydroxyanagrelide.
[0054] Disclosed herein are methods for treating patients with
pulmonary arterial hypertension. The hypertension may be mild
(resting arterial pressure between 20-25 mm Hg) or complete
(resting arterial pressure greater than 25 mm Hg). The patient to
be treated may have a pulmonary arterial pressure greater than 25
mm Hg, greater than 28 mm Hg, greater than 30 mm Hg, greater than
32 mm Hg, greater than 34 mm Hg, greater than 36 mm Hg, greater
than 38 mm Hg, or greater than 40 mm Hg.
[0055] Anagrelide (or a derivative thereof) can be used to treat
patients with sporadic idiopathic PAH, heritable PAH, as well as
PAH due to disease of small pulmonary muscular arterioles. In some
embodiments, anagrelide (or a derivative thereof) is administered
to a patient (which may be a human or other mammal) in an amount
sufficient to cause at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, or
40% reduction in resting arterial pressure relative to the
pulmonary arterial pressure prior to commencing treatment. In some
instances, anagrelide (or a derivative thereof) is administered at
a dose effective such that the patient's final resting arterial
pressure is about 25 mm Hg, about 24 mm Hg, about 23 mm Hg, about
22 mm Hg, about 21 mm Hg, about 20 mm Hg, about 19 mm Hg, about 18
mm Hg, about 17 mm Hg, about 16 mm Hg, about 15 mm Hg, or about 14
mm Hg. In certain embodiments, anagrelide (or a derivative thereof)
is administered in combination with other agents, as described
below, to achieve these therapeutic outcomes.
[0056] In some instances, the anagrelide (or a derivative thereof)
may be administered to a patient a single time, while in other
cases anagrelide (or a derivative thereof) can be administered
using an intervallic dosing regimen. For instance, anagrelide (or a
derivative thereof) may be administered once, twice, or three times
a day for a period at least 1 week, for example 2 weeks, 4 weeks, 6
weeks, 8 weeks, 10 weeks, 20 weeks, 40 weeks, or 52 weeks. In some
instances, anagrelide (or a derivative thereof) administration can
be suspended for some period of time (e.g., 1, 2, 3, 4, 6, 8, 10,
20, 40 or 52 weeks) followed by another period of
administration.
[0057] In some instances, the anagrelide (or a derivative thereof)
can be administered to the patient using an interval greater than a
day. For instance, the anagrelide (or a derivative thereof) can be
administered once every other day, once every third day, once a
week, once every two weeks, once every four weeks, once a month,
once every other month, once every third month, once every six
months, or once a year. In some instance injectable formulations,
such as depot formulations, are suitable for dosing regimens with
extended periods in between administration, however, oral
formulations can also be used in such systems.
[0058] In some embodiments, pulmonary arterial hypertension can be
alleviated or treated by administration of anagrelide (or a
derivative thereof) in combination with one or more other drugs
either simultaneously, sequentially, or separately.
[0059] Preferably, one or more standard of care drugs that may be
envisaged under the scope of the present invention may comprise
from categories of for the treatment of pulmonary hypertension such
as, but not limited to phosphodiesterase inhibitors, endothelin
receptor antagonist, Inotropic agents, and stimulators of soluble
guanylate cyclase, such as riociguat.
[0060] Specifically, one or more standard of care drugs include but
not limited to sildenafil, tadalafil, bosentan, ambrisentan,
macitentan, nifedipine, diltiazem, digoxin. There are others which
dilate the pulmonary arteries and prevent blood clot formation.
Examples of such drugs are Epoprostenol (Veletri, Flolan),
treprostinil sodium (Remodulin, Tyvaso), iloprost (Ventavis); PDE 5
inhibitors such as Sildenafil (Revatio), tadalafil (Adcirca),
relaxes pulmonary smooth muscle cells, which leads to dilation of
the pulmonary arteries.
[0061] The use of anagrelide may preferably be associated with one
or more of the above referenced drugs as a combination therapy
(either of the same functional class or other) depending on various
factors like drug-drug compatibility, patient compliance and other
such factors wherein the said combination therapy may be
administered either simultaneously, sequentially, or separately for
the treatment of PAH.
[0062] Anagrelide (or a derivative thereof) may be provided with
one or more drugs in the form of a kit, wherein the kit includes
anagrelide and at least one other drug, and instructions for their
administration to a PAH patient.
[0063] In certain embodiments, the administration of anagrelide (or
a derivative thereof), either alone or in combination with one or
more drugs selected from but not limited to phosphodiesterase
inhibitors such as sildenafil, tadalafil etc., endothelin receptor
antagonist such as bosentan, macitentan etc. and stimulators of
soluble guanylate cyclase such as riociguat. In certain
embodiments, anagrelide (or a derivative thereof) can be
co-administered with one or more additional agents effective to
lower pulmonary hypertension. In some embodiments the
co-administration includes a unitary dosage form containing
anagrelide (or a derivative thereof) and at least one more agent.
In other embodiments, anagrelide (or a derivative thereof) is
administered separately from the other agent(s). The additional
agent can be a PDE-5 inhibitor, for example, avanafil, lodenafil,
mirodenafil, sildenafil, tadalafil, vardenafil, udenafil,
zaprinast, or icariin. Other agents include calcium channel
blockers like dihydropyridines (e.g., amlodipine, nifefipine) and
diltiazem; prostacyclin pathway agonists such as epoprostenol,
treprostinil, iloprost, and selexipag; endothelin receptor
antagonists such as bosentan, macitentan, ambrisentan, and
sitaxsentan; guanylate cyclase stimulators such as riociguat;
diuretics; toprimate; fusadil; or anti-coagulants like
warfarin.
[0064] It may be well appreciated by a person skilled in the art
that the pharmaceutical composition comprising anagrelide in
combination with one or more drugs may require specific dosage
amounts and specific frequency of administrations specifically
considering their individual established doses, the dosing
frequency, patient adherence and the regimen adopted. As described
herein, considering that there are various parameters to govern the
dosage and administration of the combination composition as per the
present invention, it would be well acknowledged by a person
skilled in the art to exercise caution with respect to the dosage,
specifically, for special populations associated with other
disorders.
EXAMPLES
[0065] The following examples are set forth below to illustrate the
methods and results according to the disclosed subject matter.
These examples are not intended to be inclusive of all aspects of
the subject matter disclosed herein, but rather to illustrate
representative methods, compositions, and results. These examples
are not intended to exclude equivalents and variations of the
present invention, which are apparent to one skilled in the
art.
[0066] Efforts have been made to ensure accuracy with respect to
numbers (e.g., amounts, temperature, etc.) but some errors and
deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, temperature is in .degree. C. or is at
ambient temperature, and pressure is at or near atmospheric. There
are numerous variations and combinations of reaction conditions,
e.g., component concentrations, temperatures, pressures, and other
reaction ranges and conditions that can be used to optimize the
product purity and yield obtained from the described process. Only
reasonable and routine experimentation will be required to optimize
such process conditions.
Example 1--Pulmonary Arterial Hypertension Efficacy Model:
Monocrotaline Rat
[0067] Method:
[0068] Adult male Sprague-Dawley rats (287.+-.4 g) were obtained
from Charles River Laboratories (Raleigh, N.C.). Animals housed
individually in a temperature/humidity controlled room with 12-hour
light/dark cycles, had free access to water and food and were
acclimated for one week prior to the study. Rats were randomly
assigned to one of the experimental groups (n=10 per group). Rats
in groups 1 and 2 served as healthy controls; the remaining rats
were injected subcutaneously on Day 0 with 60 mg/kg body weight
monocrotaline, the toxic alkaloid of Crotalaria spectabilis,
(dissolved in DMSO at a concentration of 60 mg/ml, Sigma Aldrich,
St. Louis, Mo.). On days 1-21, the rats were dosed via oral gavage
(2 ml/kg) with vehicle (PBS), or the test compound--Anagrelide.
Rats were weighed daily, and the dosages of test compound adjusted
appropriately.
[0069] Monocrotaline (MCT) is an 11-membered macrocyclic
pyrrolizidine plant alkaloid. A single SQ injection into rats
results in hepatic generation of toxic metabolite--MCT pyrrole.
Phase II metabolism of MCT is through glutathione conjugation.
Reactive metabolite is transported to lungs, injuring pulmonary
vasculature.
Results:
[0070] Anagrelide was shown to prevent the development of PAH in
the rat monocrotaline (MCT) model. Thus, Anagrelide, a
phosphodiesterase 3A inhibitor, when administered to rats for three
weeks in daily oral doses, prevents not only monocrotaline
(MCT)-induced elevations in pressure in the pulmonary arterial
circuit but also hypertrophy of the right ventricle.
Example 2--Hemodynamic Evaluation of Anagrelide in Anesthetized
Sprague Dawley Rats Treated with Monocrotaline to Induce Pulmonary
Arterial Hypertension
Method:
[0071] The effects of sildenafil and anagrelide were evaluated in
rats with monocrotaline induced pulmonary arterial hypertension.
Male Sprague-Dawley rats were orally administered vehicle
(variable, see below), anagrelide (1 mg/kg given once daily for 28
days or 2 mg/kg total daily dose, divided into a BID regimen given
every day for 28 days starting on Day 1), or sildenafil (30 mg/kg,
administered twice daily) (n=10 in each group). Rats received a
single injection of monocrotaline (60 mg/kg, s.c.) on Study Day 1.
On the twenty-eighth day following monocrotaline dosing, the rats
were anesthetized with ketamine/xylazine for terminal monitoring of
pulmonary and systemic arterial pressures along with heart rate.
The study design for the test article and vehicle administrations
are detailed below:
TABLE-US-00001 Test Compound Dose Dose No. of Test Dose Level Conc.
Volume Dose Dose Dose Male Group Compound (mg/kg) (mg/mL) (mL/kg)
Period Route Days Rats 2-5 Monocrotaline.sup.1 80 80 1 AM SC 1 100
1 DMSO.sup.2 NA NA 1 AM SC 1 5 2 Vehicle NA NA 5 AM Oral 1-28 10 3
Anagrelide 1 0.2 5 AM Oral 1-28 10 5 PM 4 Anagrelide 1 0.2 5 AM
Oral 1-28 10 1 0.2 5 PM 5 Sildenafil 30 6 5 AM Oral 1-28 10 30 6 5
PM .sup.1Single dose in DMSO administered 28 days prior to terminal
procedure. .sup.2Single dose administered 28 days prior to terminal
procedure.
Results:
[0072] There were differences in systolic and mean pulmonary
arterial pressures after 28 days in rats treated with anagrelide at
2 mg/kg/day given BID compared to the vehicle group. Rats treated
with anagrelide showed a reduction at this dose with systolic
pulmonary arterial pressure--the variable used as an arbiter of
protection. There was paradoxically no effect with respect to right
ventricular hypertrophy (as measured by RV/LV+S--Fulton's Index) in
the anagrelide group (no change) compared to vehicle. When
correcting RV (wt) by body weight, anagrelide showed a decrease in
hypertrophy at either dose. Mean arterial pressure was lower in
rats treated with anagrelide compared to vehicle.
TABLE-US-00002 Treatment Cohort - Parameter Vehicle (mg/kg) Mean
.+-. SEM DMSO Systolic PAP (mm Hg) 16 .+-. 2 Mean PAP (mm Hg) 14
.+-. 2 MAP (mm Hg) 84 .+-. 9 HR (bpm) 313 .+-. 13 Heart Wt (g) 1.17
.+-. 0.03 HW/BW 2.75 .+-. 0.07 LV Wt (g) 0.82 .+-. 0.01 RV Wt (g)
0.22 .+-. 0.02 Lung Wt (g) 1.65 .+-. 0.08 RV/LV + S 0.26 .+-. 0.02
RV/BW 0.50 .+-. 0.03 Body Weight (kg) 0.43 .+-. 0.01
TABLE-US-00003 Treatment Cohort (mg/kg) Parameter Anagrelide
Anagrelide Sildenafil Mean .+-. SEM Vehicle 1.sup.# 2/day bid
60/day bid Systolic PAP (mm Hg) 60 .+-. 2 44 .+-. 2 43 .+-. 4 46
.+-. 7 Mean PAP (mm Hg) 46 .+-. 1 36 .+-. 2 36 .+-. 2 38 .+-. 6 MAP
(mm Hg) 70 .+-. 6 59 .+-. 5 52 .+-. 6 69 .+-. 5 HR (bpm) 274 .+-.
10 325 .+-. 28 258 .+-. 10 278 .+-. 21 Heart Wt (g) 1.36 .+-. 0.05
1.37 .+-. 0.03 1.21 .+-. 0.04* 1.24 .+-. 0.02 HW/BW 4.43 .+-. 0.15
4.34 .+-. 0.45 3.98 .+-. 0.24 3.89 .+-. 0.17 LV Wt (g) 0.78 .+-.
0.01 0.76 .+-. 0.01 0.69 .+-. 0.02* 0.74 .+-. 0.02 RV Wt (g) 0.46
.+-. 0.02 0.47 .+-. 0.01 0.41 .+-. 0.02 0.38 .+-. 0.02* Lung Wt (g)
2.90 .+-. 0.53 2.10 .+-. 0.19 2.21 .+-. 0.07 2.36 .+-. 0.13 RV/LV +
S 0.59 .+-. 0.03 0.62 .+-. 0.01 0.59 .+-. 0.04 0.51 .+-. 0.03 RV/BW
1.50 .+-. 0.06 1.49 .+-. 0.16 1.35 .+-. 0.12 1.19 .+-. 0.09 Body
Weight (kg) 0.31 .+-. 0.02 0.32 .+-. 0.02 0.31 .+-. 0.01 0.32 .+-.
0.01
Example 3--Formulations
[0073] Compositions useful for treating pulmonary arterial
hypertension can include the following ingredients:
TABLE-US-00004 Ingredients Qty/Tab (mg) Anagrelide hydrochloride
0.5-10 Microcrystalline cellulose 10-25 Lactose Monohydrate 20-80
Lactose Anhydrous 10-30 Sodium lauryl sulfate (SLS) 0.2-1.5
Croscarmellose Sodium 5-10 Povidone 3-10 Aerosil 200 1-5 Magnesium
Stearate 1-5
TABLE-US-00005 Ingredients Quantity Mg/tablet Anagrelide
hydrochloride 0.5-10 Lactose monohydrate 10-50 Microcrystalline
cellulose (Avicel PH 102) 20-60 Croscarmellose sodium (Ac-Di-sol)
5-20 Polysorbate 80 0.5-2.0 Povidone 10-25 Lactose anhydrous 5-20
Colloidal silicon dioxide (Aerosil 200) 1-5 Magnesium stearate
2-8
The compositions and methods of the appended claims are not limited
in scope by the specific compositions and methods described herein,
which are intended as illustrations of a few aspects of the claims
and any compositions and methods that are functionally equivalent
are intended to fall within the scope of the claims. Various
modifications of the compositions and methods in addition to those
shown and described herein are intended to fall within the scope of
the appended claims. Further, while only certain representative
compositions and method steps disclosed herein are specifically
described, other combinations of the compositions and method steps
also are intended to fall within the scope of the appended claims,
even if not specifically recited. Thus, a combination of steps,
elements, components, or constituents may be explicitly mentioned
herein or less, however, other combinations of steps, elements,
components, and constituents are included, even though not
explicitly stated. The term "comprising" and variations thereof as
used herein is used synonymously with the term "including" and
variations thereof and are open, non-limiting terms. Although the
terms "comprising" and "including" have been used herein to
describe various embodiments, the terms "consisting essentially of"
and "consisting of" can be used in place of "comprising" and
"including" to provide for more specific embodiments of the
invention and are also disclosed. Other than in the examples, or
where otherwise noted, all numbers expressing quantities of
ingredients, reaction conditions, and so forth used in the
specification and claims are to be understood at the very least,
and not as an attempt to limit the application of the doctrine of
equivalents to the scope of the claims, to be construed in light of
the number of significant digits and ordinary rounding
approaches.
* * * * *