(12) United States Patent
`Olschewski et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,358,240 B2
`Jun. 7, 2016
`
`USOO9358240B2
`
`(54) TREPROSTINIL ADMINISTRATION BY
`NHALATION
`
`(75) Inventors: Horst Olschewski, Graz (AT); Robert
`Roscigno, Chapel Hill, NC (US); Lewis
`J. Rubin, LaJolla, CA (US); Thomas
`Schmehl, Giessen (DE); Werner
`.
`Seeger, Giessen (PE) Carl Sterritt,
`Weybridge (GB); Robert Voswinckel,
`Giessen (DE)
`(73) Assignee: United Therapeutics Corporation,
`Silver Spring, MD (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 357 days.
`
`(*) Notice:
`
`(21) Appl. No.: 12/591.200
`
`(22) Filed:
`
`Nov. 12, 2009
`
`(65)
`
`Prior Publication Data
`US 201O/OO76083 A1
`Mar. 25, 2010
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`W - I
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`FOREIGN PATENT DOCUMENTS
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`AU
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`2/2000
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`(Continued)
`OTHER PUBLICATIONS
`
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`A6 IK3I/92
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`C-IR Operating Instructions, Sep. 2005.*
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`(Continued)
`
`Primary Examiner — Jeffrey S Lundgren
`Assistant Examiner — Sara E Townsley
`(74) Attorney, Agent, or Firm — Foley & Lardner LLP
`
`ABSTRACT
`(57)
`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
`
`Liquidia's Exhibit 1046
`Page 1
`
`

`

`US 9,358,240 B2
`Page 2
`
`(56)
`
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`Liquidia's Exhibit 1046
`Page 2
`
`

`

`US 9,358,240 B2
`Page 3
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`* cited by examiner
`
`Liquidia's Exhibit 1046
`Page 3
`
`

`

`U.S. Patent
`
`Jun. 7, 2016
`
`Sheet 1 of 12
`
`US 9,358,240 B2
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`Liquidia's Exhibit 1046
`Page 4
`
`

`

`U.S. Patent
`
`Jun. 7, 2016
`
`Sheet 2 of 12
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`US 9,358,240 B2
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`Liquidia's Exhibit 1046
`Page 5
`
`

`

`US. Patent
`
`Jun. 7, 2016
`
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`Liquidia's Exhibit 1046
`Page 6
`
`Liquidia's Exhibit 1046
`Page 6
`
`

`

`U.S. Patent
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`Jun. 7, 2016
`
`Sheet 4 of 12
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`Liquidia's Exhibit 1046
`Page 7
`
`

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`U.S. Patent
`
`Jun. 7, 2016
`
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`Liquidia's Exhibit 1046
`Page 8
`
`

`

`U.S. Patent
`
`Jun. 7, 2016
`
`Sheet 6 of 12
`
`US 9,358,240 B2
`
`FIGURE 6
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`Liquidia's Exhibit 1046
`Page 9
`
`

`

`U.S. Patent
`
`Jun. 7, 2016
`
`Sheet 7 of 12
`
`US 9,358,240 B2
`
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`Liquidia's Exhibit 1046
`Page 10
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`

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`U.S. Patent
`
`Jun. 7, 2016
`
`Sheet 8 of 12
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`US 9,358,240 B2
`
`FIGURE 8
`
`PAP
`
`-- placebo
`-- 30gtreprosti
`-- Sigteresti
`-- Sigtreprostini:
`
`PMR
`
`t
`
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`in
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`23
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`time mir
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`88
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`time mini
`
`Liquidia's Exhibit 1046
`Page 11
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`

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`U.S. Patent
`
`Jun. 7, 2016
`
`Sheet 9 of 12
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`US 9,358,240 B2
`
`FIGURE 9
`
`PVR
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`
`Liquidia's Exhibit 1046
`Page 12
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`

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`U.S. Patent
`
`Jun. 7, 2016
`
`Sheet 10 of 12
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`US 9,358,240 B2
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`FIGURE 10
`
`
`
`0.
`
`20
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`time min
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`
`0.
`
`60
`80 100 120 140 160 180
`time (min)
`
`Liquidia's Exhibit 1046
`Page 13
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`

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`U.S. Patent
`
`Jun. 7, 2016
`
`Sheet 11 of 12
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`US 9,358,240 B2
`
`FIGURE 11
`
`
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`Liquidia's Exhibit 1046
`Page 14
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`

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`U.S. Patent
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`Jun. 7, 2016
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`Sheet 12 of 12
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`US 9,358,240 B2
`
`
`
`u/buluoeupueouoo eused up Soude
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`
`Liquidia's Exhibit 1046
`Page 15
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`US 9,358,240 B2
`
`1.
`TREPROSTINIL ADMINISTRATION BY
`NHALATION
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`The present application is a Continuation of U.S. applica
`tion Ser. No. 1 1/748.205, filed May 14, 2007, which claims
`priority to U.S. provisional application No. 60/800,016 filed
`May 15, 2006, which are incorporated herein by reference in
`their entirety.
`
`10
`
`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.
`
`15
`
`BACKGROUND OF THE INVENTION
`
`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 of the 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 becaused 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). Zapolet 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 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 thereofatherapeutically effective amount of treprosti
`nil, or treprostinil 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
`
`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 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):5S-12S. 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% of patients 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
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
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`60
`
`65
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`Liquidia's Exhibit 1046
`Page 16
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`US 9,358,240 B2
`
`3
`thereoftreprostinil 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 of treprostinil using a metered dose inhaler
`can provide patients, such as pulmonary hypertension
`patients, with a high degree of autonomy.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`10
`
`15
`
`25
`
`4
`pared to iloprost. Due to carryover effects from the first
`period, in the second period, the effects of both drugs
`appeared shortened. Data are shown as percent of baseline
`values (mean value.95% confidence interval).
`FIG. 6 presents response of PVR and systemic arterial
`pressure (SAP) to inhalation of treprostinil vs. iloprost—dose
`effects.a) Inhalation of 7.5 ugiloprost (in 6 min) vs. 7.5 ug
`treprostinil (6 min) (n=14, in a randomized order). b) Inhala
`tion of 7.5 ugiloprost (6 min) vs. 15 ug treprostinil (6 min)
`(n=14, in randomized order). c) Inhalation of 7.5 ugiloprost
`(6 min) vs. 15ug treprostinil (3 min) (n=16, in randomized
`order). Data are shown as percent of baseline values
`(mean+95% confidence interval). Iloprost, filled circles; Tre
`prostinil, open triangles.
`FIG. 7 presents hemodynamic response to inhalation of
`treprostinil vs. iloprost. Data from n=44 patients, who inhaled
`both drugs in randomized order, shown as percent of baseline
`values (mean value--95% confidence interval). PVR, pulmo
`nary vascular resistance; PAP mean pulmonary arterial pres
`Sure; SAP, mean systemic arterial pressure; CO, cardiac out
`put.
`FIG. 8 presents pharmacodynamics after treprostinil inha
`lation vs. placebo. Placebo or treprostinil in doses of 30 ug, 60
`ug or 90 ug were inhaled (means-95% confidence intervals).
`Maximal decrease of PVR was comparable for all doses. The
`duration of pulmonary vasodilation (PVR-decrease)
`appeared to be dose dependent. PVR, pulmonary vascular
`resistance; PAP mean pulmonary arterial pressure; SAP.
`mean systemic arterial pressure; CO, cardiac output; SaO2,
`arterial oxygen Saturation; SvO2, mixed venous oxygen Satu
`ration.
`FIG. 9 presents Areas Between the placebo and the trepro
`stinil Curves (ABC). ABCs were calculated for a 3-hour
`period after inhalation of TRE or placebo from the relative
`changes of hemodynamic parameters (means-95% confi
`dence intervals). PVR, pulmonary vascular resistance; PAP.
`mean pulmonary arterial pressure; SAP, mean systemic arte
`rial pressure; SVR, systemic vascular resistance.
`FIG. 10 presents hemodynamic responses to the inhalation
`of 15 ug treprostinil. The inhalation time by increasing tre
`prostinil concentration. A pulse of aerosol was generated
`every 6 seconds. TRE aerosol was inhaled in concentrations
`of 100 g/ml (18 pulses; n=6), 200 ug/ml (9 pulses; n=6), 600
`ug/ml (3 pulses; n=21), 1000 ug/ml (2 pulses; n=7) and 2000
`ug/ml (1 pulse; n=8). Placebo data correspond to FIG.8. Data
`are shown as means-95% confidence intervals. PVR, pulmo
`nary vascular resistance; PAP mean pulmonary arterial pres
`Sure; SAP, mean systemic arterial pressure; CO, cardiac out
`put.
`FIG. 11 presents areas between the placebo curve and the
`responses to 15ug treprostinil applied at increasing concen
`trations to minimize inhalation time. Meant SEM of relative
`changes of hemodynamic parameters (observation time 120
`min). PAP pulmonary arterial pressure, SAP, systemic arte
`rial pressure, PVR, pulmonary vascular resistance, CO, car
`diac output, SaO2, Systemic arterial oxygen Saturation, SvO2,
`pulmonary arterial oxygen Saturation.
`FIG. 12 presents pharmacokinetics of treprostinil after a
`single inhalation. Treprostinil plasma levels after inhalation
`of 30 Jug, 60 ug, 90 ug or 120 ug treprostinil (6 mininhalation
`period; experiments correspond to those shown in FIGS. 8
`and 9). Data with error bars represent mean values-SEM.
`
`30
`
`FIG. 1 pulmonary and systemic changes in hemodynamics
`following the inhalation of placebo (open circles), 30 Jug
`treprostinil (triangles), 45 ug treprostinil (squares) or 60 ug
`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 observation period of 120 minu