(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2012/0177693 A1
`Cipolla et al.
`(43) Pub. Date:
`Jul. 12, 2012
`
`US 20120177693A1
`
`(54) DEEP LUNG PULMONARY DELIVERY OF
`TREPROSTINIL
`
`(75) Inventors:
`
`David C. Cipola, San Ramon, CA
`(US); Igor Gonda, San Francisco,
`CA (US); Babatunde Otulana,
`Danville, CA (US); Richard
`Morishige, Castro Valley, CA (US);
`Paul R. Bruinenberg, Livermore,
`CA (US)
`
`(73) Assignee:
`
`Aradigm Corporation
`
`(21) Appl. No.:
`(22) PCT Filed:
`(86). PCT No.:
`S371 (c)(1),
`(2), (4) Date:
`
`13/120,015
`Sep. 24, 2009
`PCT/USO9/58217
`
`Jun. 2, 2011
`
`Related U.S. Application Data
`(60) Provisional application No. 61/100,017, filed on Sep.
`25, 2008.
`
`Publication Classificati
`DCOSSO
`
`(51) Int. Cl.
`A63L/92
`A6IP 9/12
`A6IP II/00
`A6IR 9/12
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(52) U.S. Cl. ......................................... 424/400: 514/569
`
`ABSTRACT
`(57)
`Administration of aerosolized Treprostinil formulations may
`provide a more homogeneous lung deposition of treprostinil,
`whereby making deep lung delivery possible.
`
`IPR2021-00406
`United Therapeutics EX2088
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 1 of 20
`
`US 2012/0177693 A1
`
`Fig. 1
`Disposition of Subjects
`
`Subjects Screened
`n=22
`
`
`
`Screen Failures/Non-Runners
`n=8
`
`
`
`Subject Received Study
`Medication
`n=14
`
`
`
`Subject Completed Study
`n=14
`
`Fig. 2
`Mean Plasma Treprostinil Concentrations (ng/mL) (Linear Plot) following
`Administration via AERx and Optineb (n=14)
`
`Mean Concentration
`(ng/ml)
`
`
`
`0.8
`0.7
`0.6
`0.5
`
`0.4
`0.3
`0.2
`0.1
`O.O.
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 2 of 20
`
`US 2012/0177693 A1
`
`Fig. 3
`Mean Plasma Treprostinil Concentrations (ng/mL) (Semi Log Plot) following
`Administration via AERx and Optineb (n=14)
`
`
`
`1.000
`
`0.100
`Mean Concentration
`(ng/ml)
`
`0.010
`
`O.OO
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 3 of 20
`
`US 2012/0177693 A1
`
`Fig. 4
`Summary of Demographic Data
`
`
`
`Height (cm)
`
`BMI (kg/m2)
`
`Stod DeV
`Minimum
`Maximum
`
`Std Dev
`Minimum
`Maximum
`
`Stod DeV
`Minimum
`Maximum
`
`Std Dev
`Minimum
`Maximum
`
`Race Caucasian
`Mixed
`
`1
`
`2121 64.4.14.
`
`3 7.1O i
`
`

`

`Patent Application Publication
`
`US 2012/0177693 Al
`
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`Patent Application Publication
`
`Jul. 12, 2012 Sheet 5 of 20
`
`US 2012/0177693 A1
`
`
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`Patent Application Publication
`
`Jul. 12,2012 Sheet 6 of 20
`
`US 2012/0177693 Al
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`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 7 of 20
`
`US 2012/0177693 A1
`
`
`
`8 (61-)
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 8 of 20
`
`US 2012/0177693 A1
`
`
`
`6 (61-)
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 9 of 20
`
`US 2012/0177693 A1
`
`
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`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 10 of 20
`
`US 2012/0177693 A1
`
`Fig.11
`Summary of Individual Treprostinil Pharmacokinetic Parameters (n=14)
`Admin Subject|Ca(ng)Tmax (h)AUCs (ngmi hAUCNEos (ngmin) Lambda 2(n). Ta () Vz F obstm)
`AERx
`1
`0.299 0500
`0.375
`0.407
`0.532
`1.304 73067328
`2
`1.035
`0.117
`0.635
`0.650
`0.712
`0.974 57509.530
`3
`0.754
`0.117
`0661
`0.674
`1362
`27626.116
`4
`0.312 0.17
`0.399
`32623.438
`0.726
`5
`0.5
`0500
`1038
`297.16.261
`0.792
`6
`0805 0500
`0906
`2881,469
`0.47
`7
`0.721
`0.250
`0.936
`727 36699.541
`O
`2732
`8
`0.481
`0.333
`0.707
`32 133550.416
`9
`1347 0.117
`1.196
`0.589
`21692.705
`O
`10
`0.784 0250
`0743
`0.583
`33569,089
`11
`0.438 0500
`0.755
`0.785
`39332,828
`12
`0.451
`0500
`0.793
`0804 40703,000
`13
`0.440
`0.500
`0580
`0.570
`35069,694
`14
`0.584 0500
`0.760
`0.608 33214517
`Mean 0640 0.343
`0.742
`70
`44018.281
`0.292
`0,174
`0.220
`77 29122,975
`0.299
`O. 117
`0.375
`21692.705
`Median 0.548 O47
`0749
`272 34319,392
`Max 1347 0500
`1196
`732 133550.416
`GM 0.586
`NP
`0.709
`771
`38614,996
`O 7
`1
`0.543
`0.167
`0.407
`0.541
`27286.295
`2
`1,169
`0.083
`0413
`28971.091
`3
`0.791
`0.117
`0.350
`30619.267
`0.445
`4
`0.673
`0.167
`0.559
`0.768 47210,784
`5
`0.639
`0.167
`0.568
`0.732
`16866,083
`6
`1.016
`0.117
`0.615
`0.497 20356.674
`7
`0.649
`0.083
`0503
`0.873
`42896.65
`8
`0.719
`0.117
`0.635
`0.593
`40009.285
`9
`0.880
`0.167
`0.746
`0.734
`22019.208
`0.816
`0.469
`22183.854
`0.689
`957 42701.203
`107 92051.057
`34430.806
`36231622
`0669 35988,134
`18666,952
`0.205
`0.426
`16866,083
`0622 32525,036
`1.107 92051.057
`0.642
`32721.114
`
`1059
`0.92
`0.854
`0.758
`1205
`0.763
`0.784
`0808
`0.603
`0.771
`0.762
`0.218
`0.407
`0.767
`1205
`0.731
`0.415
`0.366
`0.573
`0.582
`0.650
`0.519
`
`E.
`
`
`0.87 5
`147
`
`1.177
`1.189
`0.883
`0.662
`1217
`1.140
`0.97
`O
`0.326
`0.254
`
`147
`0.89
`9
`1,282
`2 6
`1556
`0.902
`0948
`1393
`0.794
`1,169
`0.944
`147
`0.724.
`
`1219
`1063
`1.123
`0.317
`0.626
`1,116
`1626
`1080
`
`
`
`Optineb
`
`0.167
`0.439
`12
`0.333
`0.312
`13
`0.117
`0.549
`14
`0.149
`Mean 0.762
`0.062
`SD 0.319
`0.083
`Min
`0.312
`0.142
`Median 0.696
`Max 1559 0333
`GM 0.707
`NP
`?h raamrtric Mean
`Sented
`
`0.426
`0.390
`0.531
`0.155
`0.315
`0.531
`0816
`0510
`
`0.757
`0.852
`0.705
`
`0.441
`0435
`0.553
`0.154
`0.360
`0.546
`0.852
`0.533
`
`

`

`Patent Application Publication
`
`US 2012/0177693 A1
`
`Jul. 12, 2012 Sheet 11 of 20
`Fig. 12
`Summary of Individual Treprostinil Dose Adjusted Pharmacokinetic Parameters (n=14)
`on selotola. It al..."
`Admin Subject DOSe (ug) (ng/mLug) (hr.ng/mLug) (hring/mL/Ug)
`AERx
`1
`15.830
`0.019
`0.024
`0.026
`2
`26,614
`0.039
`0.024
`0.024
`3
`25.364
`0.030
`0.026
`0.027
`4
`12770
`0.024
`0.031
`0.032
`5
`27.533
`0.019
`0.038
`0.038
`6
`29,630
`0.027
`0.031
`0.031
`8
`25,686
`0.019
`0.028
`0.030
`9
`30756
`0.044
`0.039
`0.039
`10
`30.450
`0.026
`0.024
`0.025
`11
`27.233
`0.016
`0.028
`0.029
`
`
`
`Optineb
`
`0.026
`0.020
`29.98
`14
`0.028
`0.024
`Mean 26,072
`0.005
`0.008
`SD
`5.332
`0.023
`0.016
`Min
`12770
`0.028
`0.022
`Median 27383
`0.039
`0.044
`Max 30756
`0.028
`0.023
`GM
`NP
`0.028
`0.037
`14512
`0.021
`0.058
`2
`20082
`0.020
`0.045
`17464
`3
`0.061
`0.069
`5
`9.296
`0.033
`0.055
`6
`18,433
`0.028
`0037
`7
`17685
`0.02
`0.023
`8
`30.691
`0.047
`0.056
`9
`15,725
`0.029
`0.056
`10
`27.957
`0.015
`0.02
`12
`20.757
`0.023
`0.033
`14
`16,754
`0.029
`0.04
`Mean 19579
`0.012
`0.016
`SD
`5467
`0.015
`0.017
`Min
`9.296
`0.026
`0037
`Median 18470
`0.06
`0.069
`Max 30.69
`0.027
`0.037
`GM
`NP
`GM - Geometric Mean
`NP - Not Presented
`
`0.026
`0.029
`0.005
`0.023
`0.029
`0.039
`0.029
`0.029
`0021
`0021
`0.063
`0.035
`0.029
`0021
`0.048
`0.030
`0.017
`0.026
`0080
`0.012
`0.017
`0.027
`0.063
`0.028
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 12 of 20
`
`US 2012/0177693 A1
`
`
`
`Fig. 13
`Summary of Adverse Events by Organ System a Preferred Term: Safety/ITTPopulation
`Number of Subjects
`(%brackets)
`Nebu-TeC
`Optineb
`
`AERXESSence
`
`Preferred Term
`Organ System
`General disorders and CHEST DISCOMFORT
`administration site
`COnditions
`Nervous system
`disorders
`
`Respiratory, thoracic
`and mediastinal
`disorders
`
`2 (143)
`2 (143)
`2 (143)
`O
`DZZINESS
`O
`(7.1)
`SYNCOPE VASOVAGAL
`(71)
`1
`0
`|
`DRYTHROAT
`O
`(7.1)
`DYSPNOEA
`(7.1)
`1
`OT
`PHARYNGOLARYNGEALPAIN
`O
`(7.1)
`PLEURITICPAIN
`(7.1)
`1
`0
`PRODUCTIVECOUGH
`NB: Each subject contributes only once to the count of each adverse avent within each dose
`regardless of the number of reported episodes
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 13 of 20
`
`US 2012/0177693 A1
`
`
`
`Fig. 14
`Summary of Adverse Events by Relationship: Safety/ITTPopulation
`Number of Subjects
`PROBABLE POSSIBLE UNLIKELY
`
`AERx Essence
`
`Preferred Term
`Organ System
`Generaldisorders and CHEST DISCOMFORT
`administration site
`COnditions
`HEADACHE
`Nervous system
`SYNCOPE WASOWAGAL
`disorders
`Respiratory, thoracic COUGH
`and mediastinal
`DYSPNOEA
`disorders
`PLEURITIC PAIN
`Nebu-Teo OptinebGeneral disorders and CHEST DISCOMFORT
`administration site
`COnditions
`Nervous system
`DZZINESS
`disorders
`HEADACHE
`2
`4
`Respiratory, thoracic COUGH
`1
`0
`and mediastinal
`DRY THROAT
`1
`0
`disorders
`PHARYNGOLARYNGEAL PAIN
`O.
`O
`PRODUCTIVE COUGH
`NB: Counts represent the number of subjects experiencing the adverse event within a relationship within
`each administration.
`
`3
`
`O
`
`O
`0.
`0.
`1
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 14 of 20
`
`US 2012/0177693 A1
`
`
`
`Fig. 15
`Summary of Adverse Events by Severity: Safety/ITTPopulation
`Number of Subjects
`MILD
`MODERATE
`
`AERx Essence
`
`Preferred Term
`Organ System
`General disorders and CHEST DISCOMFORT
`administration site
`COnditions
`Nervous system
`HEADACHE
`disorders
`SYNCOPE WASOVAGAL
`Respiratory, thoracic COUGH
`and mediastinal
`DYSPNOEA
`disorders
`PLEURITIC PAIN
`Nebu-Teo Optineb|General disorders and CHEST DISCOMFORT
`administration site
`COnditions
`DZZINESS
`Nervous system
`HEADACHE
`disorders
`Respiratory, thoracic COUGH
`and mediastinal
`DRY THROAT
`disorders
`PHARYNGOLARYNGEAL PAIN
`PRODUCTIVE COUGH
`NB: Counts represent the number of subjects experiencing the adverse event within a severity within
`each administration.
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 15 of 20
`
`US 2012/0177693 A1
`
`Abnormal Laboratory Value Listing (Each Subject)
`Biochemistry Out of Range Results
`Parameter
`Result low Range High Range Units
`Calcium
`223 226
`2.67 MMOLL
`Calcium
`221
`226
`2.67 MMOLL
`Creatinine
`719 734
`13.8 UMOLL
`Cholesterol
`6.14
`000
`520 MMOLL
`Cholesterol
`552 000
`520 MMOLL
`Urea
`82
`29
`75 MMOLL
`
`Visit
`Pre-Study
`Post-Study
`Post-Study
`Pre-Study
`Post-Study
`Post-Study
`
`Pre-Study
`Post-Study
`
`Uric Acid
`Urea
`
`052 0.23
`76
`29
`
`0.45 MMOLL
`75 MMOLL
`
`
`
`Subject
`
`2
`3
`3
`3
`
`4
`4
`
`Pre-Study
`
`Cholesterol
`
`0.00
`
`5.20
`
`MMOLL
`
`E. E. E. G. ME
`
`E. E. A. E. E.
`Post-Stud
`Glucose
`7.2
`3.6
`6
`Post-Study
`Total Protein
`825 657
`6
`Post-Study Rpt.
`Cholesterol
`527 000
`Fig 16 s
`PostSucy Rp.
`Creatinine
`585 734
`6
`Post-Study Rpt.
`Total Protein
`839
`66.7
`8
`Pre-Study
`Cholesterol
`529 000
`8
`Post-Study
`AST
`152
`160
`8
`Post-Study
`Calcium
`214 2.25
`8
`Post-Study
`Cholesterol
`562 000
`8
`Pre-Study
`Albumin
`51.1
`420
`9
`Pre-Study
`Total Protein
`828
`66.7
`9
`Pre-Study
`Uric Acid
`022
`0.23
`9
`Post-Study
`Albumin
`508 420
`9
`Post-Study
`Sodium
`1446 1360
`9
`Post-Study
`Uric Acid
`022 023
`11
`Pre-Study
`Cholesterol
`570
`000
`11
`Post-Study
`AST
`15.8
`160
`12
`Pre-Study
`Cholesterol
`512 000
`12
`Post-Study
`Cholesterol
`596
`000
`13
`Pre-Study
`Albumin
`57 420
`13
`Pre-Study
`Sodium
`1451 1380
`13
`Pre-Study
`Total Protein
`839 66.7
`13
`Post-Study
`Albumin
`59 420
`13
`Post-Study
`Sodium
`1454. 1360
`13
`Post-Study
`Total Protein
`820
`66.7
`14
`Pre-Study
`Cholesterol
`650 000
`14
`Post-Study Alkaline Phosphatase 1206 1249
`
`5
`5
`6
`6
`
`Pre-Study
`Post-Study
`Pre-Study
`Pre-Study
`
`Sodium
`Cholestero
`Creatinine
`Total Protein
`
`1444. 1360
`521
`000
`729 734
`826
`66.7
`
`1449 MMOLL
`520 MMOLL
`1188 UMOLL
`808
`G/L
`
`E. E.
`MMOLL
`5.7
`GL
`808
`520 MMOLL
`1138 UMOLL
`808
`G/L
`
`U/L
`257 MMOLL
`520 MMOLL
`505
`G/L
`808
`G/L
`0.45 MMOLL
`505
`GL
`144.3 MMOLL
`0.46 MMOLL
`520 MMOLL
`
`G/L
`505
`144.3 MMOLL
`808
`GL
`505
`GL
`144.3 MMOLL
`808
`G/L
`520 MMOLL
`294.3
`IU/L
`
`Post-Stud
`Post-Study
`
`Cholesterol
`Uric Acid
`
`5,27
`O.47
`
`0.00
`0.23
`
`MMOLL
`5.20
`0.45 MMOLL
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 16 of 20
`
`US 2012/0177693 A1
`
`Fig. 17
`Hematology Out of Range Results
`
`2.0
`15
`Neutrophis
`40
`White Blood Cells 38
`20
`Neutrophis
`78
`Mean Cell Volume 795 80.6
`Mean Cell Volume 79.9
`80.6
`
`74
`106
`74
`96.4
`96.4
`
`10"9/L
`10"9/L
`10"9/L
`FL
`FL
`
`HematoCrit
`Hemoglobin
`Red Blood Cells
`
`Platelets
`
`0.365 0.396
`
`426 445
`
`5.67
`
`10"12/L
`
`10"9/L
`
`806
`
`96.4
`
`FL
`
`Mean Cell Volume
`Mean Cell Volume 79.9
`Hemoglobin
`
`Platelets
`
`Post-Study
`Post-Study
`Pre-Study
`re-Stud
`Pre-Study
`Pre-Study
`Post-Study
`OSt-Stud
`Post-Study
`Ost-Study
`Post-Study
`ost-Study
`Post-Study
`OSt-Stud
`Post-Study
`Ost-Study
`Pre-Study
`Pre-Stud
`Post-Study
`POSt-Stud
`Post-Study
`ost-Study
`Pre-Study
`Pre-Study
`
`Ost-Study
`Post-Study
`OSt-Stud
`Ost-Study
`Pre-Study
`re-Study
`re-Stud
`Pre-Study Rp
`Pre-Study Rpt.
`Pre-Study RO
`
`HematoCrit
`Hemodlobin
`Red Blood Cells
`Neutrophis
`White Blood Cells
`Neutrophils
`White Blood Cells
`
`0.396
`
`441. 445
`11.3
`2.0
`
`5.67
`74
`
`10"12/L
`10"9/L
`
`
`
`1
`1
`2
`3
`3
`5
`5
`5
`6
`7
`7
`8
`8
`
`11
`
`13
`
`1
`13
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 17 of 20
`
`US 2012/0177693 A1
`
`
`
`Subject
`1
`1
`1
`1
`
`4
`
`9
`
`Fig. 18
`Urinalysis Out of Range Results
`Parameter
`Result
`Protein
`Trace
`Protein
`Trace
`
`Visit
`Pre-Study
`Post-Study
`POSt-Stud
`Post-Study Rpt
`Post-Study Rpt
`
`Normal Range
`Negative
`Negative
`
`3.0 -> 15.0 Umol/L
`
`POSt-Stud
`
`Pre-Study
`
`POSt-Stud
`
`Pre-Study
`
`Pre-Stud
`Post-Stud
`
`POSt-Stud
`
`SG
`
`>=1030
`
`1.005-> 1.030
`
`Blood
`
`Trace
`
`Negative
`
`>=1030
`
`1.005 -> 1,030
`
`1.005 -> 1,030
`
`>=1030
`
`1.005-> 1.030
`
`Pre-Stud
`
`>=1.030
`
`1.005-> 1,030
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 18 of 20
`
`US 2012/0177693 A1
`
`Fig. 19A
`Summary of Lung Function Test Results: Safety/ITTPopulation
`FEV1 Value (Litres)
`
`AERXESSence
`
`Time Point
`Day -1
`
`Sid Dev
`
`N. Mean
`14
`4.282
`
`Min Median Max
`2.75
`4.08 6.35
`
`Nebu-Teo Optineb
`
`Day 1 (Approx 4hrs after dose)
`Day 1 (Approx65mins after dose)
`Day 1 (Approx 4hrs after dose)
`
`14.
`14
`14.
`
`4.104
`3,846
`4.105
`
`2.79
`0.956
`0.643 245
`0.95 2.55
`
`372 6.11
`3.625,74
`3.88 6.60
`
`FEV1% Predicted
`
`Fig. 19B
`
`AERXESSence
`
`Admin.
`
`Time Point
`Day 1 (Approx 4hrs after dose)
`Nebu-Teo OptinebDay-1
`Day 1 (Approx65mins after dose)
`Day 1 (Approx 4hrs after dose)
`
`N. Mean Sid Dev
`14
`105.7
`13.3
`
`14
`14
`14.
`14
`
`100.2
`106.3
`95.1
`101.2
`
`15.2
`15.3
`11.7
`12.9
`
`Median Max
`Min
`el tale
`128
`77
`99 123
`80
`104
`132
`72
`98
`16
`77
`102
`133
`
`PVC Value (Litres)
`
`
`
`AERX Essence
`
`Nebu-Teo Optineb
`
`Fig. 19C
`
`Time Point
`Day 1 (AOOrox 65mins after dose
`
`N. Mean
`14
`
`Min Median Max
`Std Dev
`re
`1078 3.67
`7.78
`
`Day 1 (Approx65mins after dose)
`
`14
`
`5.054
`
`1,081
`
`3.18
`
`498 7.34
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 19 of 20
`
`US 2012/0177693 A1
`
`Fig. 19D
`Summary of Lung Function Test Results: Safety/ITTPopulation
`
`Time Point
`Day -
`Day 1 (Approx65mins after dose)
`
`N. Mean
`14
`113.4
`13
`98.1
`
`Sid Dev
`13.6
`139
`
`Min
`
`85
`
`Median Max
`112
`135
`98 115
`
`FWC Predicted
`
`Admin.
`AERX Essence
`
`Nebu-Teo Optineb
`
`FEV1/FWC Walue
`
`Admin.
`
`AERx Essence
`
`Nebu-Teo Optineb
`
`Day 1 (Approx 4hrs after dose)
`
`14
`
`1091
`
`126
`
`80
`
`109 137
`
`Fig. 19E
`
`Median Max
`Min
`Sid Dev
`N Mean
`anal slie roles
`Time Point
`78.99 84.24
`4.254 71.48
`14 77.736
`Day 1 (Approx65mins after dose) 1877.375
`8,210 65.25 753898.55
`
`Day 1 (Approx 4hrs after dose)
`
`14 77.369
`
`5.272 68.06
`
`78,5784.55
`
`Fig. 19F
`
`FEV1/FVC 9, Predicted
`
`
`
`AERX Essence
`
`Time Point
`Day -1
`Day 1 (ADOrOX 65mins after dose
`Day 1 (Approx 4hrs after dose)
`Nebu-Teo OptinebDay-1
`Day 1 (Approx65mins after dose)
`Day 1 (Approx 4hrs after dose)
`
`N. Mean Std Dev
`14
`
`Min
`88
`
`Median Max
`95 101
`
`14
`14
`14
`14.
`
`92.9
`94.5
`93.5
`939
`
`50
`45
`3.7
`50
`
`86
`89
`89
`89
`
`93 101
`95 100
`95 101
`95 100
`
`

`

`Patent Application Publication
`
`Jul. 12, 2012 Sheet 20 of 20
`
`US 2012/0177693 A1
`
`Fig. 19G
`Summary of Lung Function Test Results: Safety/ITT Population
`PEFR Value (Litres)
`
`AERXESSence
`
`Day -1
`
`Nebu-Teo Optineb
`
`Min
`N. Mean Sid Dev
`14598.886 94.457438.20
`
`Median Max
`758.50
`
`Fig. 19H
`
`PEFR% Predicted
`
`
`
`Admin.
`
`AERX Essence
`
`Nebu-Teo Optineb
`
`Time Point
`Day -1
`Day 1 (Approx65mins after dose)
`Day 1 (Approx 4hrs after dose)
`Day 1 (Approx65mins after dose)
`Day 1 (Approx 4hrs after dose)
`
`Median Max
`Min
`Sid Dev
`N. Mean
`is a el toll to
`14
`105.9
`13.4
`82
`104
`130
`839
`93
`69
`84 100
`13
`99.1
`12.6
`81
`102
`125
`14
`107.6
`12,
`94
`104
`127
`14
`91.9
`11.3
`76
`90
`14
`972
`14.1
`76
`96 121
`14
`
`

`

`US 2012/0177693 A1
`
`Jul. 12, 2012
`
`DEEP LUNG PULMONARY DELVERY OF
`TREPROSTNL
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`0001. The present application claims priority to U.S. pro
`visional patent application No. 61/100,017 filed Sep. 25.
`2009, which is incorporated herein by reference in its entirety.
`
`FIELD
`0002 The present application relates in general to thera
`peutic methods and in particular to therapeutic methods,
`which may involve pulmonary delivery of inhaled com
`pounds. Such pulmonary delivery may reduce a dose, a side
`effect profile and/or a frequency of administration. In addi
`tion, such delivery may provide a depot effect in the periph
`eral lung with associated prolonged release into the systemic
`circulation.
`
`BACKGROUND
`0003) A large number of drugs may be generally admin
`istered by some type of injection. Although injecting drugs
`can provide a number of advantages, at times, for some
`patients, it may be inconvenient, and/or painful. One class of
`drugs generally administered by injection is prostacyclin and
`its analogues, such as Treprostinil.
`0004 Treprostinil is a synthetic analogue of prostacyclin.
`Treprostinil is marketed as Remodulin. As an analogue of
`protacyclin PGI2, treprostinil may affect vasodilation, which
`in turn may lower the blood pressure. Treprostinil may also
`inhibit platelet aggregation, though the role this phenomenon
`may play in relation to pulmonary hypertension has yet to be
`determined.
`0005 Treprostinil was first described in U.S. Pat. No.
`4,306,075. U.S. Pat. No. 5,153,222 discloses use of trepros
`tinil for treatment of pulmonary hypertension. U.S. Pat. No.
`5,234,953 discloses treatment of congestive heart failure with
`treprostinil. U.S. Pat. Nos. 6,765,117 and 6,809,223 disclose
`stereoselective process for treprostinil synthesis. U.S. Pat.
`Nos. 6,521,212 and 6,756,033 describe administration of tre
`prostinil by inhalation for treatment of pulmonary hyperten
`Sion, peripheral vascular disease and other diseases and con
`ditions. U.S. Pat. No. 6,054,486 discloses treatment of
`peripheral vascular disease with Treprostinil. U.S. Pat. No.
`6,803.386 discloses administration of treprostinil for treating
`cancer. Such as lung, liver, brain, pancreatic, kidney, prostate,
`breast, colon and head-neck cancer. US patent application
`publication no. 2005/0165111 discloses treprostinil treat
`ment of ischemic lesions. U.S. Pat. No. 7,199,157 discloses
`that treprostinil treatment improves kidney functions. US
`patent application publication no. 2005/0282903 discloses
`treprostinil treatment of diabetic neuropathic foot ulcers. US
`patent application publication no. 2008/0280986 discloses
`treatment of interstitial lung disease with Treprostinil. US
`patent application publication no. 2008/0200449 discloses
`administration of Treprostinil via a metered dose inhaler. US
`patent application publication no. 2009/0163738 discloses an
`alternative process for preparation treprostinil. U.S. Pat. Nos.
`7,417,070; 7,384,978 and 7,544,713 disclose oral forms of
`treprostinil. US patent application publication no. 2009/
`0036,465 discloses administration of treprostinil in combina
`tion with Rho-kinase inhibitors. U.S. provisional application
`No. 61/176,268 discloses solid formulations of treprostinil.
`
`0006 Treprostinil may be used in the treatment and/or
`prevention of for: pulmonary hypertension, ischemic dis
`eases (e.g. peripheral vascular disease including peripheral
`arterial
`disease, Raynaud's phenomenon including
`Raynaud's disease and Raynaud's syndrome, Scleroderma
`including systemic Sclerosis, myocardial ischemia, ischemic
`stroke, renal insufficiency), ischemic ulcers including digital
`ulcers, heart failure (including congestive heart failure), con
`ditions requiring anticoagulation (e.g., post MI, post cardiac
`Surgery), thrombotic microangiopathy, extracorporeal circu
`lation, central retinal vein occlusion, atherosclerosis, inflam
`matory diseases (e.g., COPD, psoriasis), hypertension (e.g.,
`preeclampsia), reproduction and parturition, cancer or other
`conditions of unregulated cell growth, cell/tissue preserva
`tion and other emerging therapeutic areas where prostacyclin
`treatment appears to have a beneficial role.
`0007 Treprostinil may be administered via a small infu
`sion pump that a patient must wear at all times. Treprostinil
`may be given Subcutaneously using an infusion set, or intra
`venously via acentral venous catheter if the patient is unable
`to tolerate the potential pain and discomfort of Subcutaneous
`administration.
`0008 Treprostinil, under the trademark Remodulin, may
`be supplied in 20 mL vials, ranging in concentrations of 1
`mg/mL, 2.5 mg/ML, 5 mg/mL, and 10 mg/mL. Treprostinil
`can be administered subcutaneously as Supplied. For intrave
`nous infusion, treprostinil is usually diluted with either sterile
`water or a 0.9% sodium chloride solution prior to adminis
`tration.
`0009. The infusion rate may be normally initiated at 1.25
`ng/kg/min for new patients, but may be reduced to 0.625
`ng/kg/min if the normal rate provokes unwanted side effects
`in the patient. The infusion rate of treprostinil may be
`increased no more than 1.25 ng/kg/min per week for the first
`month, then no more than 2.5 ng/kg/min per week for the
`remaining duration of infusion. The infusion rate should ide
`ally be high enough to improve symptoms of pulmonary
`hypertension, while minimizing unpleasant side effects.
`0010. A high percentage of patients report pain or other
`reaction at the infusion site. Other side effects may include
`headache, diarrhea, nausea, rash, jaw pain, vasodilation, diz
`Ziness, edema (Swelling), pruritus (itching), and hypotension.
`0011
`Remodulin(R) (treprostinil sodium) Injection can be
`a sterile sodium salt formulation for Subcutaneous or intrave
`nous administration. Remodulin can be supplied in 20 mL
`multi-use vials in four strengths, containing 1 mg/mL, 2.5
`mg/mL, 5 mg/mL or 10 mg/mL of treprostinil. Each mL also
`contains 5.3 mg Sodium chloride (except for the 10 mg/mL
`strength which contains 4.0 mg Sodium chloride), 3.0 mg
`metacresol, 6.3 mg Sodium citrate, and water for injection.
`Sodium hydroxide and hydrochloric acid may be added to
`adjust pH between 6.0 and 7.2.
`0012 Treprostinil has a degree of stability at room tem
`perature and neutral pH.
`0013 Treprostinil sodium is (1R,2R.3aS,9aS)-2,3.3a.4,
`9.9a-Hexahydro-2-hydroxyl-1-(3S)-3-hydroxyoctyl-1H
`benZIf inden-5-yloxyacetic acid monosodium salt. Trepro
`stinil Sodium has a molecular weight of 412.49 and a
`molecular formulation of C23H33NaO5.
`
`

`

`US 2012/0177693 A1
`
`Jul. 12, 2012
`
`0014. The structural formula of treprostinil sodium is:
`
`
`
`H
`
`OCH2CO
`Na"
`
`0015. A potential problem with formulation drugs for pull
`monary delivery may be that the formulation can include a
`relatively high concentration of the drug in order to reduce the
`volume so that the aerosolized volume can be readily inhaled
`by the patient. Another potential problem may be that upon
`delivery all of the drug in the formulation is immediately
`made available to the patient which can mean that too much
`drug may be made available too quickly. Further, it may be
`that the inhaled formulation does not provide any Sustained
`release of drug over time. Formulations of the present inven
`tion endeavor to solve some or all of these problems.
`
`SUMMARY
`
`0016. In one embodiment, a method of treating or prevent
`ing a disease or condition, which is treatable or preventable
`with treprostinil, comprises administering by inhalation to a
`Subject in need thereof, which may be a human, an aero
`Solized formulation comprising treprostinil or a pharmaceu
`tically acceptable salt thereof and a carrier acceptable for
`pulmonary delivery, wherein said aerosolized formulation
`has an aerodynamic diameter of particles or droplets is no
`more than 10 microns or no more than 5 microns or in a range
`from 2 to 10 microns, and wherein said administering results
`in depositing the treprostinil in a deep lung, Such that a ratio
`of central/peripheral lung deposits of the formulation is in a
`range of 1 to 2.0 or 1 to 1.9 or 1 to 1.8 or 1 to 1.7 or 1 to 1.6
`or 1 to 1.5 or 1 to 1.45 or 1:1.4.
`0017 Diseases and conditions, which are treatable or pre
`Ventable with treprostinil, include pulmonary hypertension,
`ischemic diseases (e.g. peripheral vascular disease including
`peripheral arterial disease, Raynaud's phenomenon including
`Raynaud's disease and Raynaud's syndrome, Scleroderma
`including systemic Sclerosis, myocardial ischemia, ischemic
`stroke, renal insufficiency), ischemic ulcers including digital
`ulcers, diabetic neuropathic and neuroischemic ulcer, heart
`failure (including congestive heart failure), conditions requir
`ing anticoagulation (e.g., post MI, post cardiac Surgery).
`thrombotic microangiopathy, extracorporeal circulation, cen
`tral retinal vein occlusion, atherosclerosis, inflammatory dis
`eases (e.g., COPD, psoriasis), hypertension (e.g., preeclamp
`sia), reproduction and parturition, cancer or other conditions
`of unregulated cell growth, cell/tissue preservation and other
`emerging therapeutic areas where prostacyclin treatment
`appears to have a beneficial role.
`0018 Physiologically acceptable salts of Treprostinil
`include salts derived from bases. Base salts include ammo
`nium salts (such as quaternary 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.
`0019 Quaternary ammonium salts can be formed, for
`example, by reaction with lower alkylhalides, such as methyl,
`ethyl, propyl, and butyl chlorides, bromides, and iodides,
`with dialkyl Sulphates, with long chainhalides, such as decyl.
`lauryl, myristyl, and Stearyl chlorides, bromides, and iodides,
`and with aralkyl halides, such as benzyl and phenethyl bro
`mides.
`0020. The carrier(s) must be “acceptable' in the sense of
`being compatible with the other ingredients of the formula
`tion and not deleterious to the recipient thereof. The carrier
`may be a liquid or a solid.
`0021 Aerosolized delivery of Treprostinil may result in a
`more homogeneous distribution of treprostinil in a lung, so
`that deep lung delivery is obtained. The deep lung delivery
`may result in an increased T
`and a decreased C as
`compared to upper respiratory tract delivery.
`0022. In some embodiments, the formulation may be a
`liposome free formulation. Yet in Some embodiments, trepos
`tinil may be administered together with liposomes.
`0023. Using polymer coatings or liposomes with the tre
`prostinil may further increase The T may increased fur
`ther and further decrease the C. The decreased C may
`result in reduced side effects, and the increased T results
`in a more convenient delivery.
`0024. This invention may relate to inhaled delivery of
`drugs which may exhibit delayed absorption from the periph
`eral lung or alveolar space due to sequestering in the lung
`interstitium, binding to cells, membranes or receptors, uptake
`by alveolar cells or macrophages, or via Some other mecha
`nism. Of particular interest are drugs which have systemic
`side effects and/or which exhibit pharmacological activity in
`the deep lung or alveolar space; e.g., treprostinil.
`0025. The methodology of the present invention provides
`increased efficacy at lower doses due to the Sustained pres
`ence of the drug at the site of action in the deep lung.
`0026. The invention also provides a reduction in side
`effects resulting from a decreased C as well as a prolon
`gation of T in the Systemic circulation.
`0027. There may be multiple ways to enable and optimize
`delivery of the aforementioned drugs to the deep lung. For
`example, aerosol delivery system include DPIs, MDIs, nebu
`lizers, Solution inhalers, vapor condensation aerosol genera
`tors. Delivery can also be obtained via the use of aerosols
`containing lower density or geometrically smaller droplets or
`particles, or via slower inhalation flow rates to reduce impac
`tion in the oropharynx and central airways.
`0028. Of particular interest is the use of Aradigm's AERX
`Essence system and AERX family of devices, which are
`described, for example, in U.S. Pat. Nos. 5,497,763; and
`6,123,068 and related U.S. and non-U.S. patents and publi
`cations all of which are incorporated herein by reference to
`disclose and describe delivery devices, packets that hold drug
`and methods of administration. In the present human PK and
`gamma Scintigraphic clinical trial, the AERX Essence system
`and the Nebu-Tec OPTINEB nebulizer were compared in a
`cross over fashion in 14 healthy Subjects using inhaled tre
`prostinil sodium. The AERX system provided greater deep
`lung delivery (mean Central/Peripheral lung ratio from planar
`gamma Scintigraphy of 1.39) as compared to the nebulizer
`(mean Central/Peripheral lung (C/P) ratio of 3.96) which was
`associated with a delayed Tfor the AERX Essence System
`
`

`

`US 2012/0177693 A1
`
`Jul. 12, 2012
`
`(mean 21 minutes) than for that of the nebulizer (mean 9
`minutes). The C was also lower for AERX (mean 0.64
`ng/mL) than for the nebulizer (mean 0.762 ng/mL) even with
`a 20% greater treprostinil lung dose for AERX than for the
`nebulizer, Suggesting that adverse events may be reduced for
`an AERX Essence inhalation product.
`0029 Generally, adverse events are related to the peak
`concentration of treprostinil in the blood stream (Voswinckel
`et al., “Favorable Effects of Inhaled Treprostinil in Severe
`Pulmonary Hypertension: Results from Randomized Con
`trolled Pilot Studies' J. Am. Coll. Cardiol. 48(8): 1672-1681
`(2006)) and the authors Suggest, “that the systemic plasma
`concentration might determine the systemic side effect pro
`file, while local lung tissue concentrations determine the pull
`monary vasodilator effect.”
`0030 Voswinckel et al. compare and contrast inhaledilo
`prost to inhaled treprostinil and state the following:
`0031 “The long duration of pulmonary vasodilation after
`a single inhalation of treprostinil may be partially explained
`by the stability of this prostanoid. We speculate that trepros
`tinil is stored in the lung tissue after inhalation, providing a
`slow release from the alveolar lining layer or the interstitial
`compartment to the pulmonary vascular S