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`US 20040265238A1
`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0265238 A1
`Chaudry
`(43) Pub. Date:
`Dec. 30, 2004
`
`(54) INHALABLE FORMULATIONS FOR
`TREATING PULMONARY HYPERTENSION
`AND METHODS OF USING SAME
`
`(76) Inventor: Imtiaz Chaudry, Napa, CA (US)
`
`Correspondence Address:
`ALSTON & BIRD LLP
`BANK OF AMERICA PLAZA
`101 SOUTH TRYON STREET, SUITE 4000
`CHARLOTTE, NC 282804000 ([15)
`
`(21) Appl, N()_j
`
`10/609,233
`
`(22) Filed:
`
`Jun. 27, 2003
`
`Publication Classi?cation
`
`(51) Int. Cl.7 ................... .. A61K 31/554; A61K 31/455;
`A61K 31/401; A61K 31/137
`(52) US. Cl. .................... .. 424/45; 514/355; 514/211.07;
`514 423; 514 651
`/
`/
`
`ABSTRACT
`(57)
`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.
`
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`

`US 2004/0265238 A1
`
`Dec. 30, 2004
`
`INHALABLE FORMULATIONS FOR TREATING
`PULMONARY HYPERTENSION AND METHODS
`OF USING SAME
`
`I. FIELD OF THE INVENTION
`
`[0001] The present invention relates to an inhalable for
`mulation 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 hyperten
`sion include shortness of breath With minimal exertion,
`fatigue, chest pain, diZZy spells fainting, and other symp
`toms. 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
`in?ammatory or collagen vascular diseases such as sclero
`derma, 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 fen?uramine and dexfen?uramine 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 ?uid 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 hyperten
`sion 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-block
`ers 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
`speci?c, 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 pros
`tacyclin and prostacyclin analogs as Well as calcium channel
`blockers such as diltiaZem (CardiZem) or nifedipine (Pro
`cardia) 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 hyperten
`sion. 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 special
`iZed centers familiar With the technique, equipment, and
`dose ranging. Moreover, continuous intravenous adminis
`tration of prostacyclin results in signi?cant side effects in
`patients, including jaW pain, nausea, and anorexia, plus the
`inconvenience and potential danger from prolonged cathe
`rtiZation 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.
`
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`US 2004/0265238 A1
`
`Dec. 30, 2004
`
`[0012] Epoprostenol or the prostacyclin analog treprostinil
`sodium may be administered via injection to treat pulmonary
`hypertension. Delivery, hoWever, is systemic and not local
`iZed 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 block
`ers may alleviate pulmonary vasoconstriction and prolong
`life in about 20 percent of patients With PPH. Rich S,
`Kaufmann E, Levy P S. The e?rect of high doses of calcium
`channel blockers on survival in primary pulmonary hyper
`tension. N Engl J Med 1992;327:76-81, Which is incorpo
`rated 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 admin
`istered 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 symp
`toms 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 bene?cially 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 per
`manent or temporary, lasting or transient that can be attrib
`uted 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 suit
`able 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 block
`ers or vasodilators, or any combination thereof. In one
`
`alternative embodiment, the formulation of the present
`invention comprises a combination of tWo or more hyper
`tension 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. Alter
`natively, the formulations herein may be preservative-free.
`In one embodiment, the formulations of the present inven
`tion 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, anti
`coagulants 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 embodi
`ment, the formulation of the kit is premeasured, premixed
`and prepackaged. In an alternative embodiment, the kit
`further comprises instructions for administering the formu
`lation.
`
`[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 block
`ing 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
`
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`US 2004/0265238 A1
`
`Dec. 30, 2004
`
`substance adrenaline (epinephrine), a key agent in the “sym
`pathetic” portion of the autonomic (involuntary) nervous
`system and activation of heart muscle. Beta-blockers suit
`able for use herein include, but are not limited to, Acebu
`tolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carvedilol,
`Esmolol, Labetalol, Metoprolol, Nadolol, Oxprenolol, Pen
`butolol, 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, Pra
`Zosin, 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-l; PGE-2; PGF-2.alpha.; PGA-l; PGB-l; 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-methyl-PGE-1 methyl ester;
`16,16-dimethyl-PGE-2;
`1l-deoxy-lS-methyl-PGE-l;
`16-methyl-18,18,19,19-tetrahydrocarbacyclin; (16RS)-15
`deoxy-16-hydroxy-16-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-dihy
`droxy-l,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 pros
`taglandin 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 com
`pound 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 in?am
`mation 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 throm
`boembolism, heparin-protomine reactions, sepsis, status ast
`hamaticus or hypoxia (including iatrogenic hypoxia) and
`other forms of reversible pulmonary vasoconstriction. Such
`pulmonary disorders are also characteriZed by in?ammation
`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 ammo
`nium 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, eth
`ylenediamine salt, ethanolamine salt, diethanolamine salt,
`triethanolamine salt, tris(hydroxymethylamino) ethane salt,
`monomethyl-monoethanolamine salt, procaine salt and caf
`feine 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, prefer
`able an aqueous medium. The above salts may be prepared
`by a conventional process, for example from the correspond
`ing 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 hydro
`chloride, hydrobromide, sulfate, phosphate, and nitrate;
`organic acid addition salts such as acetate, propionate,
`succinate, lactate, glycolate, malate, tartrate, citrate, male
`ate, fumarate, methansulfonate, p-toluenesulfonate, and
`ascorbate; salts With acidic amino acid such as aspartate and
`glutamate; alkali metal salts such as sodium salt and potas
`sium 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‘-dibenZyleth
`
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`US 2004/0265238 A1
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`
`ylenediamine 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-methoxy
`ethyl 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 admin
`istered 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 option
`ally substituted aryl esters such as, for example, phenyl ester,
`tosyl ester, t-butylphenyl ester, salicyl ester, 3,4-di-methox
`yphenyl 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 hyper
`tension 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) con?guration, or may be a mixture thereof. Thus, the
`compounds for use in the formulations provided herein may
`be enantiomerically pure, or be stereoisomeric or diastereo
`meric mixtures. It is to be understood that the chiral centers
`of the compounds provided herein may undergo epimeriZa
`tion 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 for
`mulation for treating pulmonary hypertension, Wherein the
`formulation comprises a therapeutically effective amount of
`a hypertension-reducing agent for the treatment of pulmo
`nary 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 vasodi
`
`lators to treat pulmonary hypertension. It is believed that the
`formulations of the present invention represent an improve
`ment 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 ef?cacy 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. Addi
`tionally, 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 hyperten
`sion-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 hyperten
`sion-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
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1004, p. 5 of 14
`
`

`

`US 2004/0265238 A1
`
`Dec. 30, 2004
`
`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 therapeuti
`cally effective amount of a pulmonary hypertension agent.
`Preferably, the inhalable solution of the present invention is
`suitable for administration via nebuliZation. The formula
`tions 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 ?uid Which is physiologi
`cally 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. Speci?ca
`tions established by the United States Pharmacopoeia for
`“Sterile Water for Injection” or “Sterile Water for Inhala
`tion” 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, suspend
`ing 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 ?uids Which is physiologically accept
`able upon administration intranasally. Pharmacologically
`suitable ?uids 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 prop