Exhibit 1001
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1001
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01799
`
`

`
`(12) Ulllted States Patent
`Kottayil et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,835,460 B2
`*Sep. 16, 2014
`
`US008835460B2
`
`(72)
`
`Inventors: S. George Kottayil, Long Grove, IL
`<Us>;R-
`AZ (US)? Zhongyuan Zhusvernon
`Hillss IL (US); Linet Katmokafalls
`Mount Prospect, IL (US); Nelia Parikli,
`Chjcagga IL (US)
`
`(73) Assignee:
`
`Insys Therapeutics, Inc., Phoenix, AZ
`(US)
`
`5/2002 McCoy et a1.
`2002/0055496 A1
`(54) SUBLINGUAL FENTANYL SPRAY AND
`12/533;
`II
`OF :33:/3123221221
`ugger,
`3
`.
`3
`4/2003
`,II
`.
`.
`.
`2003/0077228 A1
`4/2003 £33: I I
`(71) Applicant: Insys Therapeutics, Inc., Phoenix, AZ
`2003/0077229 A1
`5/2003 Dugger, 1 1
`(US)
`2003/0082107 A1
`5/2003 Dugger, II
`2003/0095925 A1
`5/2003 Duggefa I I
`2003/0095925 A1
`10/2883 3:22:11
`:33:/21232:; :1
`2003/01901290 :A1=!< 10/2003
`{Gig
`.......................... N 424/45
`2004/0092428 A1
`5/2004 Chen et al.
`2004/0120895 A1
`6/2004 Dugger, I I
`2004/0136913 Al
`7/2004 Dugger, I I et al.
`2004/0136914 Al
`7/2004
`)ugger, I I et al.
`333:: % % Z: 2%‘
`12/2004 Dugger: 1 1 et al.
`2004/0265239 A1
`jugger, I I et al.
`l/2005
`2005/0002867 A1
`7/2005 Dugger, I I et al.
`2005/0163719 A1
`8/2005 Duggefa I I et 31~
`2005/0180923 A1
`12:22: 3:::::»11
`5332/3220: :1
`12/2005
`)ugge13 11
`2005/0237075 A1
`2332/3320: :11 3/533:
`.
`c any ..................... ..
`"
`2007/0261695 A1
`11/2007
`iottayil et al.
`2009/0124554 A1
`5/2009
`)ugger, 1 1
`2009/0162300 Al
`6/2009 Dugger, II
`
`( * ) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`w4<b>byodays.
`This patent is subject to a terminal dis-
`
`(21) APP1~ N04 13/895,124
`
`(22) Filed:
`
`May 15, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2013/0327321 Al
`
`Dec. 12, 2013
`
`Related U.S. Application Data
`,
`,
`,
`,
`(63) Continuation of application No. 11/698,739, filed on
`Jan. 25, 2007, now Pat. No. 8,486,972.
`
`(60) Provisional application No. 60/762,057, filed on Jan.
`25, 2006.
`
`FOREIGN PATEl\T DOCUMENTS
`
`9/2000
`2156126
`RU
`7/2004
`2232530
`RU
`7/1990
`W0 90/07333
`W0
`8/2000
`W0 00/47203
`W0
`12/2001
`WO 01/97780
`W0
`2/2004
`WO 2004/016243 A2
`W0
`9/2004
`wo 2004/080332
`wo
`10/2004
`WO 2004/075877
`W0
`l/2007
`W0 W0 2007—007059
`3/2007
`W0
`WO 2007/087431
`OTHER PUBLICATIONS
`
`(51)
`
`(2006.01)
`2006.01
`E2006.01§
`(200601)
`(2006.01)
`(2006.01)
`
`Int_ Cl_
`A01N43/40
`A61K31/445
`A61M11/00
`A6lK 31/4468
`A61K31/435
`A6lK 9/00
`(52) US, C],
`CPC .......... .. A6lK 31/4468 (2013.01); A61M 11/00
`(2013.01); A61K31/445 (2013.01); A61K
`31/435 (2013.01);A61K 9/0056 (2013.01);
`A6lK 9/006 (201301)
`USPC .................................... .. 514/329; 128/200.14
`(58) Field of Classification Search
`CPC ......................... .. A6lK 31/4468; A61M 11/00
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,244,478 A
`5,219,083 A
`5,958,379 A
`5,976,504 A
`6,759,059 B1
`6,946,150 B2
`8,486,973 B2
`
`1/1981 Handman
`6/1993 Liebert et al.
`9/1999 Regenold et 211.
`ll/1999 Russell
`7/2004 Pettersson et al.
`9/2005 Whittle
`7/2013 Kottayil et al.
`
`Examination Report for corresponding European Patent Application
`1:0. 0177625t49.9],Ema11edo;1 Sepai), 201102.
`f
`d_
`upp emen ary uropean _ earc
`epo , _ pages, or correspon mg
`§(1)1{(5pean Patent Application No. 077625499, mailed on Sep. 30,
`Office Action on Chinese Patent Application No. 200780003555.X
`dated Jul. 9, 2010.
`International Search Report and Written Opinion, dated Jul. 11, 2008
`from corresponding Int’l Application No. PCT/US07/02163.
`Mathflra LE» ct 31; “Pulmonifiry 3dminiSt_mti°1_1 °f”a°T0S°1iS_°d
`fentanyl: pharmacokmetic analysis of systemic delivery Br. J. Clin.
`Ph“.m‘*°°1~ J3” 199} V°1~461 PP 3.7"”.
`Marier, J-F., et al. Comparative bioequivalence study between a
`novel matrix transdermal delivery system of fentanyl and a commer-
`eiauy available reservoir formulation», Br. J.C1in.PharmaeO1.Aug.
`2006, vol. 63, No. 1, pp. 121-124, esp. p. 123, Figure 1.
`.
`(commued)
`Primary Examiner — Robcrt Landsman
`(74) Attorney, Agent, or Firm — Wood, Phillips, Katz, Clark
`& Mortimer
`
`ABSTRACT
`(57)
`The present invention is directed to sublingual formulations
`containing fentanyl, a phannaceutically acceptable salt
`thereof, or derivative thereof, suitable for administration to a
`patient, and methods for treatment with the formulations.
`
`5 Claims, 7 Drawing Sheets
`
`

`
`US 8,835,460 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`International Preliminary Report on Patentability dated Sep. 4, 2008
`from corresponding Int’l Application No. PCT/US07/02163.
`Examination Report dated Aug. 6. 2009 from corresponding Austra-
`lian Application No. 2007208229.
`Examination Report dated May 5, 2010 from corresponding Cana-
`dian Application No. 2,637,672.
`Examination Report dated Mar. 18, 2010 from corresponding New
`Zealand Application No. 569949.
`An English translation ofthe Russian Examination Report dated Aug.
`2009 from corresponding Russian Application No. 2008130763.
`
`ISR and Written Opinion from related Int’l Application No. PCT/
`US08/09359 dated Jan. 9, 2009.
`Int”1 Preliminary Report on Patentability from related Int’1 Applica-
`tion No. PCTIUS08/09359 dated Feb. 2, 2010.
`Lejus. et al.. “Fentanyl Versus sufentanil: plasma concentrations dur-
`ing continuous epidural postoperative infusion in children,” British
`Journal ofAnaesthesia, Vol. 85, Issue 4, Oct. 2000, pp. 615-617.
`Examination Report dated Feb. 9, 2011 from corresponding Austra-
`lian Application No. 2008282743.
`Examination Report dated Nov. 1, 2012 from corresponding Austra-
`lian Application No. 2008282743.
`Smyth, et al., 2003, AAPS PharmSciTech 2003; 4 (3):1-11.
`
`’l‘ cited by examiner
`
`

`
`U.S. Patent
`
`Sep. 16, 2014
`
`Sheet 1 of7
`
`US 8,835,460 B2
`
`Plasma concentration-time curves afier IV & SL doses of Fentanyl
`
`Figure 1: Formula of Example 1, 50 pg IV dose
`
`F1 -IV Dose Time Concentration Profile
`
`
`
`Concentration(nglml)
`
`Time (min)
`
`'60
`
`80
`
`Mean (iS.E.) plasma concentration—time profiles following intravenous administration of
`Fentanyl (n=3).
`
`Figure 2: Formula of Example 1, 50 pg Sublingual dose
`
`F1 -SL Dose Time Concentration Profile
`
`900
`800
`700
`
`600
`
`500
`400
`300
`
`200
`100
`
`0
`
`0
`
`i I
`
`E
`
`F‘
`20
`
`3
`
`W
`40
`
`l
`60
`
`I
`80
`
`I
`100
`
`§
`
`I
`120
`
`Fl
`140
`
`Mean (d:S.E.) plasma concentration—time profiles following sublingual administration of
`Fentanyl (n=3)
`
`

`
`U.S. Patent
`
`Sep. 16, 2014
`
`Sheet 2 of7
`
`US 8,835,460 B2
`
`Figure 3: Formula of Example 2, 80 ug IV dose
`
`F#2 IV Dose Time Concentration Profile
`
`Time (min)
`
`60
`
`80
`
`Mean (:tS.E.) plasma concentration—time profiles following intravenous administration of
`Fentanyl (n=3).
`
`Figure 4: Formula of Example 2, 80 ug SL dose
`
`F#2 SL Dose Time Concentration Profile
`
`Time (min)
`
`80
`
`l 6
`
`0
`
`:EB
`
`:5C
`
`_O
`
`E8C 8
`
`Mean (:tS.E.) plasma concentration—time profiles following sublingual administration of
`Fentanyl (n=3)
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 3 of7
`
`US 8,835,460 B2
`
`Figure 5: Formula of Example 3, 50 pg IV dose
`
`F#3 IV Dose time concentration profile
`
`1 200
`
`1 000
`
`800
`
`600
`
`400
`
`200
`
`
`
`Conoeniration(nglml)
`
`0
`
`20
`
`40
`
`60
`
`80
`
`1 00
`
`Time (min)
`
`Mean (iS.E.) plasma concentration—time profiles following intravenous administration of
`Fentanyl (n=3)
`
`Figure 6: Formula of Example 3, 50 pg SL dose
`
`F#3 SL Dose Time Concentration Profile
`
`0')OO
`
`01OO
`
`3 E
`
`.5 5E § 8
`
`Time (min)
`
`60
`
`80
`
`Mean (iS.E.) plasma concentration—time profiles following sublingual administration of
`Fentanyl (n=3)
`
`

`
`U.S. Patent
`
`Sep. 16, 2014
`
`Sheet 4 of7
`
`US 8,835,460 B2
`
`Figure 7: Formula of Example 4, 50 pg IV dose
`
`F4-IV Dose Concentration Profile
`
`1000
`
`800
`
`600
`
`400
`
`(ngImL)
`Concentration
`
`200
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`120
`
`140
`
`Time (min)
`
`
`
`Mean (:tS.E.) plasma concentration—time profiles following intravenous administration of
`Fentanyl (n=3)
`
`Figure 8: Formula of Example 4, 50 pg SL dose
`
`F4-SL Dose Concentration Profile
`
`Time (min)
`
`Concentration(ngImL)
`
`60
`
`80
`
`Mean (iS.E.) plasma concentration—time profiles following sublingual administration of
`Fentanyl (n=3)
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 5 of7
`
`US 8,835,460 B2
`
`Figure 9: Formula ofExample 5, 50 pg IV dose
`
`F-5 IV Dose Time Concentration Profile
`
`1400
`
`E 1200
`E1000
`g
`800
`E
`600
`I:
`3
`400
`
`8
`
`200
`0
`
`{
`
`{
`
`E
`
`£
`
`E
`
`0
`
`20
`
`40
`
`so
`
`so
`
`100
`
`t
`120
`
`140
`
`Time (min)
`
`Mean (iS.E.) plasma concentration-time profiles following intravenous administration of
`Fentanyl (n=3)
`
`Figure 10: Fonnula ofExample 5, 50 pg SL dose
`
`F-5 SL Dose Time Concentration Profile
`
`700 —
`
`3 600 -
`
`5:
`
`E3, 500 —
`400 —
`g 300
`..
`g
`3 200 -
`=
`
`
`
`f
`
`I
`
`i
`
`l
`
`8 100 -
`
`0
`
`O
`
`20
`
`40
`
`80
`60
`Time (min)
`
`100
`
`120
`
`140
`
`Mean (iS.E.) plasma concentration—time profiles following sublingual administration of
`Fentanyl (n=3)
`
`

`
`U.S. Patent
`
`Sep. 16, 2014
`
`Sheet 6 of7
`
`US 8,835,460 B2
`
`Figure 1 1: Vignetting Results Dv10, Dv50, Dv90 vs. Distance from Range Lens
`
`0 Plume Records
`
`a 010 (pm)
`
`A CEO (um:
`
`I D90 (pm)
`
`100
`
`so
`
`so
`
`40
`
`20
`
`o
`
`'
`
`I
`'
`
`g
`
`i
`
`-
`
`-
`
`.
`I
`
`.
`
`'
`
`:
`g
`
`.
`
`'
`
`,
`‘
`
`:
`
`I
`'
`
`,
`:
`
`.
`
`o
`
`5
`
`1o
`
`is
`
`distance (cm)
`
`Figure 12: Exhaust Results DVIO, DVSO, DV90 vs. Distance to Exhaust at 4 cm Device to
`Laser Beam
`
`4cm
`
`0 Fhnmihcm-d5‘ I D1Dl1.vm) A D50(urn] IDKHMID
`
`90
`80
`70
`60
`50
`
`40
`30
`20
`10
`
`IO
`
`Q
`
`I.
`
`.
`I
`
`'
`
`I
`
`3IO9'
`
`II'PD
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`exhuast distance (cm)
`
`Note: 10 cm distance used for plotting of resuks with no exhaust fan present.
`Reference: Notebook I, LDR I08
`
`

`
`U.S. Patent
`
`Sep. 16, 2014
`
`Sheet 7 of 7
`
`US 8,835,460 B2
`
`Figure 13: Exhaust Results Dv10, Dv50, Dv90 vs. Distance to Exhaust at 7 cm Device to
`Laser Beam
`
`TCITI
`
`0 Plume Recotfis‘ I D100-‘ml A 050 (um) I 0901910
`
`80
`70
`
`60
`
`50
`40
`
`30
`20
`10
`0
`
`DOOI
`
`D
`
`2
`
`~l
`
`6
`
`B
`
`10
`
`12
`
`Note: 10 cm distance used for plotting of results with no exhaust fan present.
`Reference: Notebook l. [DR 108
`
`Figure 14: Device to Laser Beam Placement Results, Dv10, DVSO, Dv90 vs. Distance to
`Laser Beam
`
`0 Flume Records
`
`I 010 {um}
`
`1050mm)
`
`lD9°[|-ml
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`IIOO
`
`DI
`
`I
`
`'
`
`3
`
`2
`
`A
`
`I
`
`4
`distance (cm)
`
`

`
`US 8,835,460 B2
`
`1
`SUBLINGUAL FENTANYL SPRAY AND
`METHODS OF TREATING PAIN
`
`EIEID OF THE INVENTION
`
`The invention is directed to sublingual formulations con-
`taining fentanyl, a pharmaceutically acceptable salt thereof,
`or derivative thereof, suitable for administration to humans,
`and methods for treatment with the sublingual formulations.
`
`BACKGROUND OF THE INVENTION
`
`is a u-opioid receptor agonist with analgesic
`Fentanyl
`potency approximately 80-100 times that of morphine. In
`clinical settings, fentanyl exerts its principal pharrnacologic
`effects on the central nervous system. Its primary actions are
`analgesic and sedation.
`The analgesic effects of fentanyl are related to the blood
`level of the drug. In general, the minimum elfective concen-
`tration and the concentration at which toxicity occurs rise
`with increasing tolerance to any and all opioids. The rate of
`development of tolerance may vary widely among individu-
`als. All opioid mu-receptor agonists, including fentanyl, pro-
`duce dose dependent respiratory depression. The risk of res-
`piratory depression is typically less in patients receiving
`chronic opioid therapy wl1o develop tolerance to respiratory
`depression and other opioid effects. Serious or fatal respira-
`tory depression can occur, even at recommended doses, in
`vulnerable individuals.
`Orally administered fe11tanyl is subject to first pass effect
`metabolism as upwards of 50% or more of orally adminis-
`tered fentanyl is not absorbed. Other fomis of delivery such a
`parenteral, buccal, and transdern1al have been utilized to
`decrease or avoid this first pass effect for fentanyl.
`Fe11tanyl is currently available in injectable fom1, as a
`lozenge (e.g. Actiq®; fentanyl citrate; Actiq is a registered
`trademark of Anesta, LLC), and as a transdermal patch (e.g.
`Duragesic® 25, 50, 75, and 100 ug of fentanyl per hour;
`Duragesic is a registered trademark of Johnson & Johnson
`Corporation). Duragesic® provides continuous systemic
`delivery of fentanyl for approximately 72 hours. Duragesic®
`is indicated in the management of chronic pain in patients
`requiring continuous opioid analgesia for pain that is not
`optimally managed with lesser means such as acetarni—
`nophen-opioid combinations, non-steroidal analgesics, or
`pm (as needed) dosing with short-acting opioids. Duragesic®
`is typically not suitable for patients experiencing acute pain
`due to the delay ir1 absorption of the fentanyl through the
`patch, or postoperative pain because serious or life-threaten-
`ing hypoventilation could result.
`Actiq® is a solid formulation of fentanyl citrate, intended
`for oral transmucosal administration. Actiq® is a lozenge
`attached to a handle similar in shape to a lollipop. The handle
`is purportcdly to allow the Actiq® unit to bc rcn1ovcd from
`the mouth if signs of excessive opioid effects appear during
`administration. Actiq® is indicated for the management for
`breakthrough cancer pain in patients with malignancies who
`are already receiving and who are tolerant to opioid therapy
`for their underlying persistent cancer pai11. Actiq® is con-
`traindicated in the management of acute or postoperative
`pair1.
`Sublingual tablets and lozenges (e.g., Actiq®) which may
`be used for acute pain or breakthrough pain have certain
`disadvantages. A disadvantage, amongst others, is that after
`intake the active agent in these pharmaceutical agents must
`first be released and dispersed prior to being available for
`resorption in dissolved form. In addition, the absorption phar-
`
`l0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`2
`macokinetics of fentanyl from Actiq® may vary depending
`on the fraction of the dose that is absorbed through the oral
`mucosa and the fraction swallowed. Further, certain lozenges
`may be in the form ofa candy which require medical super-
`vision and may be socially questionable.
`There exists a need in art for a sublingual formulation
`including fentanyl, a pharmaceutically acceptable salt
`thereof, or derivative thereof, which is suitable for effective
`pain management.
`
`SUMMARY AND OBJECTS OF THE
`INVENTION
`
`t is an object of the invention to provide a fentanyl formu-
`lation suitable for sublingual administration for effective pain
`management.
`t is an object of certain embodiments of the invention to
`provide methods and compositions capable of rapidly induc-
`ing a state of sedation, analgesia, and/or anesthesia.
`t is a further object of certain embodiments of the inven-
`tion to provide methods and compositions for fentanyl admin-
`istration wl1icl1 minimize the u11derdo sing a11d/or overdosing
`of a patient in need of fentanyl therapy.
`t is a further object of certain embodiments of the inven-
`tion to provide methods and compositions suitable for the
`treatment of breakthrough pain in patients receiving chronic
`pain treatment.
`t is a further object of certain embodiments of the present
`invention to provide a method for sublingual administration
`of fentanyl, a pharmaceutically acceptable salt thereof, or
`derivative thereof, in a controlled amount for the treatment of
`pain.
`It is a further object of certain embodiments of the present
`invention to provide a dosage form of an opioid analgesic
`wl1icl1 car1 be ad111i11istered subli11gually i11 a 111a1111er wl1ich
`will cause substantial sublingual absorption witl1out substan-
`tial risk of the dose passing into the lungs of the recipient.
`The above-mentioned objects a11d others are achieved by
`virtue of the present invention, which is directed in part to a
`method for sublingually administering fentanyl, a pharrna-
`ceutically acceptable salt thereof, or derivative thereof, to
`provide fast-acting relief in a formulation in which a substan-
`tial portion ofthe fentanyl, a pharmaceutically acceptable salt
`thereof, or derivative thereof will not be passed into the lungs
`of the patient.
`In certain embodiments the present invention is directed to
`a sublingual fentanyl formulation comprising discrete liquid
`droplets comprising ar1 effective amount of fer1tar1yl, a pl1ar-
`maceutically acceptable salt thereof, or derivative thereof,
`said droplets having a mean diameter of at least about 10
`microns, preferably at least about 20 microns, more prefer-
`ably a mean diameter of fron1 about 20 to about 200 microns.
`In certain embodiments, the present invention is directed to
`a sublingual fentanyl formulation comprising discrctc liquid
`droplets of fentanyl, a pharmaceutically acceptable salt
`thereof, or derivative thereof; in a pharmaceutically accept-
`able liquid carrier; said droplets having a size distribution of
`from about 5 microns to about 500 microns, preferably from
`about 10 microns to about 200 microns, preferably from
`about 20 microns to about 100 microns, more preferably from
`about 30 microns to about 70 microns.
`In certain preferred embodiments, none of the particles
`have a diameter which would allow the fentanyl, pharrnaceu-
`tically acceptable salt thereof, or derivative thereof to be
`delivered to the lung upon sublingual administration.
`In certain embodiments, the present invention is directed to
`a unit dose of a sublingual fentanyl formulation, said unit
`
`

`
`US 8,835,460 B2
`
`3
`dose comprising discrete liquid droplets of fentanyl, a phar-
`maceutically acceptable salt thereof, or derivative thereof;
`and a pharmaceutically acceptable liquid carrier; said drop-
`lets having a mean diameter of at least about 10 microns,
`preferably at least about 20 microns, more preferably a mean
`diameter of from about 20 to about 200 microns.
`In certain embodiments, the present invention is directed to
`a tmit dose of a sublingual fentanyl formulation, said unit
`dose comprising discrete liquid droplets of fentanyl, a phar-
`maceutically acceptable salt thereof, or derivative thereof;
`and a pharmaceutically acceptable liquid carrier; said drop-
`lcts having a size distribution of from about 5 microns to
`about 500 microns, preferably from about 10 microns to
`about 200 microns, preferably from about 20 microns to
`about 100 microns, more preferably from about 30 microns to
`about 70 microns.
`
`In certain embodiments, the present invention is directed to
`a method of treating pain comprising sublingually adminis-
`tering a liquid spray formulation in the form of discrete liquid
`droplets having a mean diameter of at least about 10 microns,
`preferably at least about 20 microns, more preferably a mean
`diameter of fror11 about 20 to about 200 microns, to a human
`patient experiencing pain, said liquid spray formulation com-
`prising an effective amount of fentanyl, a pharmaceutically
`acceptable salt thereof, or derivative thereof, dispersed in a
`pharmaceutically acceptable liquid carrier.
`In certain embodiments, the present invention is directed to
`a method of treating pain comprising sublingually adminis-
`tering a liquid spray formulation in the form of discrete liquid
`droplets having a size distribution of from about 5 microns to
`about 500 microns, preferably from about 10 microns to
`about 200 microns, preferably from about 20 microns to
`about 100 microns, more preferably from about 30 microns to
`about 70 microns to a human patient experiencing pain; said
`liquid spray fon11ulatior1 comprising ar1 effective amount of
`fentanyl, a pharmaceutically acceptable salt
`thereof, or
`derivative thereof, dispersed in a pharmaceutically acceptable
`liquid carrier.
`In certain embodiments, the present invention is directed to
`a device which includes a reservoir containing a unit dose of
`a liquid formulation comprising an effective amount of fen-
`anyl, a pharmaceutically acceptable salt thereof, or deriva-
`ive thereof in a pharmaceutically acceptable liquid carrier;
`he device having an actuator which when actuated delivers
`he unit dose of the liquid formulation in the form of liquid
`droplets having a mean diameter of at least about 10 microns,
`oreferably at least about 20 microns, more preferably a mean
`diameter of fror11 about 20 to about 200 microns. Preferably,
`he device delivers a therapeutically elfective dose of the
`liquid formulation in the form of liquid droplets having a size
`distribution of from about 5 microns to about 500 microns,
`oreferably from about 10 microns to about 200 microns,
`areferably from about 20 microns to about l00 microns, more
`orcfcrably from about 30 microns to about 70 microns.
`In certain embodiments, the present invention is directed to
`a multi-dose device which includes a reservoir containing a
`liquid formulation comprising fentanyl, a pharmaceutically
`acceptable salt thereof, or derivative thereof in a phannaceu-
`tically acceptable liquid carrier; the device having an actuator
`which when actuated delivers a therapeutically effective dose
`oftl1e liquid formulation ir1 the form ofliquid droplets having
`a mean diameter of at least about 10 microns, preferably at
`least about 20 microns, more preferably a mean diameter of
`from about 20 to about 200 microns. Preferably, the device
`delivers a therapeutically effective dose of the liquid formu-
`lation in the form ofliquid droplets having a size distribution
`of from about 5 microns to about 500 microns, preferably
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`from about 10 microns to about 200 microns, preferably from
`about 20 microns to about 100 microns, more preferably from
`about 30 microns to about 70 microns.
`
`In certain embodiments, the present invention is directed to
`a method of treating pai11 comprising utilizing a spray device
`which includes a reservoir including a liquid formulation
`comprising fentanyl, a pharmaceutically acceptable salt
`thereof, or derivative thereof in a pharmaceutically accept-
`able liquid carrier; and an actuator which upon actuation
`delivers a therapeutically effective amount of liquid droplets
`to be sprayed from the device having a mean diameter of at
`lcast about 10 microns, preferably at lcast about 20 microns,
`more preferably a mean diameter of fron1 about 20 to about
`200 microns.
`In certain embodiments, the present invention is directed to
`a method of treating pain comprising utilizing a spray device
`which includes a reservoir including a liquid formulation
`comprising fentanyl, a pharmaceutically acceptable salt
`thereof, or derivative thereof; and a pharmaceutically accept-
`able liquid carrier; and an actuator which upon actuation
`delivers a therapeutically effective amotmt of liquid droplets
`having a size distribution of fro111 about 5 microns to about
`500 microns, preferably from about 10 microns to about 200
`microns, preferably from about 20 microns to about 100
`microns, more preferably from about 30 microns to about 70
`microns.
`
`In certain embodiments, the present invention is directed to
`a method of treating breakthrough pain comprising sublin-
`gually administering a liquid spray formulation comprising
`an effective amount of fentanyl, a pharmaceutically accept-
`able salt thereof, or derivative thereof, dispersed in a pharrna-
`ceutically acceptable liquid carrier to a human patient to treat
`breakthrough pain experienced by said human patient.
`In certain embodiments, the present invention is directed to
`a method of treating breakthrough pai11 comprising sublir1-
`gually administering a liquid spray formulation comprising
`an effective amount of fentanyl, a pharmaceutically accept-
`able salt thereof, or derivative thereof, dispersed in a pharrna-
`ceutically acceptable liquid carrier to a human patient who is
`receiving chronic pain treatment, and is experiencing break-
`through pain.
`In certain embodiments, the present invention is directed to
`a method of reducing patient to patient variability for the
`treatment of breakthrough pain, comprising sublingually
`administering to a human patient experiencing breakthrough
`pain a dose of fentanyl in a liquid spray formulation compris-
`ing fentanyl, a pharmaceutically acceptable salt thereof, or
`derivative thereof, and a pharmaceutically acceptable liquid
`carrier said liquid spray formulation being administered as
`discrete liquid droplets having a mean diameter of at least
`about 10 microns, preferably at least about 20 microns, more
`preferably a mean diameter of from about 20 to about 200
`microns.
`
`In ccrtain cmbodimcnts, thc prcscnt invcntion is directed to
`a method of reducing patient to patient variability for the
`treatment of breakthrough pain, comprising sublingually
`administering to a human patient experiencing breakthrough
`pain a dose of fentanyl in a liquid spray formulation compris-
`ing fentanyl, a pharmaceutically acceptable salt thereof, or
`derivative thereof, and a pharmaceutically acceptable liquid
`carrier said liquid spray formulation being administered as
`discrete liquid droplets having a size distribution of from
`about 5 microns to about 500 microns, preferably from about
`10 microns to about 200 microns.
`
`In certain preferred embodiments, the liquid spray formu-
`lation further includes a pharmaceutically acceptable solvent.
`Preferably the pharmaceutically acceptable solvent is an
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`US 8,835,460 B2
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`5
`organic solvent which is included in an amount suitable for
`dissolving the fentanyl, a pharmaceutically acceptable salt
`hereof, or derivative thereof.
`In certain preferred embodiments the formulations of the
`oresent invention provide a mean time to maximum plasma
`concentration (Tmm) of fentanyl at from about 5 minutes to
`about 120 minutes, after
`sublingual administration to
`1umans.
`
`In certain preferred embodiments the formulations of the
`oresent invention provide a mean maximum plasma concen-
`ration (CWM) of fentanyl of about 127 pg/ml to about 213
`3g/ml per 100 pg fcntanyl aftcr sublingual administration to
`1umans.
`
`In certain preferred embodiments of the present invention
`he formulations of the present invention do not include a
`oropellant.
`In certain embodiments, the formulations of the present
`invention are suitable for
`transmucosal administration,
`including, for example, buccal administration.
`In certain embodiments, the present invention is further
`directed to a method of transmucosally administering fenta-
`nyl, a pl1an11aceutically acceptable salt thereof, or derivative
`hereof, to a human to provide fast-acting relief in a formu-
`lation in which a substantial portion of the fentanyl, a phar-
`maceutically acceptable salt thereof, or derivative thereofwill
`1ot be passed into the lungs ofthe patient. In certain preferred
`embodiments, the transmucosal area is the buccal area of a
`iuman.
`
`In certain embodiments, the present invention is further
`directed to the use of a formulation as defined above for the
`manufacture of a medicament for use as an analgesic, for the
`reatment of acute pain and/or breakthrough pain, as an anes-
`hetic premedication, for the induction of anesthesia, as a
`sedative and/or for the treatment of anxiety.
`The invention is also directed to a subli11gual fe11ta11yl
`formulation comprising discrete liquid droplets of an effec-
`ive amount of fentanyl, a pharmaceutically acceptable salt
`hereof, or derivative thereof; in a pharmaceutically accept-
`able liquid carrier; said droplets having a mean diameter of at
`least about 10 microns, and upon administration to a human
`oatient, at least about 90% ofthe discrete liquid droplets have
`a mean diameter equal or greater than about 9 pm. In other
`embodiments, not more than about 5% of the discrete liquid
`droplets have a mean diameter less than 9 pm. In still other
`embodiments, the formulation provides a respirable dose of
`not more than about 5% of the total fentanyl dose contained.
`The invention is also directed to a method of treating pain
`comprising sublingually administering a liquid spray formu-
`lation in the form of discrete liquid droplets having a mean
`diameter of at least about 10 microns to a human patient
`experiencing pain and at least about 90% ofthe discrete liquid
`droplets have a mean diameter equal or greater than about 9
`pm upon administration to a human patient, said liquid spray
`formulation comprising an cffcctivc amount of fentanyl, a
`pharmaceutically acceptable salt
`thereof, or derivative
`thereof, dispersed in a pharmaceutically acceptable liquid
`carrier. In certain other embodiments, not more than about
`5% of the discrete liquid droplets have a mean diameter less
`than 9 pm. In other embodiments, the formulation provides a
`respirable dose ofnot more than about 5% ofthe total fentanyl
`dose contained.
`The invention is also directed to a unit dose or bi-dose
`device for sublingual administration of a drug comprising:
`a reservoir containing a unit dose or a bi-dose of a liquid
`formulation comprising an effective amount of fentanyl, a
`pharmaceutically acceptable salt
`thereofi or derivative
`thereof in a pharmaceutically acceptable liquid carrier; and
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`the device having an actuator which when actuated delivers
`the unit dose of the liquid formulation in the form of liquid
`droplets having a mean diameter of at least about 10 microns,
`and wherein upon administration to a human patient, at least
`about 90% of the discrete liquid droplets have a mean diam-
`eter equal or greater than about 9 pm.
`In other embodiments, not more than about 5% of the
`discrete liquid droplets have a mean diameter less than 9 pm.
`In still other embodiments, the formulation provides a respi-
`rable dose ofnot more than about 5% ofthe total fentanyl dose
`contained.
`
`Many patients witl1 e.g., cancer, typically continue to expe-
`rience moderate to severe pain despite chronic analgesic
`therapy and this can occur as intermittent breakthrough pain,
`often due to increases in a patient’s activity level. Attempts to
`counteract this type of pain by increasing the dose of long-
`acting formulations ofanalgesics often produce slow onset of
`analgesia a11d unwantcd side-effects of sedation, constipation
`or nausea and vomiting. However, in certain embodiments the
`present invention is directed to a formulation which prefer-
`ably provides a rapidly acting, potent analgesic which
`rec uces the pain, such as breakthrough pain, for the required
`time and then preferably wears off fairly quickly thereby
`minimizing the side-effects of the fentanyl, a pharrnaceuti-
`cally acceptable salt thereof, or derivative thereof.
`7or purposes of the present invention, derivatives of fenta-
`ny include sufentanil, carfentanil, lofentanil, alfentanil, or
`the like.
`
`7or purposes ofthe present invention, “breakthrough pain”
`refers to a pain that exceeds a threshold in a patient which
`causes cognizablc discomfort wherein the pain cxpcricnccd
`by the patient
`is otherwise typically controlled e.g., by
`chronic analgesic therapy, and tolerated. For example, pain
`related to medical illnesses, such as cancer, typically fluctu—
`ates, and patients often report the experience of cognizable
`discomfort (e.g., breakthrough pain). Typically breakthrough
`pain is currently treated with immediate release oral dosage
`forms which may take up to about 45 minutes or longer for the
`drug to be absorbed a11d may result i11 a delay of the relief of
`breakthrough pain, as opposed to a liquid spray formulation
`of he present invention which begins to provide relief of the
`breakthrough pain almost immediately after administration.
`7or purposes of the present invention, “chronic pain treat-
`ment” refers to a daily or round-the-clock pain treatment.
`Chronic pain treatment can be oral, parenteral, transdermal,
`or other suitable means of administration.
`7or purposes of the present invention, “sublingual” is
`defined herein as beneath or co11cerning the area under the
`tongue.
`7or purposes of the present invention the term “sublingual
`administration” is defined herein as the therapeutic adminis-
`tra ion of a pharmaceutical composition under the tongue.
`7or purposes of the present
`invention an “effective
`amount” of a drug is a11 amount effective to demonstrate a
`desired activity of the drug. According to the instant inven-
`tion, a therapeutically effective amount of fentanyl, pharrna-
`ceutically acceptable salt thereof, or derivative thereof, is an
`amount effective to treat, e.g., noticeably reduce, pain in a
`patient.
`For purposes of the present invention the terms droplets
`and particles may be used interchangeably.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 depicts the mean (:S.E.) plasma concentration-time
`profiles following intravenous administration of Fentanyl of
`Example 1 (n:3) in the study of Example 6.
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`US 8,835,460 B2
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`7
`FIG. 2 depicts the mean (:SE.) olasma concentration-time
`orofiles following sublingual administration of Fentanyl of
`Example I (n:3) in the stucy of Example 6.
`FIG. 3 depicts the mean (:S.F,.) alasma concentration-time
`orofiles following intravenous administration of Fentanyl of
`Example 2 (n:3) in the stucy of Example 6.
`FIG. 4 depicts the mean (:SE.) olasma concentration-ti ne
`orofiles following sublingual administration of Fentanyl
`Example 2 (n:3) in the stucy of Example 6.
`FIG. 5 depicts t