U.S. patent application number 10/609233 was filed with the patent office on 2004-12-30 for inhalable formulations for treating pulmonary hypertension and methods of using same.
Invention is credited to Chaudry, Imtiaz.
Application Number | 20040265238 10/609233 |
Document ID | / |
Family ID | 33540807 |
Filed Date | 2004-12-30 |
United States Patent
Application |
20040265238 |
Kind Code |
A1 |
Chaudry, Imtiaz |
December 30, 2004 |
Inhalable formulations for treating pulmonary hypertension and
methods of using same
Abstract
The present invention is directed to an inhalable formulation
for the treatment of pulmonary hypertension in a mammal (e.g.,
humans), wherein the formulation comprises at least one
hypertension reducing agent, including but not limited to an
angiotensin converting enzyme inhibitor, angiotensin receptor
blocker, beta-blocker, calcium-channel blocker or vasodilator, or
any combination thereof. The formulations of the present invention
may be a solution or suspension, and preferably are suitable for
administration via nebulization. The present invention is also
directed to a method and kit for treating a mammal suffering from
pulmonary hypertension.
Inventors: |
Chaudry, Imtiaz; (Napa,
CA) |
Correspondence
Address: |
ALSTON & BIRD LLP
BANK OF AMERICA PLAZA
101 SOUTH TRYON STREET, SUITE 4000
CHARLOTTE
NC
28280-4000
US
|
Family ID: |
33540807 |
Appl. No.: |
10/609233 |
Filed: |
June 27, 2003 |
Current U.S.
Class: |
424/45 ;
514/211.07; 514/355; 514/423; 514/651 |
Current CPC
Class: |
A61K 31/00 20130101;
A61P 7/10 20180101; A61P 11/00 20180101; A61K 31/675 20130101; A61K
31/472 20130101; A61K 31/5585 20130101; A61P 9/08 20180101; A61P
43/00 20180101; A61K 31/55 20130101; A61P 7/02 20180101; A61K
31/401 20130101; A61P 9/12 20180101; A61K 31/5575 20130101; A61K
9/0078 20130101; A61K 31/404 20130101; A61K 38/556 20130101; A61K
45/06 20130101 |
Class at
Publication: |
424/045 ;
514/355; 514/211.07; 514/423; 514/651 |
International
Class: |
A61K 031/554; A61K
031/455; A61K 031/401; A61K 031/137 |
Claims
What is claimed is:
1. An inhalable formulation for the treatment of pulmonary
hypertension, said formulation comprising a therapeutically
effective amount of a hypertension reducing agent, wherein said
pulmonary hypertension reducing agent is at least one of an ACEI,
ARB, beta-blocker, calcium-channel blocker or vasodilator and
wherein said formulation is suitable for administration via
inhalation to a mammal in need thereof.
2. The formulation of claim 1, wherein said formulation is suitable
for administration via nebulization.
3. The formulation of claim 2 comprising about 0.001 mg/ml to about
20 mg/ml of said pulmonary hypertension reducing agent.
4. The formulation of claim 2 comprising about 0.1 mg/ml to about
15 mg/ml of said pulmonary hypertension reducing agent.
5. The formulation of claim 2 comprising about 1 mg/ml to about 10
mg/ml of said pulmonary hypertension reducing agent.
6. The formulation of claim 2, wherein said formulation is a
solution.
7. The formulation of claim 6, wherein said solution is
sterile.
8. The formulation of claim 7, wherein said solution is
isotonic.
9. The formulation of claim 8, wherein said solution has a pH of
about 3 to about 8.
10. The formulation of claim 9, wherein said solution comprises a
buffer.
11. The formulation of claim 10, wherein said buffer is at least
one selected from the group consisting of sodium hydroxide, sodium
citrate and citric acid.
12. The formulation of claim 2, wherein said formulation is an
aqueous suspension.
13. The formulation of claim 12, wherein said suspension is
sterile.
14. The formulation of claim 13, wherein said suspension comprises
an emulsifier.
15. The formulation of claim 14, wherein said suspension is
isotonic.
16. The formulation of claim 2, wherein said formulation comprises
a preservative.
17. The formulation of claim 2, wherein said formulation is
preservative-free.
18. The formulation of claim 2, wherein said ACEI is at least one
of the group consisting of benazepril, captopril, enalapril,
fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril
and trandolapril.
19. The formulation of claim 2, wherein said ARB is at least one of
the group consisting of candesartan, eprosartan, irbesartan,
losartan, olmesartan, telmisartan and valsartan.
20. The formulation of claim 2, wherein said beta-blocker is at
least one of the group consisting of acebutolol, atenolol,
betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol,
metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol,
sotalol and timolol.
21. The formulation of claim 2, wherein said calcium-channel
blocker is at least one of the group consisting of amlodipine,
bepridil, diltiazem, felodipine, flunarizine, isradipine,
nicardipine, nifedipine, nimodipine and verapamil.
22. The formulation of claim 2, wherein said vasodilator is at
least one of the group consisting of adenine, arginine, doxazosin,
hydralazine hydrochloride, isosorbide dinitrate, isosorbide
mononitrate minoxidil, nicotinates, nitroglycerin, phentolamine,
prazosin and terazosin.
23. The formulation of claim 2, wherein said vasodilator comprises
one or more prostaglandins.
24. The formulation of claim 23, wherein said prostaglandin is
prostacyclin or an analog thereof.
25. The formulation of claim 2, wherein said formulation is
suitable for treating primary pulmonary hypertension.
26. The formulation of claim 2, wherein said formulation is
suitable for treating secondary pulmonary hypertension.
27. A method of treating pulmonary hypertension in a mammal, said
method comprising the step of administering to said mammal a
formulation comprising a therapeutically effective amount of a
hypertension reducing agent, wherein said hypertension reducing
agent is at least one of an ACEI, ARB, beta-blocker,
calcium-channel blocker or vasodilator, and wherein said
formulation is suitable for administration via inhalation.
28. The method of claim 27, wherein said formulation is
administered via nebulization to said mammal.
29. The method of claim 28, wherein said formulation is
administered via jet nebulizer, ultrasonic nebulizer or
breath-actuated nebulizer to said mammal.
30. The method of claim 27, wherein said formulation is
premeasured, premixed and prepackaged.
31. The method of claim 30, wherein said formulation comprises
about 0.05 mg/ml to about 15 mg/ml of said hypertension reducing
agent.
32. The method of claim 31, wherein said formulation is sterile and
stable.
33. The method of claim 27, said method further comprising the step
of administering to said mammal an anticoagulant.
34. The method of claim 27, said method further comprising the step
of administering to said mammal an inotropic agent.
35. The method of claim 27, said method further comprising the step
of administering to said mammal low-flow supplemental oxygen
therapy.
36. The method of claim 27, said method further comprising the step
of administering to said mammal a diuretic.
37. The method of claim 27, said method further comprising the step
of administering to said mammal a low salt diet.
38. A kit for treating pulmonary hypertension in a mammal, said kit
comprising an prepackaged formulation comprising a therapeutically
effective amount of a hypertension reducing agent, wherein said
hypertension reducing agent is at least one of an ACEI, ARB,
beta-blocker, calcium-channel blocker or vasodilator, and wherein
said formulation is suitable for administration via nebulization to
a mammal in need thereof.
39. The kit of claim 38, wherein said formulation is
prepackaged.
40. The kit of claim 38, further comprising instructions relating
to said formulation.
41. An inhalable formulation for the treatment of pulmonary
hypertension, said formulation comprising about 0.2-10.0 mg/ml,
Enalaprilat, (s-1-[N-(1-carboxy-3-phenylpropyl)-L-alanyl]-L-praline
dehydrate, about 2.0-10.0 mg/ml Sodium Chloride, Sodium Hydroxide
and water, wherein said formulation is suitable for administration
via nebulization to a mammal in need thereof.
42. An inhalable formulation for the treatment of pulmonary
hypertension, said formulation comprising about 1.0-10.0 mg/ml,
Atenolol (Benzeneacetamide, 4-[2-hydroxy-3-(1-methylethyl)amino
propoxy], about 2.0-10.0 mg/ml Sodium Chloride, Sodium Citrate,
Citric Acid and water, wherein said formulation is suitable for
administration via nebulization to a mammal in need thereof.
43. An inhalable formulation for the treatment of pulmonary
hypertension, said formulation comprising about 0.1-3.0 mg/ml
Epoprostenol, about 0.2-2.0 mg/ml, Span 85 and water, wherein said
formulation is suitable for administration via nebulization to a
mammal in need thereof.
44. An inhalable formulation for the treatment of pulmonary
hypertension, said formulation comprising about 0.1-10.0 mg/ml
Treprostinil sodium, about 2.0-10.0 mg/ml, Sodium Chloride, Sodium
Hydroxide, Citric Acid and water, wherein said formulation is
suitable for administration via nebulization to a mammal in need
thereof.
45. The formulation of claims 41 to 44, wherein said formulation is
an aqueous suspension.
46. The formulation of claim 45, wherein said suspension is
sterile.
47. The formulation of claim 46, wherein said suspension has pH of
about 3 to about 8.
48. The formulation of claim 47, wherein said suspension is
isotonic.
49. The formulation of claim 48, wherein said formulation comprises
a preservative.
50. The formulation of claim 49, wherein said formulation is
preservative-free.
Description
I. FIELD OF THE INVENTION
[0001] The present invention relates to an inhalable formulation
for the treatment of pulmonary hypertension, and methods of
treating the same in mammals, including humans. The formulation of
the present invention comprises a hypertension reducing agent,
wherein the hypertension reducing agent may include an
angiotensin-converting enzyme inhibitor ("ACEI"), angiotensin
receptor blocker ("ARB"), beta adrenergic blocking agent
("beta-blockers"), calcium-channel blocker or vasodilator, or any
combination thereof. Preferably, the formulation of the present
invention is suitable for administration via nebulization. The
present invention also relates to a prepackaged kit for treating
pulmonary hypertension containing the formulation of the present
invention.
II. BACKGROUND OF THE INVENTION
[0002] Pulmonary hypertension is a disorder of the lung in which
the pressure in the pulmonary artery (the blood vessel that leads
from the heart to the lungs) rises above normal levels. If left
untreated, pulmonary hypertension may become life threatening.
Symptoms of pulmonary hypertension include shortness of breath with
minimal exertion, fatigue, chest pain, dizzy spells fainting, and
other symptoms. Pulmonary hypertension is frequently misdiagnosed
and has often progressed to late stage by the time it is accurately
diagnosed. Moreover, pulmonary hypertension has been historically
chronic and incurable with a poor survival rate.
[0003] When pulmonary hypertension occurs in the absence of a known
cause, it is referred to as primary pulmonary hypertension (PPH).
There are many unknown causes of PPH.
[0004] When the cause of pulmonary hypertension is known, it is
called secondary pulmonary hypertension (SPH). Common causes of SPH
is the breathing disorders emphysema, bronchitis and chronic
obstructive pulmonary disorder, among others. Other less frequent
causes are the inflammatory or collagen vascular diseases such as
scleroderma, CREST syndrome or systemic lupus erythematosus.
Congenital heart diseases that cause shunting of extra blood
through the lungs like ventricular and arterial septal defects,
chronic pulmonary thromboembolism (old blood clots in the pulmonary
artery), HIV infection, liver disease and diet drugs like
fenfluramine and dexfenfluramine are also causes of pulmonary
hypertension.
[0005] Angiotensin-converting enzyme inhibitors (ACEI) are drugs
used to treat hypertension (high blood pressure) and congestive
heart failure. These drugs are also used to alleviate the strain on
hearts damaged from heart attacks. ACEIs block production of an
enzyme that helps convert the protein angiotensin I into
angiotensin II, a protein that makes blood vessels constrict and
promotes retention of fluid in the body, thereby raising blood
pressure. ACEIs also make blood vessels relax, which helps lower
blood pressure and allows more oxygen-rich blood to reach the
heart. Captorpirl (Capoten), Ramipril (Altace, and Enalipril
(Vasoted) are commonly used ACE inhibitor
[0006] Angiotensin receptor blockers (ARBs) (also referred to as
angiotensin II receptor agonists) such as losartan (Cozaar) and
valsartan (Diovan) reduce hypertension by displacing angiotensin II
from receptors on the surface of cells. ARBs are used as
alternatives to the less expensive ACEI inhibitors because they
have fewer side effects.
[0007] Beta-adrenergic blocking agents, or beta-blockers, are used
in the treatment of high blood pressure. Beta-blockers are also
used to relieve angina (chest pain) and in heart attack patients to
help prevent additional heart attacks. Beta-blockers are also used
to correct irregular heartbeat, prevent migraine headaches, and
treat tremors. Beta-blockers are competitive inhibitors and
interfere with the action of stimulating hormones on
beta-adrenergic receptors in the nervous system. Beta-blockers can
be subdivided into two distinct groups, known as beta-1 and beta-2.
Beta-1 blockers mainly affect the heart, and beta-2 blockers mainly
affect receptors in bronchial tissue. Most beta-blockers are
non-specific, i.e., they have both beta-1 and beta-2 effects.
[0008] Calcium-channel blockers are presently used to control
hypertension, chest pain and irregular heartbeats. Calcium-channel
blockers slow the rate at which calcium passes into the heart
muscle and into the vessel walls, thereby relaxing the vessels. The
relaxed vessels let blood flow more easily through them, thereby
lowering blood pressure.
[0009] Vasodilators are medicines that act directly on muscles in
blood vessel walls to make blood vessels widen (dilate).
Vasodilators are used to treat high blood pressure. By widening the
arteries, these drugs allow blood to flow through more easily,
reducing blood pressure. Controlling high blood pressure is
important because the condition puts a burden on the heart and the
arteries, which can lead to permanent damage over time. If
untreated, high blood pressure increases the risk of heart attacks,
heart failure, stroke, or kidney failure. Examples of vasodilators
include prostacyclin and its analogs.
[0010] It has been shown that vasodilators such as prostacyclin and
prostacyclin analogs as well as calcium channel blockers such as
diltiazem (Cardizem) or nifedipine (Procardia) decrease pulmonary
vascular resistance in some patients when administered
systemically. For example, it has been found that continuous
intravenous infusion of the vasodilator epoprostenol (Flolan), or
prostacyclin, improves exercise capacity, quality of life,
hemodynamics and long-term survival in patients with primary
pulmonary hypertension. Epoprostenol is a potent, short-acting
vasodilator and inhibitor of platelet aggregation by vascular
endothelium.
[0011] Continuous intravenous prostacyclin is far from ideal as a
treatment for pulmonary hypertension, however, because the agent is
available only in limited supply, it is very costly, and optimal
management requires that the intravenous therapy with prostacyclin
be started in specialized centers familiar with the technique,
equipment, and dose ranging. Moreover, continuous intravenous
administration of prostacyclin results in significant side effects
in patients, including jaw pain, nausea, and anorexia, plus the
inconvenience and potential danger from prolonged cathertization
and breakdowns in the delivery system. Further, because the agent
is delivered systemically with only a small percentage of the agent
actually absorbed by the pulmonary system, it must be administered
in high dosages.
[0012] Epoprostenol or the prostacyclin analog treprostinil sodium
may be administered via injection to treat pulmonary hypertension.
Delivery, however, is systemic and not localized to the lung. Thus,
the drug must be administered in high doses, with only a small
percentage actually reaching the lungs.
[0013] It has also been shown that calcium channel blockers may
alleviate pulmonary vasoconstriction and prolong life in about 20
percent of patients with PPH. Rich S, Kaufmann E, Levy P S. The
effect of high doses of calcium-channel blockers on survival in
primary pulmonary hypertension. N Engl J Med 1992;327:76-81, which
is incorporated herein by reference. In patients who show evidence
of an acute hemodynamic response, long-term treatment with calcium
channel blockers administered orally can produce a sustained
hemodynamic response and increase survival. However, oral
administration does not produce a localized effect on the lungs and
therefore high doses must be administered producing a systemic
effect, perhaps unnecessarily. Moreover, oral administration in
high dosages over an extended period of time may produce unwanted
side-effects in some patients.
[0014] There is, therefore, a need for an improved method of
treating hypertension.
III. SUMMARY OF THE INVENTION
[0015] The formulations provided herein are used for treating,
preventing and/or ameliorating one or more symptoms of a medical
condition, disorder or disease. As used herein, treatment means any
manner in which one or more of the symptoms of the condition,
disorder or disease are ameliorated or otherwise beneficially
altered. Treatment also encompasses any pharmaceutical or medicinal
use of the formulations herein. As used herein, amelioration of the
symptoms of a particular disorder by administration of a particular
formulation refers to any lessening, whether permanent or
temporary, lasting or transient that can be attributed to or
associated with administration of the formulation. As used herein,
a "therapeutic effective amount" means a sufficient amount of drug
substance to treat, prevent and/or ameliorate one or more symptoms
of a medical condition, disorder or disease. It also may include a
safe and tolerable amount of drug substance, as based on industry
and/or regulatory standards.
[0016] In one alternative embodiment, the formulations provided
herein are used for treating, preventing and/or ameliorating one or
more symptoms of a respiratory disorder in an individual. In
another alternative embodiment, the present invention provides a
formulation for the treatment, prophylaxis and/or amelioration of
one or more symptoms of pulmonary hypertension or other related
disorders.
[0017] In one preferred embodiment, the present invention provides
a formulation for the treatment of pulmonary hypertension in a
mammal (e.g., humans), wherein the formulation is suitable for
administration via inhalation. Preferably, the formulation of the
present invention is suitable for administration via nebulization.
The formulations of the present invention comprise a
therapeutically effective amount of a hypertension reducing agent.
Hypertension reducing agents suitable for use in the present
formulations include ACEI, ARBs, beta-blockers, calcium-channel
blockers or vasodilators, or any combination thereof. In one
alternative embodiment, the formulation of the present invention
comprises a combination of two or more hypertension reducing
agents.
[0018] The formulations of the present inventions may be provided
as a solution or as aqueous suspension, so long as the formulation
is suitable for inhalation. Preferably, the present formulation is
sterile. In another embodiment, the formulation of the present
invention is stable. Further, buffering agents may be added to
adjust the pH level of the formulation. Moreover, the formulations
of the present invention may contain an anti-microbial
preservative. Alternatively, the formulations herein may be
preservative-free. In one embodiment, the formulations of the
present invention are suitable for treating any diagnosis or level
of pulmonary hypertension.
[0019] The present invention also relates to a method for treating
pulmonary hypertension in a mammal, which includes animals or
humans. In one embodiment, the method of the present invention
comprises the step of administering the formulation of the present
invention to a mammal in need thereof. In one embodiment, the
method of the present invention further comprises the step of
administering another therapy or pharmaceutical agent useful to or
related to the treatment of pulmonary hypertension. Such therapies
and/or pharmaceutical agents including, for example, anticoagulants
and diuretics.
[0020] Additionally, the present invention is directed to a kit for
treating pulmonary hypertension in a mammal. In one embodiment, the
kit of the present invention comprises the formulation of the
present invention. In another embodiment, the formulation of the
kit is premeasured, premixed and prepackaged. In an alternative
embodiment, the kit further comprises instructions for
administering the formulation.
[0021] Other embodiments, features and advantages of the present
invention will be apparent to those of ordinary skill in the art in
view of the following detailed description of the invention.
IV. DETAILED DESCRIPTION OF THE INVENTION
[0022] As used herein, the terms "angiotensin converting enzyme
inhibitor" or "ACEI" means any pharmaceutical agent that inhibits
the enzymatic activity of angiotensin converting enzyme. ACEIs
suitable for use herein include, but are not limited to,
Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril,
Moexipril, Perindopril, Quinapril, Ramipril, Trandolapril, and
prodrugs, salts and isomers thereof.
[0023] As used herein, the terms "angiotensin receptor blocker" or
"ARB" or "angiotensin II receptor agonist" means any pharmaceutical
agent that selectively blocks the binding of angiotensin II to
receptors found in many tissues. ARBs suitable for use herein
include, but are not limited to, Candesartan, Eprosartan,
Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan, and
prodrugs, salts and isomers thereof.
[0024] As used herein, the terms "beta adrenergic blocking agent"
or "beta-blocker" means any pharmaceutical agent which blocks
beta-adrenergic substances in the body. For example, a beta-blocker
may block the beta-adrenergic substance adrenaline (epinephrine), a
key agent in the "sympathetic" portion of the autonomic
(involuntary) nervous system and activation of heart muscle.
Beta-blockers suitable for use herein include, but are not limited
to, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carteolol,
Carvedilol, Esmolol, Labetalol, Metoprolol, Nadolol, Oxprenolol,
Penbutolol, Pindolol, Propranolol, Sotalol and Timolol and
prodrugs, salts and isomers thereof.
[0025] As used herein, the term "calcium-channel blocker" means any
pharmaceutical agent which slows or blocks the entry of calcium
into the muscle cells of the heart and the arteries. Calcium
channel blockers suitable for use herein include, but are not
limited to, Amlodipine, Bepridil, Diltiazem, Felodipine,
Flunarizine, Isradipine, Nicardipine, Nifedipine, Nimodipine,
Verapamil and prodrugs, salts and isomers thereof.
[0026] As used herein, the term "vasodilator" means any
pharmaceutical agent that causes dilation of blood vessels.
Vasodilators suitable for use herein include, but are not limited
to, Adenine, Arginine, Doxazosin, Hydralazine Hydrochloride,
Isosorbide Initrate, Isosorbide Mononitrate Minoxidil, Nicotinates,
Nitroglycerin, Phentolamine, Prazosin, Terazosin and prodrugs,
salts and isomers thereof. Vasodilators for use herein also include
prostaglandins (Eicosanoids), including prostacyclin (Epoprostenol)
and prostacyclin analogs, including Iloprost and Treprostinil, and
prodrugs, salts and isomers thereof. Also included herein are
various prostaglandins, including, but not limited to PGE-1; PGE-2;
PGF-2.alpha.; PGA-1; PGB-1; PGD-2; PGE-M; PGF-M; PGH-2; PGI-2;
19-hydroxy-PGA-1; 19-hydroxy-PGB-1; PGA-2; PGB-2; 19-hydroxy-PGA-2;
19-hydroxy-PGB-2; PGB-3; PGF-1.alpha.; 15-methyl-PGF-2.alpha.;
16,16-dimethyl-.DELTA.sup.2-PGE-1 methyl ester;
15-deoxy-16-hydroxy-16-me- thyl-PGE-1 methyl ester;
16,16-dimethyl-PGE-2; 11-deoxy-15-methyl-PGE-1;
16-methyl-18,18,19,19-tetrahydrocarbacyclin;
(16RS)-15-deoxy-16-hydroxy-1- 6-methyl-PGE-1 methyl ester;
(+)-4,5-didehydro-16-phenoxy-.alpha.-tetranor- -PGE-2 methyl ester;
11-deoxy-11a,16,16-trimethyl-PGE-2; (+)-11a,
16a,b-dihydroxy-1,9-dioxo-1-(hydroxymethyl)-16-methyl-trans-proste
ne; 9-chloro-16,16-dimethyl-PGE-2; arboprostil; iloprost; CL
15.347: and semisynthetic or synthetic derivatives of these natural
prostaglandins, or any derivative or any prostaglandin analog
capable of acting as a vasodilator, and prodrugs, salts and isomers
thereof.
[0027] As used herein, the term "hypertension reducing
pharmaceutical agent" means any ACEI, ARB, beta-blocker,
calcium-channel blocker, vasodilator, or any other compound capable
of treating pulmonary hypertension through oral inhalation, such as
nebulization. It is understood that the above list of hypertension
reducing agents include those not currently approved for use in
clinical practice in the U.S., and those that will be approved in
the future.
[0028] As used herein, the term "pulmonary hypertension" means any
form, diagnosis, level or stage of pulmonary hypertension,
including, but not limited to, primary or secondary pulmonary
hypertension, pulmonary arterial hypertension, pulmonary venous
hypertension, pulmonary hypertension associated with disorders of
the respiratory system or hypothermia, pulmonary hypertension
resulting from chronic thrombotic or embolic disease, or pulmonary
hypertension resulting from disorders directly affecting the
pulmonary vasculature. The term "pulmonary hypertension" also
includes other respiratory disorders characterized by acute
pulmonary vasoconstriction such as those disorders resulting from
pneumonia, traumatic injury, aspiration or inhalation injury, fat
embolism in the lung, acidosis inflammation of the lung, adult
respiratory distress syndrome, acute pulmonary edema, acute
mountain sickness, post-cardiac surgery, acute pulmonary
hypertension, persistent pulmonary hypertension of the newborn,
perinatal aspiration syndrome, hyaline member disease, acute
pulmonary thromboembolism, heparin-protomine reactions, sepsis,
status asthamaticus or hypoxia (including iatrogenic hypoxia) and
other forms of reversible pulmonary vasoconstriction. Such
pulmonary disorders are also characterized by inflammation of the
lung including those associated with the migration into the lung of
non-resident cell types including the various leucocyte
subclasses.
[0029] In one alternative embodiment, formulations of the present
invention may include pharmaceutically acceptable derivates of a
hypertension reducing agent. As used herein, pharmaceutically
acceptable derivatives of such compounds include but are not
limited to salts, esters, enol ethers, enol esters, acids, bases,
solvates, hydrates or prodrugs thereof. Such derivatives may be
readily prepared by those of skill in this art using known methods
for such derivatization. Such derivatives produced may be
administered to animals or humans without substantial toxic
effects.
[0030] Suitable "pharmaceutically acceptable salts" include
conventionally used non-toxic salts, for example a salt with an
inorganic base such as an alkali metal salt (such as sodium salt
and potassium salt), an alkaline earth metal salt (such as calcium
salt and magnesium salt), an ammonium salt; or a salt with an
organic base, for example, an amine salt (such as methylamine salt,
dimethylamine salt, cyclohexylamine salt, benzylamine salt,
piperidine salt, ethylenediamine salt, ethanolamine salt,
diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)
ethane salt, monomethyl-monoethanolamine salt, procaine salt and
caffeine salt), a basic amino acid salt (such as arginine salt and
lysine salt), tetraalkyl ammonium salt and the like, or other salt
forms that enable the pulmonary hypertension reducing agent to
remain soluble in a liquid medium, or to be prepared and/or
effectively administered in a liquid medium, preferable an aqueous
medium. The above salts may be prepared by a conventional process,
for example from the corresponding acid and base or by salt
interchange.
[0031] For example, one alternative embodiment, the hypertension
reducing agent may be employed in a free base form or in a salt
form (e.g., as pharmaceutically acceptable salts). Examples of
suitable pharmaceutically acceptable salts include inorganic acid
addition salts such as hydrochloride, hydrobromide, sulfate,
phosphate, and nitrate; organic acid addition salts such as
acetate, propionate, succinate, lactate, glycolate, malate,
tartrate, citrate, maleate, fumarate, methansulfonate,
p-toluenesulfonate, and ascorbate; salts with acidic amino acid
such as aspartate and glutamate; alkali metal salts such as sodium
salt and potassium salt; alkaline earth metal salts such as
magnesium salt and calcium salt; ammonium salt; organic basic salts
such as trimethylamine salt, triethylamine salt, pyridine salt,
picoline salt, dicyclohexylamine salt, and
N,N'-dibenzylethylenediamine salt; and salts with basic amino acid
such as lysine salt and arginine salt. The salts may be in some
cases hydrates or ethanol solvates.
[0032] Examples of the ethers may include, but are not limited to,
alkyl ethers, for example, lower alkyl ethers such as methyl ether,
ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl
ether, t-butyl ether, pentyl ether and 1-cyclopropyl ethyl ether;
and medium or higher alkyl ethers such as octyl ether, diethylhexyl
ether, lauryl ether and cetyl ether; unsaturated ethers such as
oleyl ether and linolenyl ether; lower alkenyl ethers such as vinyl
ether, allyl ether; lower alkynyl ethers such as ethynyl ether and
propynyl ether; hydroxy (lower) alkyl ethers such as hydroxyethyl
ether and hydroxyisopropyl ether; lower alkoxy (lower) alkyl ethers
such as methoxymethyl ether and 1-methoxyethyl ether; optionally
substituted aryl ethers such as phenyl ether, tosyl ether,
t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl ether and
benzamidophenyl ether; and aryl (lower) alkyl ethers such as benzyl
ether, trityl ether and benzhydryl ether, or other ether forms that
enable the pulmonary hypertension reducing agent to remain soluble
in a liquid medium, or to be prepared and/or effectively
administered in a liquid medium, preferably an aqueous medium.
[0033] Examples of the esters may include, but are not limited to,
aliphatic esters, for example, lower alkyl esters such as methyl
ester, ethyl ester, propyl ester, isopropyl ester, butyl ester,
isobutyl ester, t-butyl ester, pentyl ester and 1-cyclopropylethyl
ester; lower alkenyl esters such as vinyl ester and allyl ester;
lower alkynyl esters such as ethynyl ester and propynyl ester;
hydroxy (lower) alkyl ester such as hydroxyethyl ester; lower
alkoxy (lower) alkyl esters such as methoxymethyl ester and
1-methoxyethyl ester; and optionally substituted aryl esters such
as, for example, phenyl ester, tosyl ester, t-butylphenyl ester,
salicyl ester, 3,4-di-methoxyphenyl ester and benzamidophenyl
ester; and aryl(lower)alkyl ester such as benzyl ester, trityl
ester and benzhydryl ester, or other ester forms that enable the
pulmonary hypertension reducing agent to remain soluble in a liquid
medium, or to be prepared and/or effectively administered in a
liquid medium, preferably an aqueous medium.
[0034] Also, the hypertension reducing agent for use in the
formulations and methods provided herein may contain chiral
centers. Such chiral centers may be of either the (R) or (S)
configuration, or may be a mixture thereof. Thus, the compounds for
use in the formulations provided herein may be enantiomerically
pure, or be stereoisomeric or diastereomeric mixtures. It is to be
understood that the chiral centers of the compounds provided herein
may undergo epimerization in vivo. Thus, one of skill in the art
will recognize that administration of a compound in its (R) form is
equivalent, for compounds that undergo epimerization in vivo, to
administration of the compound in its (S) form.
[0035] The present invention provides an inhalable formulation for
treating pulmonary hypertension, wherein the formulation comprises
a therapeutically effective amount of a hypertension-reducing agent
for the treatment of pulmonary hypertension, wherein the
hypertension-reducing agent is an ACEI, ARB, beta-blocker,
calcium-channel blocker or vasodilator, or any combination
thereof.
[0036] The present invention is premised, in part, on the known
systemic hypertension reducing effects of ACEIs, ARBs,
beta-blockers, calcium-channel blockers or vasodilators to treat
pulmonary hypertension. It is believed that the formulations of the
present invention represent an improvement over conventional means
for treating pulmonary hypertension, because the delivery of the
hypertension-reducing agent would be localized to the user's
pulmonary system, as opposed to systemic delivery. It is believed
that localized therapy may increase bioavailability as well as
increased efficacy and/or prolonged therapeutic effect. Due to
increased bioavailability, the present formulations may contain
lower dosages of the hypertension-reducing agents while effectively
treating pulmonary hypertension. Additionally, it is believed that
localized therapy may result in a decrease in side-effects due to
lower dosages and a decrease in patient discomfort and
inconvenience due to the less invasive or time-consuming systemic
delivery method.
[0037] In one embodiment of the present invention, a
therapeutically effective amount of a hypertension-reducing agent
may include from about 0.001 mg/ml to about 20 mg/ml of an ACEI,
ARB, beta-blocker, calcium-channel blocker, vasodilator, or any
combination thereof. In an alternative embodiment, a
therapeutically effective amount of a hypertension-reducing agent
may include from about 0.008 mg/ml to about 15.0 mg/ml. It may also
include the following intermediate ranges: about 0.001 mg/ml to
about 0.50 mg/ml; about 0.51 mg/ml to about 1.00 mg/ml; about 1.01
mg/ml to about 1.50 mg/ml; about 1.51 mg/ml to about 2.00 mg/ml;
about 2.51 mg/ml to about 3.00 mg/ml; about 3.01 mg/ml to about
3.50 mg/ml; about 3.51 mg/ml to about 4.00 mg/ml; about 4.01 mg/ml
to about 4.50 mg/ml; about 4.51 mg/ml to about 5.00 mg/ml; about
5.01 mg/ml to about 5.50 mg/ml; about 5.51 mg/ml to about 6.00
mg/ml; about 6.01 mg/ml to about 6.50 mg/ml; about 6.51 mg/ml to
about 7.00 mg/ml; about 7.01 mg/ml to about 7.50 mg/ml; about 7.51
mg/ml to about 8.00 mg/ml; about 8.01 mg/ml to about 8.50 mg/ml;
about 8.51 mg/ml to about 9.00 mg/ml; about 9.01 mg/ml to about
9.50 mg/ml; about 9.51 mg/ml to about 10.00 mg/ml; about 10.01
mg/ml to about 10.50 mg/ml; about 10.51 mg/ml to about 11.00 mg/ml;
about 11.01 mg/ml to about 11.50 mg/ml; about 11.50 mg/ml to about
12.00 mg/ml; about 12.00 mg/ml to about 12.51 mg/ml; about 12.51
mg/ml to about 13.00 mg/ml; about 13.01 mg/ml to about 13.50 mg/ml;
about 13.51 mg/ml to about 14.00 mg/ml; about 14.01 mg/ml to about
14.50 mg/ml; about 14.51 mg/ml to about 15.00 mg/ml.
[0038] In one alternative embodiment of the present invention, a
therapeutically effective amount of a hypertension-reducing agent
may include the following intermediate ranges; about 0.001 mg/ml to
about 1.0 mg/ml; about 0.005 mg/ml to about 1.0 mg/ml; about 0.01
mg/ml to about 1.0 mg/ml; about 0.05 mg/ml to about 0.1 mg/ml;
about 0.05 mg/ml to about 0.5 mg/ml.
[0039] In another alternative embodiment of the present invention,
a therapeutically effective amount of a hypertension-reducing agent
may include from about 0.001 to about 10 mg/ml of a
hypertension-reducing pharmaceutical agent, including the following
intermediate amounts: about 0.001 mg/ml to about 1.25 mg/ml; about
1.25 mg/ml to about 1.50 mg/ml; about 1.50 mg/ml to about 1.75
mg/ml; about 1.75 mg/ml to about 2.00 mg/ml; about 2.0 mg/ml to
about 2.25 mg/ml; about 2.25 mg/ml to about 2.50 mg/ml; about 2.50
mg/ml to about 2.75 mg/ml; about 2.75 mg/ml to about 3.00 mg/ml;
about 3.0 mg/ml to about 3.25 mg/ml; about 3.25 mg/ml to about 3.50
mg/ml; about 3.50 mg/ml to about 3.75 mg/ml; about 3.75 mg/ml to
about 4.00 mg/ml; about 4.0 mg/ml to about 4.25 mg/ml; about 4.25
mg/ml to about 4.50 mg/ml; about 4.50 mg/ml to about 4.75 mg/ml;
about 4.75 mg/ml to about 5.00 mg/ml; about 5.0 mg/ml to about 5.25
mg/ml; about 5.25 mg/ml to about 5.50 mg/ml; about 5.50 mg/ml to
about 5.75 mg/ml; about 5.75 mg/ml to about 6.00 mg/ml; about 6.0
mg/ml to about 6.25 mg/ml; about 6.25 mg/ml to about 6.50 mg/ml;
about 6.50 mg/ml to about 6.75 mg/ml; about 6.75 mg/ml to about
7.00 mg/ml; about 7.0 mg/ml to about 7.25 mg/ml; about 7.25 mg/ml
to about 7.50 mg/ml; about 7.50 mg/ml to about 7.75 mg/ml; about
7.75 mg/ml to about 8.00 mg/ml; about 8.0 mg/ml to about 8.25
mg/ml; about 8.25 mg/ml to about 8.50 mg/ml; about 8.50 mg/ml to
about 8.75 mg/ml; about 8.75 mg/ml to about 9.00 mg/ml; about 9.0
mg/ml to about 9.25 mg/ml; about 9.25 mg/ml to about 9.50 mg/ml;
about 9.50 mg/ml to about 9.75 mg/ml; about 9.75 mg/ml to about
10.00 mg/ml.
[0040] In one embodiment, the formulation of the present invention
is an inhalable solution comprising a therapeutically effective
amount of a pulmonary hypertension agent. Preferably, the inhalable
solution of the present invention is suitable for administration
via nebulization. The formulations of the present invention may
also be provided as an aqueous suspension. In an embodiment, the
formulation of the present invention comprises a therapeutically
effective amount of a pulmonary hypertension reducing agent in an
aqueous suspension.
[0041] The formulations provided herein may comprise any
pharmacologically suitable fluid which is physiologically
acceptable upon administration, including, but not limited to
water, aqueous saline solutions with one or more pharmaceutically
acceptable salt(s), alcohols, glycols or any mixture thereof. In an
embodiment, the formulation of the present invention comprises
water. Water for use in the present formulations should meet or
exceed the applicable regulatory requirements for use in inhaled
drugs. Specifications established by the United States
Pharmacopoeia for "Sterile Water for Injection" or "Sterile Water
for Inhalation" are examples of water suitable for use to prepare
formulations of the invention.
[0042] In one alternate embodiment, the formulation of the present
invention may comprise a preservative, suspending agent, wetting
agent, tonicity agent and/or diluent. The formulations provided
herein may comprise from about 0.01% to about 90%, or about 0.01%
to about 50%, or about 0.01% to about 25%, or about 0.01% to about
10%, or about 0.01% to about 5% of one or more pharmacologically
suitable suspending fluids which is physiologically acceptable upon
administration intranasally. Pharmacologically suitable fluids for
use herein include, but are not limited to, polar solvents,
including, but not limited to, compounds that contain hydroxyl
groups or other polar groups. Solvents include, but are not limited
to, water or alcohols, such as ethanol, isopropanol, and glycols
including propylene glycol, polyethylene glycol, polypropylene
glycol, glycol ether, glycerol and polyoxyethylene alcohols. Polar
solvents also include protic solvents, including, but not limited
to, water, aqueous saline solutions with one or more
pharmaceutically acceptable salt(s), alcohols, glycols or a mixture
there of. In one alternative embodiment, the water for use in the
present formulations should meet or exceed the applicable
regulatory requirements for use in inhaled drugs.
[0043] Sterility or adequate antimicrobial preservation may be
provided as part of the present formulations. Since certain
formulations of the present invention are intended to be
administered orally, it is preferred that they be free of
pathogenic organisms. A benefit of a sterile liquid suspension is
that it reduces the possibility of introducing contaminants into
the individual when the suspension formulation is administered
intranasally, thereby reducing the chance of an opportunistic
infection. Processes which may be considered for achieving
sterility may include any appropriate sterilization steps known in
the art. In one embodiment, the drug substance (e.g., fluticasone)
is produced under sterile conditions, the micronization is
performed in a sterile environment, and the mixing and packaging is
conducted under sterile conditions. In alternative embodiment, the
formulations of the present invention may be sterile filtered and
filled in vials, including unit dose vials providing sterile unit
dose formulations which are used in a nasal spray device for
example. Each unit dose vial may be sterile and is suitably
administered without contaminating other vials or the next dose. In
one alternative embodiment, one or more ingredients in the present
formulation may be sterilized by steam, gamma radiation or prepared
using or mixing sterile steroidal powder and other sterile
ingredients where appropriate. Also, the formulations may be
prepared and handled under sterile conditions, or may be sterilized
before or after packaging.
[0044] In addition to or in lieu of sterilization, the formulations
of the present invention may contain a pharmaceutically acceptable
preservative to minimize the possibility of microbial
contamination. Additionally, a pharmaceutically-acceptable
preservative may be used in the present formulations to increase
the stability of the formulations. It should be noted, however,
that any preservative must be chosen for inhalation safety, as the
treated tissues may be sensitive to irritants. Preservatives
suitable for use herein include, but are not limited to, those that
protect the solution from contamination with pathogenic particles,
including phenylethyl alcohol, benzalkonium chloride or benzoic
acid, or benzoates such as sodium benzoate and phenylethyl alcohol.
Preferably, the preservative for use in the present formulations is
benzalkonium chloride. In certain embodiments, the formulations
herein comprise from about 0.001% to about 10.0% w/w of
benzalkonium chloride, or from about 0.01% v/w phenylethyl alcohol.
Preserving agents may also be present in an amount from about
0.001% to about 1%, preferably about 0.002% to about 0.02%, more
preferably 0.02% w/w.
[0045] The formulations provided herein may also comprise from
about 0.001% to about 90%, or about 0.001% to about 50%, or about
0.001% to about 25%, or about 0.001% to about 10%, or about 0.001%
to about 1% of one or more emulsifying agent, wetting agent, or
suspending agent. Such agents for use herein include, but are not
limited to, polyoxyethylene sorbitan fatty esters or polysorbates,
including, but not limited to, polyethylene sorbitan monooleate
(Polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan
monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan
tristearate), polyoxyethylene (20) sorbitan mono-oleate,
polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20)
sorbitan monostearate; lecithins; alginic acid; sodium alginate;
potassium alginate; ammonium alginate; calcium alginate;
propane-1,2-diol alginate; agar; carrageenan; locust bean gum; guar
gum; tragacanth; acacia; xanthan gum; karaya gum; pectin; amidated
pectin; ammonium phosphatides; microcrystalline cellulose;
methylcellulose; hydroxypropylcellulose;
hydroxypropylmethylcellulose; ethylmethylcellulose;
carboxymethylcellulose; sodium, potassium and calcium salts of
fatty acids; mono-and di-glycerides of fatty acids; acetic acid
esters of mono- and di-glycerides of fatty acids; lactic acid
esters of mono-and di-glycerides of fatty acids; citric acid esters
of mono-and di-glycerides of fatty acids; tartaric acid esters of
mono-and di-glycerides of fatty acids; mono-and diacetyltartaric
acid esters of mono-and di-glycerides of fatty acids; mixed acetic
and tartaric acid esters of mono-and di-glycerides of fatty acids;
sucrose esters of fatty acids; sucroglycerides; polyglycerol esters
of fatty acids; polyglycerol esters of polycondensed fatty acids of
castor oil; propane-1,2-diol esters of fatty acids; sodium
stearoyl-21actylate; calcium stearoyl-2-lactylate; stearoyl
tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan
monolaurate; sorbitan monooleate; sorbitan monopalmitate; extract
of quillaia; polyglycerol esters of dimerised fatty acids of soya
bean oil; oxidatively polymerised soya bean oil; and pectin
extract.
[0046] The present formulations may further comprise from about
0.001% to about 90%, or about 0.001% to about 50%, or about 0.001%
to about 25%, or about 0.001% to about 10%, or about 0.001% to
about 1% of one or more excipients and additives which are
pharmacologically suitable. Excipients and additives generally have
no pharmacological activity, or at least no undesirable
pharmacological activity. The concentration of these may vary with
the selected agent, although the presence or absence of these
agents, or their concentration is not an essential feature of the
invention. The excipients and additives may include, but are not
limited to, surfactants, moisturizers, stabilizers, complexing
agents, antioxidants, or other additives known in the art.
Complexing agents include, but are not limited to,
ethylenediaminetetraacetic acid (EDTA) or a salt thereof, such as
the disodium salt, citric acid, nitrilotriacetic acid and the salts
thereof. In another embodiment, particularly in the suspension
formulations provided herein, the complexing agent is sodium
edetate. In one embodiment, the compositions contain sodium edetate
at a concentration of about 0.05 mg/ml to about 0.5 mg/ml, or about
0.1 mg/ml to about 0.2 mg/ml. Also, for example, the formulations
of the present invention may comprise from about 0.001% to about 5%
by weight of a humectant to inhibit drying of the mucous membrane
and to prevent irritation. Any of a variety of
pharmaceutically-acceptable humectants can be employed, including
sorbitol, propylene glycol, polyethylene glycol, glycerol or
mixtures thereof, for example.
[0047] The formulations provided herein also may comprise about
0.001% to about 90%, or about 0.001% to about 50%, or about 0.001%
to about 25%, or about 0.001% to about 10%, or about 0.001% to
about 10% of one or more solvents or co-solvents to increase the
solubility of any of the components of the present formulation.
Solvents or co-solvents for use herein include, but are not limited
to, hydroxylated solvents or other pharmaceutically-acceptable
polar solvents, such as alcohols including isopropyl alcohol,
glycols such as propylene glycol, polyethylene glycol,
polypropylene glycol, glycol ether, glycerol, and polyoxyethylene
alcohols. In another embodiment, the formulations of the present
invention may comprise one or more conventional diluents known in
the art. The preferred diluent is purified water.
[0048] Tonicity agents (or osmotic adjusting agents) may be added
to adjust the isotonicity of the present formulations. Such agents
may include, but are not limited to sodium chloride, potassium
chloride, zinc chloride, calcium chloride or mixtures thereof.
Other osmotic adjusting agents may also include, but are not
limited to, mannitol, glycerol, and dextrose or mixtures thereof.
In an alternative embodiment, the present formulation may comprise
about 0.01% to about 10% w/w, or 1% to about 6% w/w. In one
alternative embodiment, the formulations of the present invention
are isotonic.
[0049] In certain embodiments herein, the formulations of the
present invention have a pH of about 2.0 to about 8.0. Preferably,
the pH of the present formulations is from about 3.0 to about 6.0,
preferably the pH is form about 3.0 to about 4.0. Optionally, the
formulations of the present invention contain a pH buffer to
maintain the formulation to a desired pH. Buffers suitable for use
herein include, but are not limited to, citric acid/phosphate,
sodium hydroxide, sodium citrate, acetate, barbital, borate,
Britton-Robinson, cacodylate, citrate, collidine, formate, maleate,
Mclivaine, phosphate, Prideaux-Ward, succinate,
citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES
(2-(N-morpholino)ethanesulfonic acid), BIS-TRIS
(bis(2-hydroxyethyl)imino- tris(hydroxymethyl)methane), ADA
(N-(2-acetamido)-2-iminodiacetic acid), ACES
(N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES
(piperazine-N,N'-bis(2-ethanesulfonic acid)), MOPSO
(3-(N-morpholino)-2hydroxypropanesulfonic acid), BIS-TRIS PROPANE
(1,3-bis(tris(hydroxy-methyl)methylamino)propane), BES
(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS
(3-(N-morpholino)propanesulfonic acid), TES
(N-tris(hydroxymethyl)methyl-- 2-aminoethanesulfonic.acid), HEPES
(N-(2hydroxyethyl)piperazine-N'-(2-etha- nesulfonicacid), DIPSO
(3-(N,N-bis(2hydroxyethyl)amino)-2-hydroxypropanesu- lfonicacid),
MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO
(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic
acid), TRIZMAO (tris(hydroxymethylaminomethane), HEPPSO
(N-(2-hydroxyethyl)piper- azine-N'-(2-hydroxypropanesulfonic acid),
POPSO (piperazine-N,N'-bis(2-hyd- roxypropanesulfonic acid)), TEA
(triethanolamine), EPPS(N-(2-hydroxyethyl)-
-piperazine-N'-(3-propanesulfonic acid), TRICINE
(N-tris(hydroxymethyl)met- hylglycine), GLY-GLY (glycylglycine),
BICINE (N,N-bis(2hydroxyethyl)glycin- e),
HEPBS(N-(2-hydroxyethyl)piperazine-N'-(4butanesulfonic acid)),
TAPS(N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), AMPD
(2-amino-2-methyl-1,3-propanediol), and/or any other buffers known
to those of skill in the art.
[0050] In one alternative embodiment, the formulations of the
present invention are stable. As used herein, the stability of
formulations provided herein refers to the length of time at a
given temperature that greater than 80%, 85%, 90% or 95% of the
initial amount of drug substance, e.g., fluticasone, is present in
the formulation. For example, the formulations provided herein may
be stored between about 15.degree. C. and about 30.degree. C., and
remain stable for at least 1, 2, 12, 18, 24 or 36 months. Also, the
formulations may be suitable for administration to a subject in
need thereof after storage for more than 1, 2, 12, 18, 24 or 36
months at 25.degree.. Also, in another alternative embodiment,
using Arrhenius Kinetics, more than 80%, or more than 85%, or more
than 90%, or more than 95% of the initial amount of drug substance
(e.g., fluticasone) remains after storage of the formulations for
more than 1, 2, 12, 18, 24 or 36 months between about 15.degree. C.
and about 30.degree. C.
[0051] As used herein, the statement that a composition is stable
during "long term storage" means that the composition is suitable
for administration to a subject in need thereof when it has an
estimated shelf-life of greater than 1, 2 or 3 months usage time at
25.degree. C. and greater than or equal to 1, 2 or 3 years storage
time at 5.degree. C. In certain embodiments herein, using Arrhenius
kinetics, >80% or >85% or >90% or >95% estimated
bronchodilating agent remains after such storage.
[0052] The formulations of the present invention may be
administered in a variety of ways, preferably by inhalation. For
example, the present formulations may be administered to an
individual in need thereof by way of an inhaler, e.g., metered dose
inhaler or a dry powder inhaler, an insufflator, a nebulizer or any
other conventionally known method of administering inhalable
medicaments. Preferably, the formulation of the present invention
is administered by nebulization. In one alternative embodiment, the
formulations of the present invention may be administered by way of
a pressurized aerosol comprising, separately, a
hypertension-reducing agent, or salt or an ester thereof with at
least a suitable propellant or with a surfactant or a mixture of
surfactants. Any conventionally known propellant may be used.
[0053] In certain embodiments, the compositions are administered
via nebulization. Administration of a nebulized aerosol is
preferred over the use of dry powders for inhalation in certain
subject populations, including pediatric and geriatric groups.
[0054] Also provided herein are combinations containing a
composition provided herein and a nebulizer. The combinations can
be packaged as kits, which optionally contain other components,
including instructions for use of the nebulizer. Any nebulizer is
contemplated for use in the kits and methods provided herein. In
particular, the nebulizers for use herein nebulize liquid
formulations, including the compositions provided herein,
containing no propellant. The nebulizer may produce the nebulized
mist by any method known to those of skill in the art, including,
but not limited to, compressed air, ultrasonic waves, or vibration.
The nebulizer may further have an internal baffle. The internal
baffle, together with the housing of the nebulizer, selectively
removes large droplets from the mist by impaction and allows the
droplets to return to the reservoir. The fine aerosol droplets thus
produced are entrained into the lung by the inhaling
air/oxygen.
[0055] As used herein, a nebulized solution refers to a solution
that is dispersed in air to form an aerosol. Thus, a nebulized
solution is a particular form of an aerosol. As used herein, a
nebulizer is an instrument that is capable of generating very fine
liquid droplet for inhalation into the lung. Within this
instrument, the nebulizing liquid or solution is atomized into a
mist of droplets with a broad size distribution by methods known to
those of skill in the art, including, but not limited to,
compressed air, ultrasonic waves, or a vibrating orifice.
Nebulizers may futher contain, e.g., a baffle which, along with the
housing of the instrument, selectively removes large droplets from
the mist by impaction. Thus, the mist inhaled into the lung
contains fine aerosol droplets.
[0056] In one alternative embodiment, the compositions provided
herein are intended for administration to subject in need of such
treatment via nebulization. Nebulizers that nebulize liquid
formulations containing no propellant are suitable for use with the
compositions provided herein. Nebulizers are available from, e.g.,
Pari GmbH (Starnberg, Germany), DeVilbiss Healthcare (Heston,
Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied Health
Care, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope,
Medisana, Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd.
(Colchester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK),
Bard Ltd. (Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem
Nuiva (Brescia, Italy), Henleys Medical Supplies (London, UK),
Intersurgical (Berkshire, UK), Lifecare Hospital Supplies (Leies,
UK), Medic-Aid Ltd. (West Sussex, UK), Medix Ltd. (Essex, UK),
Sinclair Medical Ltd. (Surrey, UK), and many others.
[0057] Nebulizers for use herein include, but are not limited to,
jet nebulizers (optionally sold with compressors), ultrasonic
nebulizers, and others. Exemplary jet nebulizers for use herein
include Pari LC plus/ProNeb, Pari LC plus/ProNeb Turbo, Pari LC
plus/Dura Neb 1000 & 2000, Pari LC plus/Walkhaler, Pari LC
plus/Pari Master, Pari LC star, Omron CompAir XL Portable Nebulizer
System (NE-C18 and JetAir Disposable nebulizer), Omron CompAir
Elite Compressor Nebulizer System (NE-C21 and Elite Air Reusable
Nebilizer), Pari LC Plus or Pari LC Star nebulizer with Proneb
Ultra compressor, Pulmo-aide, Pulmo-aide LT, Pulmo-aide traveler,
Invacare Passport, Inspiration Healthdyne 626, Pulmo-Neb Traverier,
DeVilbiss 646, Whisper Jet, Acorn 11, Misty-Neb, Allied aerosol,
Schuco Home Care, Lexan Plasic Pocet Neb, SideStream Hand Held Neb,
Mobil Mist, Up-Draft, Up-Draft 11, T Up-Draft, ISO-NEB, AVA-NEB,
Micro Mist, and PulmoMate. Exemplary ultrasonic nebulizers for use
herein include MicroAir, UltraAir, Siemens Ultra Nebulizer 145,
CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic
Neb, 5004 Desk Ultrasonic Nebulizer, Mystique Ultrasonic,
Luminscope's Ultrasonic Nebulizer, Medisana Ultrasonic Nebulizer,
Microstat Ultrasonic Nebulizer, and MABISMist Hand Held Ultrasonic
Nebulizer. Other nebulizers for use herein include 5000
Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston
Neb, Lumineb I Piston Nebulizer 5500, Aeroneb' Portable Nebulizer
System, Aerodose" Inhaler, and AeroEclipse Breath Actuated
Nebulizer.
[0058] Pharmaceutical compositions containing a pulmonary
hypertension reducing agent for administration via nebulization are
provided. The compositions may be sterile filtered and filled in
vials, including unit dose vials providing sterile unit dose
formulations which are used in a nebulizer and suitably nebulized.
Each unit dose vial may be sterile and suitably nebulized without
contaminating other vials or the next dose.
[0059] The unit dose vials may be formed in a form-fill-seal
machine or by any other suitable method known to those of skill in
the art. The vials may be made of plastic materials that are
suitably used in these processes. For example, plastic materials
for preparing the unit dose vials include, but are not limited to,
low density polyethylene, high density polyethylene, polypropylene
and polyesters. In one embodiment, the plastic material is low
density polyethylene.
[0060] In another alternative embodiment, the system of the present
invention comprises one or more dispensing containers prefilled
with about 0.1 to about 5.0 ml, or about 0.5 ml to about 5.0 ml, or
about 1.0 ml to about 5.0 ml; or about 0.1 ml to about 3.0 ml, or
about 0.1 ml to about 2.0 ml, or about 0.5 ml to about 2.0 ml, or
about 1 ml, or about 1.5 ml, or about 2.0 ml, or about 2.5 ml, or
about 3.0 ml, or about 3.5 ml, or about 4.0 ml, or about 4.5 ml, or
about 5.0 ml, or about 0.1 ml to about 2.25 ml, or about 1.0 ml to
about 2.0 ml, or about 2.0 ml to about 2.4 ml of a premixed,
premeasured, aqueous inhalation solution comprising a single unit
dose of a therapeutically effective amount of one or more pulmonary
hypertension reducing agents.
[0061] Drugs administered by nebulization could play a major role
in the treatment of pulmonary hypertension. However, a possible
drawback of nebulization therapy is the number of times it must be
performed each day, and the amount of time each treatment takes.
For example, an individual may be required to receive 4 doses of
inhalation solution per day by nebulization. In some instances,
each nebulizer treatment takes about 15 minutes, or more to deliver
a 2.5 ml fill volume of a bronchodilator, though the amount of time
may vary depending on the model of the nebulizer used. The time
requirements for nebulization therapy can be burdensome, and cause
individuals to skip required dosages during the day. The impact of
not following the prescribed dosage regimen could compromise the
individual's condition.
[0062] In one alternative embodiment, the volume of the one or more
pulmonary hypertension reducing agents inhalation solutions of the
present invention is about 0.1 ml to about 2.25 ml, or about 0.1 ml
to about 2 ml, or about 1 ml to about 2 ml, or about 1.5 ml to
about 2 ml, preferably about 1 ml, about 1.5 ml, about 2.0 ml, or
about 2.25 ml while no clinical trials or other experiments were
carried out on these fill volumes, it is believed that such volumes
are more beneficial over conventional nebulizer fill volumes
solutions (e.g. 2.5 ml or 3.0 ml fill volume) because they will
enable the individual to receive more medication (e.g., one or more
pulmonary hypertension reducing agents) in less time during each
nebulization treatment. Also, it is believed that the fill volumes
of the present invention will minimize common handling
complications with nebulizer therapy, and it may extend the life of
the nebulizer.
[0063] In one alternative embodiment, the above fill volumes of the
present invention may reduce the time of each nebulization
treatment by at least 20%, 30%, 40%, 50%, 60%, 70% or 80% or more
over conventional nebulizer treatments (e.g. 2.5 ml or 3 ml fill
volume). In another alternative embodiment, the fill volumes of the
present invention may reduce each nebulization treatment to about
12, 10, 9, 8, 6, 5, 4, 3 minutes, or less over conventional
nebulizer treatments (e.g. 2.5 ml or 3.0 ml fill volume). Reducing
the amount of time to complete the treatment means individuals will
be more likely to comply with the prescribed dosing regimen and
achieve optimal benefit from the medication prescribed.
[0064] Another possible drawback of conventional nebulizer
treatments is the loss of medication during administration.
Conventional nebulizer solutions comprise about 2.5 ml fill volume
of inhalation solution, or more. For example, when nebulizing an
inhalation solution comprising 2.5 ml or more, about 0.7 ml of the
solution remains in the nebulizer system after treatment, though
the amount may vary depending on the model of the nebulizer used.
In these instances, the individual is not receiving the prescribed
dosage or optimum dosage of inhalation medication. For example, in
one day, due to the residual medication remaining in the nebulizer
system after each treatment, an individual fails to receive
approximately 2.1 ml, or more of the prescribed daily amount of
medication.
[0065] It is believed that the fill volumes of the one or more
pulmonary hypertension reducing agents inhalation solutions of the
present invention will result in lesser amounts of solution
remaining in the nebulizer system after treatment, when compared to
conventional inhalation solutions (e.g. 2.5 ml or 3 ml fill
volume). Less solution remaining in the nebulizer system means more
medication (e.g., one or more pulmonary hypertension reducing
agents) administered to the individual during each treatment. In
one alternative embodiment, the amount of solution remaining in the
nebulizer system after each treatment may be less than 0.50 ml, or
less than 0.30 ml, or less than 0.20 ml or less than 0.10 ml or
less than 0.05 ml of the one or more pulmonary hypertension
reducing agents inhalation solutions of the present invention, e.g.
an inhalation solution comprising 2.5 mg albuterol and 0.5 mg
ipratropium bromide.
[0066] Important factors to effective nebulizer treatment is deep
inspiration to ensure deep penetration of the medication into the
lungs, and steady breath-holding to ensure good retention of the
medication in the lungs. It is believed that administering about
0.1 ml to about 2.0 ml fill volume of an inhalation solution into a
nebulizer, for example, will optimize the therapeutic effect of the
individual's deep inspiration efforts during treatment, and will
optimize the therapeutic effect of the individual's breath-holding
efforts as well. This is due to the shorter treatment time and
increased concentration of the one or more pulmonary hypertension
reducing agents in the solution.
[0067] Accordingly, in one alternative embodiment, the present
invention is a method of facilitating patient care, reducing
medication error, reducing nebulizer treatment time, improving the
efficiency and efficacy of nebulizing therapy or enhancing
therapeutic compliance of an individual suffering from pulmonary
hypertension. In one alternative embodiment, such method may
comprise the step of placing about 0.1 ml to about 2.0 ml of the
inhalation solutions of the present invention into a chamber of a
nebulizer. The nebulizer having a mouthpiece or facemask associated
with the chamber of the nebulizer. The mouthpiece or facemask is
positioned in close proximity to the individual's mouth or face.
The inhalation solution may be passed in a mist form from the
nebulizer chamber through the mouthpiece or facemask to the
individual while the individual breathes into the mouthpiece or
facemask. The individual continues breathing into the mouthpiece or
facemask until the nebulization treatment is finished. This may
take about 12, 11, 10, 9, 8, 7, 6, 5, 4 or 3 minutes. In an
alternative embodiment, the nebulization treatment is finished when
at least substantially all the mist is removed from the nebulizer
chamber. This may take about 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3
minutes. In one alternative embodiment of the present invention,
the dose of the inhalation solution in each of the one or more
containers may be administered 1, 2, 3, 4, 5, 6, 7, or 8 times per
day by nebulization.
[0068] In another alternative embodiment, the system/kit of the
present invention may further comprise a label which indicates that
the inhalation solution can be used to relieve bronchospasm
associated with chronic obstructive pulmonary disease. In one
alternative embodiment, the label may comprise indicia comprising
efficacy, dosage, administration, contraindication and adverse
reaction data pertaining to the inhalation solution in each of the
one or more containers. The contraindication data may comprise data
indicating that the inhalation solution in each of the one or more
containers is contraindicated for humans with hypersensitivity to
any of the ingredients contained in the inhalation solution.
[0069] The dosage and administration data may also comprise data
indicating that the recommended dose of the inhalation solution in
each of the one or more containers may be administered 1, 2, 3, 4,
5, 6, 7 or 8 times per day by nebulization.
[0070] In an alternative embodiment, the present invention also
comprises a device for use in the relief of symptoms associated
with pulmonary hypertension, including bronchospasm. Such device
may take the form of a label, written instructions or any other
form incorporating indicia thereon. The device may comprise indicia
which indicates that a patient suffering from symptoms associated
with pulmonary hypertension can be treated with at least one
prepackaged, sterile, premixed, premeasured and/or BAC-free
inhalation solution comprising a unit dose of a therapeutically
effective amount of one or more pulmonary hypertension reducing
agents in a single vial. The inhalation solution being suitable for
nebulization in a nebulizer. The device may also comprise indicia
which provides instructions for utilizing the inhalation solution
to treat said symptoms in patients.
[0071] The inhalation formulations of the present invention may be
used to treat "pulmonary hypertension" (as that term is defined
herein) including but not limited to primary pulmonary
hypertension, secondary hypertension, and classes I-IV as shown in
Table 1, among others. For example, the formulations of the present
invention may be used to treat or ameliorate one or more of the
following symptoms of pulmonary hypertension associated with
disorders of the respiratory system and/or hypoxemia: chronic
obstructive pulmonary disease, interstitial lung disease,
sleep-disordered breathing; alveolar hypoventilation disorders;
chronic exposure to high altitudes; neonatal lung disease; and
alveolar-capillary dysplasia. The information in Table I is
presented for illustrative purposes only. It is not intended to
limit the scope of the invention.
1TABLE 1 Class Description I Patients with pulmonary hypertension
but without resulting limitation of physical activity. Ordinary
physical activity does not cause undue dyspnea or fatigue, chest
pain or near syncope. II Patients with pulmonary hypertension
resulting in slight limitation of physical activity. These patients
are comfortable at rest, but ordinary physical activity causes
undue dyspnea or fatigue, chest pain or near syncope. III Patients
with pulmonary hypertension resulting in marked limitation of
physical activity. These patients are comfortable at rest, but less
than ordinary physical activity causes undue dyspnea or fatigue,
chest pain or near syncope. IV Patients with pulmonary hypertension
resulting in inability to perform any physical activity without
symptoms. These patients manifest signs of right heart failure.
Dyspnea and/or fatigue may be present at rest, and discomfort is
increased by any physical activity.
[0072] The formulations of the present invention may comprise one
or more pulmonary hypertension reducing agents. In one embodiment,
the formulation of the present invention comprises one of an ACEI,
ARB, beta-blocker, calcium-channel blocker or vasodilator, or any
combination thereof. Such combination may explicitly exclude any
one of the pulmonary reducing agents herein. In an alternative
embodiment, the formulation of the present invention comprises an
ACEI in combination with an ARB, beta-blocker, calcium-channel
blocker or vasodilator. In another embodiment, the formulation of
the present invention comprises an ARB in combination with a
beta-blocker, calcium-channel blocker or vasodilator. In yet
another embodiment, the formulation of the present invention
comprises a beta-blocker in combination with a calcium-channel
blocker or vasodilator. In still another embodiment, the
formulation of the present invention comprises a calcium-channel
blocker and a vasodilator. In an alternative embodiment herein, the
present invention comprises any combination of at least three
ACEIs, ARBs, beta-blockers, calcium-channel blockers or
vasodilators.
[0073] Additionally, the formulations of the present invention may
be administered together with one or more other drugs or therapies.
For example, the present formulations may be administered with an
anticoagulant such as warfarin (Coumadin), which is recommended to
prevent thrombosis and has been shown to prolong life in patients
with primary pulmonary hypertension. Patients with pulmonary
hypertension are prone to thromboembolism because of sluggish
pulmonary blood flow, dilated right heart chambers, venous
insufficiency and relative physical inactivity.
[0074] Additionally, the formulations of the present invention may
be administered in conjunction or in combination with inotropic
agents such as digoxin (Lanoxin), which has been shown to produce
favorable acute hemodynamic effects in patients with right
ventricular failure and primary pulmonary hypertension. Short-term
parenterally administered inotropic drugs may also be administered
with the formulations of the present invention. Moreover, because
hypoxia is a potent pulmonary vasoconstrictor, the formulations of
the present invention may be administered in combination with
low-flow supplemental oxygen therapy, which is known to prolong
survival in hypoxemic patients.
[0075] Additionally, the formulations of the present invention may
be administered in combination with a low-salt diet and/or
diuretics, which are useful in reducing volume overload in patients
with pulmonary hypertension and right ventricular failure. However,
excessive diuresis and further reduction of cardiac output should
be avoided.
[0076] The present invention is also directed to a method of
treating pulmonary hypertension in a mammal including animals and
humans. In one embodiment, a therapeutically effective amount of a
hypertension-reducing pharmaceutical agent is administered to a
mammal in need thereof. In an alternative embodiment, the
formulation of the present invention is premeasured, premixed and
prepackaged. In one embodiment, the formulation of the method of
the present invention comprises from about 0.01 mg/ml to about 20
mg/ml of at least one of an ACEI, ARB, beta-blocker,
calcium-channel blocker or vasodilator, or any combination thereof.
In an alternative embodiment, the formulation is sterile and/or
stable. In another embodiment, the formulation is
preservative-free.
[0077] In another alternative embodiment, the method of the present
invention comprises the step of administering to a mammal in need
thereof an inhalation solution comprising a therapeutically
effective amount of a hypertension-reducing pharmaceutical agent,
wherein the inhalation solution is administered via nebulizer, such
nebulizer including, but not limited to, a jet nebulizer,
ultrasonic nebulizer and breath-actuated nebulizer. Preferably, the
nebulizer is a jet nebulizer connected to an air compressor with
adequate air flow. The nebulizer being equipped with a mouthpiece
or suitable face mask.
[0078] The present invention is also directed to a system and/or
kit for treating pulmonary hypertension in a mammal. In an
embodiment, the kit of the present invention comprises a
formulation comprising a therapeutically effective amount of a
pulmonary hypertension reducing agent. In an alternative
embodiment, the formulation is in premeasured, premixed and/or
prepackaged. Preferably, the inhalation solution is sterile.
[0079] The system and/or kit of the present invention may also
include instructions designed to facilitate user compliance.
Instructions, as used herein, refers to any label, insert, etc.,
and may be positioned on one or more surfaces of the packaging
material, or the instructions may be provided on a separate sheet,
or any combination thereof. For example, in an embodiment, a system
and/or kit of the present invention comprises instructions for
administering the formulations of the present invention. In one
embodiment, the instructions indicate that the formulation of the
present invention is suitable for the treatment of pulmonary
hypertension. Such instructions may also include instructions on
dosage, as well as instructions for administration via
nebulizer.
[0080] Non-adherence to pulmonary hypertension medication therapy
and medication error could be considerable problems. These problems
can be significantly reduced by providing pulmonary hypertension
patients a prepackaged, premixed, premeasured amount an inhalable
formulation comprising one or more pulmonary hypertension reducing
agents. Providing these compounds in this fashion makes pulmonary
hypertension therapy simple because it increases convenience and
eliminates confusion in preparing appropriate dosages.
[0081] In one alternative embodiment, the present invention may
overcome the aforementioned problems by providing therapeutically
effective amounts one or more hypertension reducing agents in
prepackaged, premixed, premeasured and/or unit dose amounts. In one
alternative embodiment, the present invention comprises one or more
prefilled containers. The one or more containers each comprising a
single unit dose of an aqueous solution comprising a
therapeutically effective amount of one or more pulmonary
hypertension reducing agents. Providing the inhalation solution in
such a manner eliminates the need to dilute or mix such medications
to obtain proper dosages for treatment. Also, no special pharmacy
compounding is required, thereby reducing the chance of medication
errors. Further, there is a lower risk of cross-contamination, and
less waste of medication when providing an inhalation solution in a
premixed, ready to use form.
[0082] Other features of the present invention include improved
user compliance and quality of life as compared to conventional
treatments for pulmonary hypertension. While the level of
compliance of any pulmonary hypertension treatment depends in part
on the motivation of the user and the skill of the individual
dispensing the treatment, compliance nevertheless may be improved
by controlling factors such as the ease with which the treatment
may be administered, as well as the desirability of receiving the
treatment.
[0083] The present invention provides a convenient, fast and
reliable treatment for pulmonary hypertension and clearly
represents an improvement over traditional pulmonary hypertension
treatments. Also, the present invention is designed to facilitate
user compliance by providing one or more dispensing containers
comprising a premixed, premeasured inhalation solution comprising a
single unit dose of a therapeutically effective amount of one or
more pulmonary hypertension reducing agents for the treatment of
pulmonary hypertension. Such containers may be utilized in a method
of treating pulmonary hypertension or the containers may be
incorporated in a system and/or kit for treating the same.
[0084] In another embodiment, the present invention provides a
system and/or kit for organizing and storing one or more prefilled
dispensing containers, each container comprising a premixed,
premeasured inhalation solution. The inhalation solution comprising
a single unit dose of a therapeutically effective amount one or
more pulmonary hypertension reducing agents. Such system and/or kit
may provide such containers in prepackaged form. The one or more
containers may be comprised of plastic including, but not limited
to, a semi-permeable plastic such as LDPE. The container may also
comprise a Twist-Flex.TM. top, such top comprising an easy-to-grip
tab-like handle such that the container may be opened, for example,
by twisting off the tab by hand. The Twist-Flex.TM. top is
advantageous in that it allows for easy dispensing of the solution,
prevents spillage and eliminates the need to open the container by
cutting or tearing off the top, or the like, thereby reducing
cross-contamination. In one alternative embodiment, the design of
the container substantially conforms to those designs illustrated
in U.S. Pat. Des. Nos. 317,715; 296,869; 289,609; or 275,732, which
are incorporated herein by reference. One or more of the
semi-permeable single unit dose containers may be prepackaged in an
aluminum foil pouch, such that the foil provides a protective
barrier against environmental contaminants and light. Such a
barrier improves the shelf-life and stability of the inhalation
solution.
[0085] In another alternative embodiment, the present invention
comprises a prepackaged inhalation system and/or kit suitable for
patients suffering from pulmonary hypertension. Such prepackaged
system and/or kit comprising: (a) one or more single unit dosages
of a therapeutically effective amount of one or more pulmonary
hypertension reducing agents; (b) administration instructions for
the use of said unit dose as a treatment for pulmonary
hypertension; and (c) a dispensing container prefilled with the one
or more unit doses of one or more pulmonary hypertension reducing
agents.
[0086] The formulations of the present invention may be
manufactured in any conventional manner by thoroughly mixing the
ingredients described herein at ambient or elevated temperatures in
order to achieve solubility of ingredients where appropriate.
[0087] Articles of manufacture, containing packaging material, a
formulation provided herein, may be useful for treatment,
prevention or amelioration of one or more symptoms of diseases or
disorders associated with pulmonary hypertension. such articles of
manufacture may also comprise a label that indicates that the
composition is used for treatment, prevention or amelioration of
one or more symptoms of diseases or disorders associated with
pulmonary hypertension.
[0088] In one alternative embodiments, the articles of manufacture
provided herein contain packaging materials. Packaging materials
for use in packaging pharmaceutical products are well known to
those of skill in the art. Examples of pharmaceutical packaging
materials include, but are not limited to, blister packs, bottles,
tubes, inhalers, pumps, bags, vials, containers, syringes, bottles,
and any packaging material suitable for a selected formulation and
intended mode of administration and treatment.
V. EXAMPLES
[0089] Examples 1-4 herein are prophetic examples provided to
illustrate, but not to limit, the formulations and methods of the
present invention. They are presented with the understanding that
changes can be and may need to be made to a specific composition in
order to obtain or optimize the formulation. Such modifications to
the following prophetic examples, if needed, are normal and
understandable to those of ordinary skill in the art, and shall not
be used to limit the invention.
[0090] It is believed that prophetic examples 1-4 would be suitable
for administration via nebulization to an individual suffering from
pulmonary hypertension. The formulations may be sterile. The
objective of these formulations is to provide localized delivery of
a pulmonary hypertension reducing agent to a mammal (e.g. humans)
in need thereof.
Example 1
[0091]
2 Enalaprilat (s-1-[N-(1-carboxy-3- 0.2-10.0
phenylpropyl)-L-alanyl]-L-praline dehydrate mg/ml Sodium Chloride
2.0-10.0 mg/ml Sodium Hydroxide q.s. Water q.s.
[0092] Example 1 is a prophetic example of a formulation comprising
the ACEI enalapril. Sodium chloride may be added to the solution to
adjust tonicity, and sodium hydroxide may be added to adjust the pH
of the solution. The solution of Example 1 may be made by methods
known to those of ordinary skill in the art.
Example 2
[0093]
3 Atenolol (Benzeneacetamide, 4-[2-hydroxy-3- 1.0-10.0
(1-methylethyl)amino propoxy] mg/ml Sodium Chloride 2.0-10.0 mg/ml
Sodium Citrate q.s. Citric Acid q.s. Water q.s.
[0094] Example 2 is a prophetic example of a formulation comprising
the beta-blocker atenolol. Sodium chloride may be added to the
solution to adjust tonicity, and sodium hydroxide and citric acid
are added to adjust the pH of the solution. The solution of Example
2 may be made by methods known to those of ordinary skill in the
art.
Example 3
[0095]
4 Epoprostenol 0.1-3.0 mg/ml Span 85 0.2-2.0 mg/ml Water q.s.
[0096] Example 3 is a prophetic example of a formulation comprising
the vasodilator epoprostenol in suspension form. Span 85 may be
added as an emulsifier. The suspension of Example 3 may be made by
methods known to those of ordinary skill in the art.
Example 4
[0097]
5 Treprostinil sodium 0.1-10.0 mg/ml Sodium Chloride 2.0-10.0 mg/ml
Sodium Hydroxide q.s. Citric Acid q.s. Water q.s.
[0098] Example 4 is a prophetic example of a formulation comprising
the vasodilator epoprostenol. Sodium chloride may be added to the
solution to adjust tonicity, and sodium hydroxide and citric acid
are added to adjust the pH of the solution. The solution of Example
4 may be made by methods known to those of ordinary skill in the
art.
[0099] The Figures and attachments herein are presented for
illustrative purposes only. They are not intended to limit the
scope of the invention. Further, it should be understood that
various changes and modifications to the embodiment described
herein will be apparent to those skilled in the art. Such changes
and modifications can be made without departing from the spirit and
scope of the present invention and without diminishing its
attendant advantages. It is therefore intended that such changes
and modifications be covered by the appended claims. Also, the
invention may suitably comprise, consist of or consist essentially
of the elements or steps described herein. Further, the invention
described herein suitably may comprise or be practiced in the
absence of any element or step which is not specifically disclosed
herein. Further, one or more step described herein may be performed
simultaneously with another step.
* * * * *