(12) Unlted States Patent
`(10) Patent No.:
`US 9,358,240 B2
`
`Olschewski et al.
`(45) Date of Patent:
`Jun. 7, 2016
`
`USOO9358240B2
`
`(54) TREPROSTINIL ADMINISTRATION BY
`INHALATION
`
`(75)
`
`.
`Inventors: Horst Olschewskl, Oraz (AT); Robert
`ROSCignos Chapel H111, NC (US); Lewis
`J. Rubin, LaJolla, CA (US); Thomas
`schmehl G1essen
`Werner
`-
`’
`.
`’~
`seeger.’ Glessen .(DEL car] Stefmt’
`Weybr1dge (GB), Robert Voswmckel,
`G1essen (DE)
`
`(73) Assignee: United Therapeutics Corporation,
`-
`-
`Sllver Spnng’ MD (Us)
`.
`.
`.
`.
`Subject to any d1scla1mer, the term of th1s
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 357 days.
`
`.
`( * ) Not1ce:
`
`.
`(21) Appl‘ No“ 12/591’200
`.
`Flledi
`
`(22)
`
`NOV- 12: 2009
`
`(65)
`
`Prior Publication Data
`
`US 2010/0076083 A1
`
`Mar. 25, 2010
`
`4,984,158 A
`5,063,922 A
`5,080,093 A
`5,153,222 A
`5,234,953 A
`5,322,057 A
`5,361,989 A
`5,363,842 A
`5,497,763 A
`5,551,416 A
`5,727,542 A
`5,865,171 A
`5,881,715 A
`2,323,: 2
`,
`,
`6,123,068 A
`6,357,671 B1*
`6,521,212 B1
`6,626,843 B2
`6,756,033 B2
`6,765,117 B2
`6,803,386 B2
`6,809,223 B2
`7,172,557 B1
`7,199,157 B2
`7,384,978 B2
`7,417,070 B2
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`Nebu-Tec med. Produkte Eike Kern GmbH. VENTA-NEB®-ir A-I-
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`(Continued)
`
`Primary Examiner 7 Jeffrey S Lundgren
`Assistant Examiner 7 Sara E Townsley
`(74) Attorney, Agent, or Firm 7 Foley & Lardner LLP
`
`(57)
`
`ABSTRACT
`
`Treprostinil can be administered using a metered dose
`inhaler. Such administration provides a greater degree of
`autonomy to patients. Also disclosed are kits that include a
`metered dose inhaler containing a pharmaceutical formula-
`tion containing treprostinil.
`
`9 Claims, 12 Drawing Sheets
`
`WATSON LABORATORIES, mc. , IPR2017-01622, Ex. 1056, p. 1 of 24
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 1 of 24
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`

`

`US 9,358,240 B2
`
`Page 2
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`* cited by examiner
`
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`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 1 of 12
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`US 9,358,240 B2
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`WATSON LABORATORIES, mc. , IPR2017-01622, Ex. 1056, p. 4 of 24
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 4 of 24
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`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 2 of 12
`
`US 9,358,240 B2
`
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 5 of 24
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 5 of 24
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`

`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 3 of 12
`
`US 9,358,240 B2
`
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`WATSON LABORATORIES, mc. , IPR2017-01622, Ex. 1056, p. 6 of 24
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 6 of 24
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`

`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 4 of 12
`
`US 9,358,240 B2
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`U)
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 7 of 24
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 7 of 24
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`

`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 5 of 12
`
`US 9,358,240 B2
`
`PVR
`
`40
`
`[min] -§_—iloprost—Etreprostinil
`
`20 time
`
`FIGURE5
`
`anleA auuaseq ;o %
`
`PVR
`
`-}iloprost%treprostinil
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`
`60
`
`
`
`time[min]
`
`20
`
`WATSON LABORATORIES, mc. , IPR2017-01622, Ex. 1056, p. a of 24
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 8 of 24
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`

`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 6 of 12
`
`US 9,358,240 B2
`
`SAP
`
`FIGURE 6
`
`1
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`11
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`WATSON LABORATORIES, mc. , IPR2017-01622, Ex. 1056, p. 9 of 24
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 9 of 24
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`

`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 7 of 12
`
`US 9,358,240 B2
`
`FIGURE7
`
`60
`
`20
`
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`
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`
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`
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`WATSON LABORATORIES, mc. , IPR2017-01622, Ex. 1056, p. 10 of 24
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 10 of 24
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`

`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 8 of 12
`
`US 9,358,240 B2
`
`FIGURE 8
`
`PVR
`
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`
`WATSON LABORATORIES, mc. , IPR2017-01622, Ex. 1056, p. 11 of 24
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 11 of 24
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`

`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 9 of 12
`
`US 9,358,240 B2
`
`FIGURE 9
`
`PVR
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`WATSON LABORATORIES, mc. , IPR2017-01622, Ex. 1056, p. 12 of 24
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 12 of 24
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`

`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 10 of 12
`
`US 9,358,240 B2
`
`FIGURE 10
`
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`WATSON LABORATORIES, mc. , IPR2017-01622, Ex. 1056, p. 13 of 24
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 13 of 24
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`

`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 11 of 12
`
`US 9,358,240 B2
`
`FIGURE 1 1
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`WATSON LABORATORIES, mc. , IPR2017-01622, Ex. 1056, p. 14 of 24
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 14 of 24
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`

`

`US. Patent
`
`Jun. 7, 2016
`
`Sheet 12 0f 12
`
`US 9,358,240 B2
`
`100120140160180200220240
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 15 of 24
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1056, p. 15 of 24
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`

`

`US 9,358,240 B2
`
`1
`TREPROSTINIL ADMINISTRATION BY
`INHALATION
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`The present application is a Continuation of US. applica-
`tion Ser. No. 11/748,205, filed May 14, 2007, which claims
`priority to US. provisional application No. 60/800,016 filed
`May 15, 2006, which are incorporated herein by reference in
`their entirety.
`
`FIELD OF THE INVENTION
`
`The present application relates to methods and kits for
`therapeutic treatment and, more particularly, to therapeutic
`methods involving administering treprostinil using a metered
`dose inhaler and related kits.
`
`BACKGROUND OF THE INVENTION
`
`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 ofthe
`body via the systemic circulation. The flow 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 flow increases, the pressure in
`the circulation is greater for any particular flow. The above
`described condition is referred to as pulmonary hypertension
`(PH). Generally, pulmonary hypertension is defined through
`observations of pressures above the normal range pertaining
`in the majority of people residing at the same altitude and
`engaged in similar activities.
`Pulmonary hypertension may occur due to various reasons
`and the different entities of pulmonary hypertension were
`classified based on clinical and pathological grounds in 5
`categories according to the latest WHO convention, see e.g.
`Simonneau G., et al. J. Am. Coll. Cardiol. 2004; 43(12 Suppl
`S):SS-l2S. Pulmonary hypertension can be a manifestation
`of an obvious or explicable increase in resistance, such as
`obstruction to blood flow 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 reflex response to alveolar hypoxia due to lung
`diseases or high altitude, or a mismatch of vascular capacity
`and essential blood flow, such as shunting of blood in con-
`genital abnormalities or surgical removal of lung tissue. In
`addition, certain infectious diseases, such as HIV and liver
`diseases with portal hypertension may cause pulmonary
`hypertension. Autoimmune disorders, such as collagen vas-
`cular diseases, also often lead to pulmonary vascular narrow-
`ing and contribute to a significant number of pulmonary
`hypertension patients. The cases of pulmonary hypertension
`remain where the cause of the increased resistance is as yet
`inexplicable are defined as idiopathic (primary) pulmonary
`hypertension (iPAH) and are diagnosed by and after exclu-
`sion of the causes of secondary pulmonary hypertension and
`are in the majority of cases related to a genetic mutation in the
`bone morphogenetic protein receptor-2 gene. The cases of
`idiopathic pulmonary arterial hypertension tend to comprise a
`recognizable entity of about 40% ofpatients cared for in large
`specialized pulmonary hypertension centers. Approximately
`65% of the most commonly afflicted are female and young
`adults, though it has occurred in children and patients over 50.
`Life expectancy from the time of diagnosis is short without
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`specific treatment, 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. Gener-
`ally, however, disease 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, can be defined as mean PAP above 25 mmHg, assessed
`by right heart catheter measurement. Pulmonary arterial pres-
`sure may reach systemic pressure levels or even exceed these
`in severe forms of pulmonary hypertension. When the PAP
`markedly increases due to pulmonary venous congestion, i.e.
`in left heart failure or valve dysfunction, 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 edema, however, is not a feature of even
`severe pulmonary hypertension due to pulmonary vascular
`changes in all other entities of this disease.
`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 ofthe pulmonary blood vessels, which may be
`triggered by such conditions as hypoxia (as in high-altitude
`sickness), acidosis, inflammation, 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, collagen vascular diseases, pulmonary
`hypercirculation due to left-to-right shunt, HIV infection,
`portal hypertension or a combination of genetic mutation and
`unknown causes as in idiopathic pulmonary arterial hyper-
`tension.
`
`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. 9321005 (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 newbom’s
`heart. Mortality rates range from 12-50%. Fox, Pediatrics
`592205 (1977); Dworetz, Pediatrics 84:1 (1989). Pulmonary
`hypertension may also ultimately result in a potentially fatal
`heart condition known as “cor pulmonale,” or pulmonary
`heart disease. Fishman, “Pulmonary Diseases and Disorders”
`2’” Ed., McGraw-Hill, New York (1988).
`Currently, there is no treatment for pulmonary hyperten-
`sion that can be administered using a compact inhalation
`device, such as a metered dose inhaler.
`
`SUMMARY OF THE INVENTION
`
`One embodiment is a method of delivering to a subject in
`need thereof a therapeutically effective amount of treprosti-
`nil, or trepro stinil derivative or a pharmaceutically acceptable
`salt thereof comprising administering to the subject a thera-
`peutically effective amount of the treprostinil or treprostinil
`derivative or a pharmaceutically acceptable salt thereofusing
`a metered dose inhaler.
`
`Another embodiment is a method for treating pulmonary
`hypertension comprising administering to a subject in need
`
`WATSON LABORATORIES, mc. , IPR2017-01622, Ex. 1056, p. 16 Of 24
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`

`US 9,358,240 B2
`
`3
`thereof treprostinil or its derivative, or a pharmaceutically
`acceptable salt thereof using a metered dose inhaler.
`Yet another embodiment is a kit comprising a metered dose
`inhaler containing a pharmaceutical formulation comprising
`treprostinil or treprostinil derivative, or a pharmaceutically
`acceptable salt thereof.
`And yet another embodiment is a kit for treating pulmo-
`nary hypertension in a subject, comprising (i) an effective
`amount of treprostinil or its derivative, or a pharmaceutically
`acceptable salt thereof;
`(ii) a metered dose inhaler; (iii)
`instructions for use in treating pulmonary hypertension.
`Administration oftreprostinil using a metered dose inhaler
`can provide patients,
`such as pulmonary hypertension
`patients, with a high degree of autonomy.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 pulmonary and systemic changes in hemodynamics
`following the inhalation of placebo (open circles), 30 pg
`treprostinil (triangles), 45 pg treprostinil (squares) or 60 pg
`TREprostinil (black circles) applied by a Metered Dose
`Inhaler (MDI-TRE). A single short inhalation of treprostinil
`induced sustained reduction of PAP and PVR that outlasted
`
`the observationperiod of 120 minutes at doses of45 and 60 pg
`MDI-TRE. Systemic arterial pressure and resistance were not
`significantly affected. PAP:mean pulmonary artery pressure;
`PVR:pulmonary vascular resistance; SAP:mean systemic
`arterial pressure; SVR:systemic vascular resistance. Data are
`given as mean valueistandard error of the mean (SEM).
`FIG. 2 presents hemodynamic changes induced by the
`inhalation of placebo (open circles), 30 pg treprostinil (tri-
`angles), 45 pg treprostinil (squares) or 60 pg treprostinil
`(black circles) applied by a metered dose inhaler. Treprostinil
`induced sustained elevation of cardiac output. Heart rate was
`rather unchanged as a sign for low spillover of MDI-TRE to
`the systemic circulation. Gas exchange was not negatively
`affected. CO:cardiac output; HR:heart rate; SaO2:arterial
`oxygen saturation; SvO2:central venous oxygen saturation