(12) United States Patent
`Cloutier et al.
`
`US006521212B1
`US 6,521,212 B1
`*Feb. 18,2003
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54)
`
`METHOD FOR TREATING PERIPHERAL
`VASCULAR DISEASE BY ADMINISTERING
`BENZINDENE PROSTAGLANDINS BY
`INHALATION
`
`(75)
`
`Inventors:
`
`Gilles Cloutier; James Crow; Michael
`Wade, all of Chapel Hill, NC (US);
`Richard E. Parker, Spring Hill; James
`E. Loyd, Nashville, both of TN (US)
`
`(73)
`
`Assignee:
`
`United Therapeutics Corporation,
`Silver Spring, MD (US)
`
`(*)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis
`claimer.
`
`Appl. No.:
`
`Filed:
`
`09/525,471
`Mar. 15, 2000
`
`5,153,222 A
`6,054,486 A *
`
`10/1992 Tadepalli et al.
`4/2000 Crow et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`
`0 159 784 A
`
`10/1985
`
`OTHER PUBLICATIONS
`
`W. M. Zapol et al., Pulmonary Circulation During ARDS,
`“Pulmonary Circulation During Adult Respiratory Distress
`Syndrome,” pp. 241—273 (1985).
`W. W. Fox et al., Pediatrics, “Pulmonary Hypertension in the
`Perinatal Aspiration Syndromes,” vol. 59, No. 2, pp.
`205—211 (1977).
`A. R. DWoretZ et al. Pediatrics, “Survival of Infants With
`Persistent Pulmonary Hypertension Without Extracorporeal
`Membrane Oxygenation,” vol. 84, No. 1, pp. 1—6 (1989).
`G. J. Peckham et al., The Journal of Pediatrics, “Physiologic
`factors affecting pulmonary artery pressure in infants With
`persistent pulmonary hypertension,” vol. 93, No. 6, pp.
`1005—1010 (1978).
`R. C. WetZel, Anesthesiology, “AerosoliZed Prostacyclin,”
`vol. 82, No. 6 (1995).
`
`(21)
`(22)
`
`(60)
`
`(51)
`(52)
`
`(58)
`
`(56)
`
`Related US. Application Data
`Provisional application No. 60/124,999, ?led on Mar. 18,
`1999, and provisional application No. 60/124,999, ?led on
`Man 18’ 1999'
`
`* cited by examiner
`
`Primary Examiner—Jose‘ G. Dees
`Assistant Examiner—M. Haghighatrai
`(74) Attorney, Agent, or Firm—Foley & Lardner
`
`
`
`IIlt. Cl-7 . . . . . . . . . . . . . . . . . . . . . . . . . .. US. Cl. ......................... .. 424/45; 424/46; 424/489;
`
`514/573; 514/571
`Field of Search .......................... .. 424/45, 46, 489;
`514/573, 571
`
`References Cited
`
`A method of delivering benZindene prostaglandins to a
`patient by inhalation is discussed. Abenzindene prostaglan
`din known as UT-15 has unexpectedly superior results When
`administered by inhalation compared to parenterally admin
`istered UT-15 in sheep With induced pulmonary hyperten
`
`U.S. PATENT DOCUMENTS
`
`Sm‘
`
`4,306,075 A 12/1981 Aristoff
`
`12 Claims, 18 Drawing Sheets
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`US. Patent
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`Feb. 18, 2003
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1018, p. 2 of 27
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1018, p. 7 of 27
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`U.S. Patent
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1018, p. 14 of 27
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`US. Patent
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`US 6,521,212 B1
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`Feb. 18,2003
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`

`

`US 6,521,212 B1
`
`1
`METHOD FOR TREATING PERIPHERAL
`VASCULAR DISEASE BY ADMINISTERING
`BENZINDENE PROSTAGLANDINS BY
`INHALATION
`
`This application claims the bene?t of provisional appli
`cation Serial No. 60/124,999, ?led Mar. 18, 1999.
`
`BACKGROUND OF THE INVENTION
`
`BenZindene prostaglandins are noW knoWn to be useful to
`treat a variety of conditions. US. Pat. No. 5,153,222
`describes the use of a preferred class of benZindene pros
`taglandins in the treatment of pulmonary hypertension,
`including both primary and secondary pulmonary hyperten
`sion. In particular, this patent discusses the use of the
`compound 9-deoxy-2‘,9-alpha-methano-3-oxa-4,5,6-trinor
`3,7-(1‘,3‘-interphenylene)-13,14-dihydro-prostaglandin F1
`(also knoWn as UT-15).
`HoWever, this patent does not speci?cally suggest the
`administration of such benZindene prostaglandins by inha
`lation or the surprising bene?ts that result from their deliv
`ery by inhalation.
`US. Pat. No. 4,306,075 describes a large group of car
`bacyclin analogs, including, benZindene prostaglandins
`Which produce various pharmacological responses, such as
`inhibition of platelet aggregation, reduction of gastric
`secretion, and bronchodilation. It is indicated that the com
`pounds have useful application as anti-thrombotic agents,
`anti-ulcer agents, and anti-asthma agents. The patent does
`mention administration by inhalation. The patent speci?
`cally discloses the compound UT-15 in Example 33.
`HoWever., this patent provides only limited biological data
`relating to the use of such compounds. At column 59,
`example 31, the patent discloses a compound that is struc
`turally similar to that of example 33 (UT-15), but it is not the
`same compound. Example 31 discloses (column 59, lines
`41—45) that “[t]he compounds [sic] 9-deoxy-2‘, 9-methano
`3-oxa4,5,6-trinor-3,7-(1‘,3‘-interphenylene)- PGF1, methyl
`ester, given to a rat orally at a dose of 1 mg/kg loWered blood
`pressure 44 mmHg. After 52 min the blood pressure Was still
`loWer 14 mm.”
`All blood is driven through the lungs via the pulmonary
`circulation in order, among other things, to replenish the
`oxygen Which it dispenses in its passage around the rest of
`the body via the systemic circulation. The How through both
`circulations is in normal circumstances equal, but the resis
`tance offered to it in the pulmonary circulation is generally
`much less than that of the systemic circulation. When the
`resistance to pulmonary blood ?oW increases, the pressure in
`the circulation is greater for any particular ?oW. This is
`referred to as pulmonary hypertension. Generally, pulmo
`nary hypertension is de?ned through observations of pres
`sures above the normal range pertaining in the majority of
`people residing at the same altitude and engaged in similar
`activities.
`Most often pulmonary hypertension is a manifestation of
`an obvious or explicable increase in resistance, such as
`obstruction to blood ?oW by pulmonary emboli, malfunction
`of the heart’s valves or muscle in handling blood after its
`passage through the lungs, diminution in pulmonary vessel
`caliber as a re?ex response to hypoventilation and loW
`oxygenation, or a mismatch of vascular capacity and essen
`tial blood ?oW, such as shunting of blood in congenital
`abnormalities or surgical removal of lung tissue. Such
`pulmonary hypertension is referred to as secondary hyper
`tension.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`There remain some cases of pulmonary hypertension
`Where the cause of the increased resistance is as yet inex
`plicable. They are described as primary pulmonary hyper
`tension (PPH) and are diagnosed by and after exclusion of
`the causes of secondary pulmonary hypertension. Despite
`the possibility of a varied etiology, cases of primary pulmo
`nary hypertension tend to comprise a recogniZable entity.
`Approximately 65% are female and young adults are most
`commonly af?icted, though it has occurred in children and
`patients over 50. Life expectancy from the time of diagnosis
`is short, about 3 to 5 years, though occasional reports of
`spontaneous remission and longer survival are to be
`expected given the nature of the diagnostic process.
`Generally, hoWever, progress is inexorable via syncope and
`right heart failure and death is quite often sudden.
`Pulmonary hypertension refers to a condition associated
`With an elevation of pulmonary arterial pressure (PAP) over
`normal levels. In humans, a typical mean PAP is approxi
`mately 12—15 mm Hg. Pulmonary hypertension, on the other
`hand, is sometimes marked by PAP increases by at least 5 to
`10 mm Hg over normal levels. PAP readings as high as 50
`to 100 mm Hg over normal levels have been reported. When
`the PAP markedly increases, plasma can escape from the
`capillaries into the lung interstitium and alveoli. Fluid
`buildup in the lung (pulmonary edema) can result, With an
`associated decrease in lung function that can in some cases
`be fatal.
`Pulmonary hypertension may either be acute or chronic.
`Acute pulmonary hypertension is often a potentially revers
`ible phenomenon generally attributable to constriction of the
`smooth muscle of the pulmonary blood vessels, Which may
`be triggered by such conditions as hypoxia (as in high
`altitude sickness), acidosis, in?ammation, or pulmonary
`embolism. Chronic pulmonary hypertension is characteriZed
`by major structural changes in the pulmonary vasculature,
`Which result in a decreased cross-sectional area of the
`pulmonary blood vessels. This may be caused by, for
`example, chronic hypoxia, thromboembolism, or unknoWn
`causes (idiopathic or primary pulmonary hypertension).
`Pulmonary hypertension has been implicated in several
`life-threatening clinical conditions, such as adult respiratory
`distress syndrome (“ARDS”) and persistent pulmonary
`hypertension of the neWborn (“PPHN”). Zapol et al., Acute
`Respiratory Failure, p. 241—273, Marcel Dekker, NeW York
`(1985); Peckham, J. Ped. 93:1005 (1978). PPHN, a disorder
`that primarily affects full-term infants, is characteriZed by
`elevated pulmonary vascular resistance, pulmonary arterial
`hypertension, and right-to-left shunting of blood through the
`patent ductus arteriosus and foramen ovale of the neWborn’s
`heart. Mortality rates range from 12—50%. Fox, Pediatrics
`59:205 (1977); DWoretZ, Pediatrics 84:1 (1989). Pulmonary
`hypertension may also result in a potentially fatal heart
`condition knoWn as “cor pulmonale”, or pulmonary heart
`disease. Fishman, “Pulmonary Diseases and Disorders” 2”d
`Ed., McGraW-Hill, NeW York (1988).
`The treatment of pulmonary hypertension by the
`parenteral administration of certain prostaglandin
`endoperoxides, such as prostacyclin (also knoWn as ?olan),
`is also knoWn and is the subject of US. Pat. No. 4,883,812.
`Prostacyclin has been administered by inhalation and is used
`to treat pulmonary hypertension by inhalation.
`Anesthesiology, vol. 82, no. 6, pp. 1315—1317.
`
`SUMMARY OF THE INVENTION
`
`This invention relates to the administration of a therapeu
`tically effective amount of a benZindene prostaglandin to a
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1018, p. 20 of 27
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`US 6,521,212 B1
`
`4
`FIG. 18 is the dose-response effect of intravenously
`infused and aerosolized UT15 on pulmonary vascular driv-
`ing pressure (PPA-PLA) during intravenously infused
`U44069.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Unless otherwise specified, all references to a
`mean at least one.
`
`or “an”
`
`One embodiment of the present invention is a method of
`delivering a benzindene prostaglandin or a pharmaceutically
`acceptable salt or ester thereof to a mammal in need thereof
`by inhalation.
`Apreferred group of benzindene prostaglandins for deliv-
`ery by inhalation according to the present invention is as
`follows:
`
`(I)
`
`X O
`
`H
`
`/
`HOZC\
`(CI—12):)
`
`wherein a is an integer of from 1 to 3; X and Y, which may
`be the same or different, are selected from —O— and
`—CH2—; R is —(CH2)5—Rl wherein R1 is hydrogen
`or methyl, or R is cyclohexyl, or R is —CH(CH3)
`CHZCECCH3; and the dotted line represents an
`optional double bond; or a physiologically acceptable
`salt or acid derivative thereof.
`
`The most preferred benzindene prostaglandin is UT—15,
`which is 9-deoxy-2', 9-alpha-methano-3-oxa-4,5,6-trinor-3,
`7-(1',3'-interphenylene)-13,14-dihydro-prostaglandin F1.
`“Inhalation” delivery in the context of this invention
`refers to the delivery of the active ingredient or combination
`of active ingredients through a respiratory passage, wherein
`the mammal in need of the active ingredient(s) inhales the
`active ingredient(s) through the mammal’s airways, such as
`the nose or mouth.
`
`Active ingredients, which are aerosolized, atomized, and/
`or nebulized for delivery by inhalation according to the
`present invention include liquid formulations comprising a
`benzindene prostaglandin, such as UT—15, alone or in com-
`bination with other active ingredients described below.
`UT—15 may be used as a free acid or in the form of a
`pharmaceutically acceptable salt or ester or other acid
`derivative. In addition, sustained release formulations com-
`prising UT—15 may be used, including PEGylated forms
`and/or protein-conjugated forms of UT—15.
`The term “acid derivative” is used herein to describe
`
`Cl—C4 alkyl esters and amides, including amides wherein
`the nitrogen is optionally substituted by one or two Cl—C4
`alkyl groups.
`The invention also includes bioprecursors or “pro-drugs”
`of UT—15, that is, compounds which are converted in vivo to
`UT—15 or its pharmaceutically active derivatives thereof.
`Further aspects of the present invention are concerned
`with the use of UT—15, or a pharmaceutically acceptable salt
`or acid derivative thereof, in the manufacture of a medica-
`ment for the treatment of peripheral vascular disease
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`mammal in need thereof by inhalation. More particularly,
`the invention relates to a method of treating pulmonary
`hypertension by administering an effective amount of a
`benzindene prostaglandin to a mammal in need thereof by
`inhalation.
`
`Inhalation of benzindene prostaglandins provides uneX-
`pectedly superior results compared to parenteral adminis-
`tration of benzindene prostaglandins.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph of pulmonary vascular resistance
`(cmHzO*min/liter) intravenously induced by U44069 over
`time (min).
`FIG. 2 describes the effects of a high dose of UT15, given
`as an aerosol, on the hemodynamic variables of the sheep.
`Specifically, FIG. 2 depicts the effects of the aerosolized
`UT15 administered to the sheep intravenously induced with
`U44069 on systemic arterial pressure (PSA or PSYS); on
`pulmonary arterial pressure (PPA); and pulmonary vascular
`resistance (PVR), respectively.
`FIG. 3 is the dose-response effect of intravenously infused
`LT15 and aerosolized UT15 on the heart rate during base-
`line conditions.
`
`FIG. 4 is the dose-response effect of intravenously infused
`LT15 and aerosolized UT15 on the systemic arterial pres-
`sure during baseline conditions.
`FIG. 5 is the dose-response effect of intravenously infused
`LT15 and aerosolized UT15 on the central venous pressure
`during baseline conditions.
`FIG. 6 is the dose-response effect of intravenously infused
`LT15 and aerosolized UT15 on the pulmonary arterial
`pressure during baseline conditions.
`FIG. 7 is the dose-response effect of intravenously infused
`LT15 and aerosolized UT15 on the left atrial pressure
`during baseline conditions.
`FIG. 8 is the dose-response effect of intravenously infused
`LT15 and aerosolized UT15 on cardiac output during base-
`line conditions.
`
`
`
`FIG. 9 is the dose-response effect of intravenously infused
`LT15 and aerosolized UT15 on pulmonary vascular resis-
`tance during baseline conditions.
`FIG. 10 is the dose-response effect on the heart rate of
`intravenously infused UT15 and aerosolized UT15 during
`intravenously infused U44069.
`FIG. 11 is the dose-response effect of intravenously
`infused and aerosolized UT15 on central venous pressure
`during intravenously infused U44069.
`FIG. 12 is the dose-response effect of intravenously
`infused and aerosolized UT15 on systemic arterial pressure
`during intravenously infused U44069.
`FIG. 13 is the dose-response effect of intravenously
`infused and aerosolized UT15 on pulmonary arterial pres-
`sure during intravenously infused U44069.
`FIG. 14 is the dose-response effect of intravenously
`infused and aerosolized UT15 on left atrial pressure during
`intravenously infused U44069.
`FIG. 15 is the dose-response effect of intravenously
`infused and aerosolized UT15 on cardiac output during
`intravenously infused U44069.
`FIG. 16 is the dose-response effect of intravenously
`infused and aerosolized Ut15 on pulmonary vascular resis-
`tance during intravenously infused U44069.
`FIG. 17 is the dose-response effect of intravenously
`infused and aerosolized UT15 on pulmonary vascular driv-
`ing pressure (PPA minus PLA) during baseline-conditions.
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1013, p. 21 of 27
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`US 6,521,212 B1
`
`5
`invention extends to non-physiologically
`The present
`acceptable salts of UT—15 which may be used in the prepa-
`ration of the pharmacologically active compounds of the
`invention. The physiologically acceptable salts of UT—15
`include salts derived from bases.
`Base salts include ammonium salts, alkali metal salts such
`as those of sodium and potassium, alkaline earth metal salts
`such as those of calcium and magnesium, salts with organic
`bases such as dicyclohexylamine and N-methyl-D-
`glucamine, and salts with amino acids such as arginine and
`lysine.
`Quaternary ammonium salts can be formed, for example,
`by reaction with lower alkyl halides, such as methyl, ethyl,
`propyl, and butyl chlorides, bromides, and iodides, with
`dialkyl sulphates, with long chain halides, such as decyl,
`lauryl, myristyl, and stearyl chlorides, bromides, and
`iodides, and with aralkyl halides, such as benzyl and phen-
`ethyl bromides.
`Optionally, one or more pharmaceutically acceptable car-
`riers or excipients may be included in the formulation to be
`aerosolized, atomized, or nebulized according to the inven-
`tion.
`
`Apreferred solution for administration by inhalation with
`a nebulizer includes a sterile solution of UT—15 comprising
`UT—15, sodium citrate, citric acid, sodium hydroxide,
`sodium chloride, and meta-cresol. Amore preferred solution
`is prepared by mixing 0.125 grams UT—15, 1.25 grams
`hydrous sodium citrate, 0.125 grams of anhydrous citric
`acid, 0.05 grams of sodium hydroxide, and approximately
`250 ml of water for injection.
`Preferably, a nebulizer, inhaler, atomizer or aerosolizer is
`used which forms droplets from a solution or liquid con-
`taining the active ingredient(s). The droplets are preferably
`less than 10 micrometers in diameter. One preferred nebu-
`lizer is the AM-601 MEDICATOR AEROSOL DELIVERY
`
`SYSTEMTM (a nebulizer manufactured by Healthline Medi-
`cal in Baldwin Park, Calif.).
`Alternatively, solid formulations, usually in the form of a
`powder, may be inhaled in accordance with the present
`invention. In such case, the particles are preferably less than
`10 micrometers in diameter, and more preferably, less than
`5 micrometers in diameter.
`
`This invention further relates to delivering a benzindene
`prostaglandin and/or its salts or esters by inhalation for
`applications where inhalation delivery is appropriate for the
`treatment of that particular condition. Benzindene
`prostaglandins, including UT—15 and its salts or esters, have
`been shown to be useful for multiple applications. For
`example, UT—15 has been shown to exhibit a potent anti-
`aggregatory action on blood platelets, and therefore has a
`particular utility in mammals as an anti-thrombotic agent.
`Further known uses of UT-15 include treatment of peripheral
`vascular disease (covered in co-pending application Serial
`No. 09/190,450, now US. Pat. No. 6,054,486, the entire
`contents of which are incorporated by reference herein). In
`the case of treating peripheral vascular disease by inhalation
`of a benzindene prostaglandin of the present invention, the
`dosage for inhalation, taking into account that some of the
`active ingredient is breathed out and not taken into the
`bloodstream, should be sufficient to deliver an amount that
`is equivalent to a daily infusion dose in the range of 25 pg
`to 250 mg; typically from 0.5 tg to 2.5 mg, preferably from
`7 Mg to 285 pg, per day per kilogram bodyweight. For
`example, an intravenous dose in the range 0.5 pg to 1.5 mg
`per kilogram bodyweight per day may conveniently be
`administered as an infusion of from 0.5 ng to 1.0 pg per
`kilogram bodyweight per minute. A preferred dosage is 10
`ng/kg/min.
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`Benzindene prostaglandins, including UT—15 and its salts
`or esters, may also be administered according to the present
`invention by inhalation to reduce and control excessive
`gastric secretion, thereby reducing or avoiding gastrointes-
`tinal ulcer formation, and accelerating the healing of ulcers
`and lesions already present in the gastrointestinal tract. In
`addition, benzidene prostaglandins may also be adminis-
`tered according to the present invention by inhalation to treat
`congestive heart failure,
`to reduce inflammation and/or
`pulmonary hypertension associated with lung transplants[,].
`Benzindene prostaglandins, including UT—15 and its salts
`or esters, further exhibit vasodilatory action on blood vessels
`and therefore have a particular utility as anti-hypertensives
`for
`the treatment of high blood pressure in mammals,
`including man. Use as an anti-hypertensive (or hypotensive
`agent) may be accomplished by administering a pharmaceu-
`tical composition containing a benzindene prostaglandin,
`including UT-15.
`including UT-15, may be
`Benzindene prostaglandins,
`used according to the present invention by inhalation to treat
`any condition where it is desired to reduce blood pressure,
`inhibit platelet aggregation, to reduce the adhesive character
`of platelets, and/or to treat or prevent
`the formation of
`thrombi in mammals, including man. For example, they may
`be used in the treatment and prevention of myocardial
`infarcts and in the treatment of peripheral vascular disease,
`to treat and prevent post-operative thrombosis, to promote
`patency of vascular grafts following surgery, and to treat
`complications of arteriosclerosis and conditions such as
`atherosclerosis, blood clotting defects due to lipemia, and
`other clinical conditions in which the underlying etiology is
`associated with lipid imbalance or hyperlipidemia.
`Moreover, benzidene prostaglandins, including UT—15 and
`its salts or esters, have a further utility in the promotion of
`wound healing in mammals, including man.
`Benzindene prostaglandins, including UT—15 and its salts
`or esters, may also be used as additives to blood, blood
`products, blood substitutes, and other fluids, which are used
`in artificial extra-corporeal circulation and perfusion of
`isolated body portions, e.g.,
`limbs and organs, whether
`attached to the original body, detached and being preserved
`or prepared for transplant, or attached to a new body. During
`these circulations and perfusions, aggregated platelets tend
`to block the blood vessels and portions of the circulation
`apparatus. This blocking is avoided by the presence of
`UT—15. For this purpose, UT-15 or its salts or esters may be
`introduced by inhalation until
`it reaches a level
`in the
`circulating blood, the blood of the donor animal, or the blood
`of the perfused body portion, or to two or all of those
`equivalent to a steady state dose of 0.001 micrograms to 10
`micrograms, per liter of circulating fluid. Another embodi-
`ment is to use UT—15 in laboratory animals, e.g., cats, dogs,
`rabbits, monkeys and rats, for these purposes in order to
`develop new methods and techniques for organ and limb
`transplants.
`In accordance with the present invention, a benzindene
`prostaglandin is delivered by inhalation to a patient in need
`thereof in a “therapeutically effective amount”. A “thera-
`peutically effective amount” refers to that amount that has
`therapeutic effects on the condition intended to be treated or
`prevented. For example, an “antihypertensive effective
`amount” refers to that amount in which the effects from
`
`pulmonary hypertension, and particularly, pulmonary arte-
`rial pressure (PAP), are reduced towards a normal level
`relative to hypertensive levels, or maintained at normal
`levels. The precise amount that is considered effective for a
`particular therapeutic purpose will, of course, depend upon
`
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`US 6,521,212 B1
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`7
`the specific circumstances of the patient being treated and
`the magnitude of effect desired by the patient’s doctor.
`Titration to effect may be used to determine proper dosage.
`Such formulations, both for veterinary and for human
`medical use, of the present invention comprise the active
`ingredient, a benzindene prostaglandin or salt or ester
`thereof,
`together with one or more pharmacologically
`acceptable carriers therefore and optionally other therapeu-
`tic ingredients. The carrier(s) must be “acceptable” in the
`sense of being compatible with the other ingredients of the
`formulation and not deleterious to the recipient thereof.
`Furthermore, the formulations may conveniently be pre-
`sented in unit dosage form and may be prepared by any of
`the methods well known in the art of pharmacy. All methods
`include the step of bringing into association the active
`ingredient with the carrier which constitutes one or more
`pharmacologically acceptable accessory ingredients.
`The invention further relates to a method of treating
`pulmonary hypertension by inhalation of a benzindene pros-
`taglandin. “Pulmonary hypertension” refers to both acute
`and chronic hypertension,
`including primary pulmonary
`hypertension and secondary pulmonary hypertension, and is
`associated with an elevated pulmonary arterial pressure over
`normal levels.
`
`The efficacy of benzindene prostaglandins, such as
`UT—15, for treating pulmonary hypertension can be assessed
`by determining the hemodynamics associated with pulmo-
`nary hypertension. In particular, measurements of pulmo-
`nary arterial pressure (PPA),
`left atrial pressure (PLA),
`central venous pressure (PCV), systemic arterial pressure
`(PSYS), heart rate (HR), and cardiac output (C0) are useful
`in determining the effects of benzindene prostaglandins
`delivered by inhalation or parenterally.
`Although pulmonary arterial pressure can be directly
`measured and is often used to quantify pulmonary arterial
`hypertension, PPA can be affected by 3 other variables: Co,
`PLA and PVR, as indicated by Equation 1:
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`PPA=(CO*PVR)+PLA
`
`(1)
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`As can be seen from Equation 1, PPA can be elevated by
`increases in PLA (e.g.,
`left heart failure, mitral valve
`stenosis, mitral valve regurgitation), increases in CO (e.g.,
`low hematocrit, peripheral vasodilation, left to right shunt,
`etc.), and by increases in PVR (decreased pulmonary vas-
`cular surface area, decreased pulmonary vascular radii,
`pulmonary vascular obstructions, etc.).
`On the other hand, PVR can not be directly measured and
`must be calculated by the following Equation 2:
`
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`PVR=(PPA—PLA)/CO
`
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`
`(2)
`
`PVR is a better index of pulmonary arterial hypertension
`(PAH), since interventions used to treat PAH are best if they
`only affect PVR and have no or little effect on C0 and PLA.
`Heart
`rate was determined by measuring the time
`(seconds) required for 25 heart beats to occur (tzs) as
`indicated by the pulsations on the blood flow meter; the
`beats per minute (BPM) were calculated by the following
`equation:
`
`BPM=(25 beats/t5)*60 seconds
`
`All pressure may be monitored by commercially available
`transducers, such as Model 1290A HEWLETT PACK-
`ARDTM transducer (Andover, Me.), which is attached to
`VALIDYNE CD19A Carrier Dmod. Amplifiers (Northridge,
`Calif.). Cardiac output may be measured by a Transonic
`Systems T101 Ultrasonic Bloodfiow. Meter (Ithaca,
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`The pressure and blood flow signals may be recorded on
`ASTROMED MT—9500 Stripchart Recorder (West Warwick,
`RI.) and digitally recorded with a personal-computer using
`Easy Data Acquisition Software (Nashville, Tenn.).
`It has been discovered that aerosolized UT—15 has both
`
`greater potency and efficacy relative to attenuating chemi-
`cally induced pulmonary hypertension as shown by an
`increase in pulmonary vascular resistance. Furthermore,
`aerosolized UT—15 has a greater potency as compared to
`intravascularly administered UT—15, since the actual amount
`of UT—15 delivered via aerosolization delivery is only a
`fraction (10—50%) of the dosage delivered intravascularly.
`While the mechanism(s)
`that acc