EXHIBIT 1001 
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1001
`Coalition For Affordable Drugs XI LLC v Insys
`Pharma, Inc. IPR2015-01797
`
`

`
`US008835459B2
`
`(12) Ulllted States Patent
`Kotta il et al.
`
`(10) Patent No.:
`45 Date of Patent:
`
`US 8,835,459 B2
`a
`*Se . 16 2014
`
`(54) SUBLINGUAL FENTANYL SPRAY
`
`2002/0055496 A1
`2002/0160991 A1
`
`5/2002 McCoy et al.
`10/2002 Shao
`
`(72)
`
`(71) Applicant: Igssys Therapeutics, Inc., Phoenix, AZ
`(
`)
`_
`Inventors: S. George Kottayil, Long Grove, IL
`(US); Venkat R. Goskonda, Phoenix,
`A.z<vs>;
`Hills, IL (US); Linet Kattookaran,.
`M011I1tPr0SPeCt, IL (US); Neha Parlkhs
`Chicago, IL (US)
`
`(73) Assignee:
`
`.
`( * ) Notice:
`
`Insys Therapeutics, Inc., Phoenix, AZ
`(US)
`.
`.
`.
`.
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.g.C. 154(b)by odays,
`
`This patent is subject to a terminal dis-
`Claimer.
`
`,
`(21) APP1~N°~~ 13/895411
`.
`Flledi
`
`(22)
`
`May 15, 2013
`
`(65)
`
`Prior Publication Data
`US 2013/0296368 A1
`Nov. 7, 2013
`
`_
`_
`Related U.S. Application Data
`(63) Continuation of application No. 12/221,333, filed on
`Aug 1, 2008, now Pat. No. 8,486,973.
`.
`.
`.
`.
`(60) Provisional application No. 60/963,076, filed on Aug.
`2, 2007, provisional application No. 60/963,253, filed
`011 Aug. 3, 2007.
`
`(51)
`
`(2006.01)
`(200601)
`(200601)
`(2006.01)
`(2005.01)
`(2006.01)
`
`Int- Cl-
`A01N 43/40
`A61K 31/445
`A6IM 11/00
`A61K 31/435
`/1611(3)/4463
`A61K 9/00
`(52) US_ CL
`CPC ......... .. A61K31/4468 (2013.01); A61K31/435
`(2013.01);A61M11/00 (2013.01);/161K
`31/445 (2013.01); A61K 9/006 (2013.01);
`A61K 9/0056 (2013.01)
`USPC .................................... .. 514/329; 128/200.14
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`4/2003 Dugger, III
`2003/0077229 A1
`5/2003 Dugger, III
`2003/0082107 A1
`5/2003 Dugger, 111
`2003/0095925 A1
`5/2003 Duggef, 111
`2003/0095925 A1
`10/2883 31:32:11
`5322/3133; :1
`2003/0190290 A1,, 10/2003 ROSS
`.......................... H 424/45
`2004/0092428 A1
`5/2004 Chen et al.
`2004/0120895 A1
`6/2004 Dugger, III
`2004/0136913 A1
`7/2004 Dugger, III et al.
`2004/0135914 A1
`7/2004 Duggefa 111 et 31~
`2004/0136915 A1
`7/2004 Dugger, III et al.
`2004/0141923 A1
`7/2004 Dugger, III et al.
`2004/0265239 A1
`12/2004 Dugger, III et al.
`2005/0002357 A1
`1/2005 Dugger, 111 et 31,
`2005/0163719 A1
`7/2005 Dugger, III et al.
`2005/0180923 A1
`8/2005 Dugger, IIIeta1.
`2005/0281752 A1
`12/2005 Dugger, III
`2005/0281753 A1
`12/2005 Dugger, III
`2005/0287075 A1
`12/2005 Dugger, 111
`2006/0062812 A1
`3/2006 Ross et al.
`2007/0071806 A1*
`3/2007 McCarty ..................... .. 424/451
`2007/0261695 A1
`11/2007 Kottayil et al.
`2009/0124554 A1
`5/2009 Dugger, III
`2009/0162300 A1
`6/2009 Dugger, iii
`2012/0035216 A1*
`2/2012 Palmer et al.
`
`............... .. 514/326
`
`RU
`RU
`W0
`
`FOREIGN PATENT DOCUMENTS
`2156126
`9/2000
`2232580
`7/2004
`W0 90/07333
`7/1990
`
`A2
`WO 2004/016243 A2
`W0
`WO 2004/080382
`W0
`WO 2004/075877
`W0
`W0 W0 2007.007059
`W0
`WO 2007/087431
`
`2/2004
`9/2004
`10/2004
`1/2007
`8/2007
`
`OTHER PUBLICATIONS
`
`Int’1 Preliminary Report on Patentability from related Int’1 Applica-
`tion N0. PCTIUS08/09359 dated Feb. 2, 2010.
`_Lejus, eta1., “Fentanyl versus sufentanil: pla_sma_conc_entrations diir.
`ing continuous epidural postoperative infusion in children,” British
`Journal ofAnaesthesia, vol. 85, Issue 4, Oct. 2000, pp. 615-617.-
`Examination Report for correspondingAustralian PatentApplication
`N°' 2008282742’ “‘*“1‘°'d °“ Feb" 9’ 20”‘
`,
`,
`Smyth, et al., 2003, AAPS PharmSciTech 2003, 4 (3).1-11.
`(Continued)
`
`Primary Examiner — Robert Landsman
`(74) Attorney, Agent, or Firm — Wood, Phillips, Katz, Clark
`& M0ITiI11€1‘
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`(
`
`)57
`
`ABSTRACT
`
`4,244,478 A
`5219083 A
`5,958,379 A
`5,976,504 A
`6,759,059 B1
`6,946,150 B2
`8,486,972 B2
`
`1/ 1981 Handman
`6/1993 Liebefi et 31'
`9/1999 Regenold et al.
`11/1999 Russell
`7/2004 Pettersson et al.
`9/2005 Whittle
`7/2013 Kottayil et al.
`
`The present invention is directed to sublingual formulations
`containing fentanyl, a pharmaceutically acceptable sale
`thereof, or derivative thereof, suitable for administration to a
`t.
`t
`d
`th d f
`t
`t
`t
`.th th f
`1 t.
`pa ien , an me o s or rea men W1
`e ormu a ions.
`
`6 Claims, 10 Drawing Sheets
`
`

`
`US 8,835,459 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`Examination Report for corresponding Australian Patent Application
`No. 2008282743, mailed on Nov. 1, 2012.
`Examination Report for corresponding European Patent Application
`No. 07762549.9, mailed on Sep. 30, 2010.
`Supplementary European Search Report, 2 pages, for corresponding
`European Patent Application No. 07762549.9, mailed on Sep. 30,
`2010.
`Oflice Action on Chinese Patent Application No. 200780003555.X
`dated Jul. 9, 2010.
`International Search Report and Written Opinion, dated Jul. 1 1, 2008
`from corresponding Int’l Application No. PCT/US07/02163.
`Mathar, L.E., et al. “Pulmonary administration of aerosolised
`fentanyl: pharmacokinetic analysis of systemic delivery” Br. J. Clin.
`Pharmacol. Jan. 1998, vol. 46, pp. 37-43.
`
`Marier, J-F., et al. “Comparative bioequivalence study between a
`novel matrix transdermal delivery system of fentanyl and a commer-
`cially available reservoir formulation”, Br. J. Clin. Pharmacol. Aug.
`2006, vol. 63, No. 1, pp. 121-124, esp. p. 123, Figure 1.
`International Preliminary Report on Patentability dated Aug. 26,
`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 datedAug.
`2009 from corresponding Russian Application No. 2008130763.
`ISR and Written Opinion from related Int’l Application No. PCT/
`US08/09359 dated Jan. 9, 2009.
`
`* cited by examiner
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 1 of 10
`
`US 8,835,459 B2
`
`Plasma c;oncentration~time curves afler IV & SL doses cf Fentg_1_1_r;§{§
`
`Figure I: Formuiaof Example 1, 50 pg IV dose
`
`F1-W [Jase Time Concentration Profile
`
`900
`
`800
`
`§
`
`500
`500
`
`mo
`490we =
`
`
`
`Concentration(nglml)
`
`E
`'1
`
`§2.
`
`5 §
`
`£
`
`{
`
`i
`
`20:: g
`,
`mo
`0 ‘“ “‘*” i
`0
`2:1
`40
`so
`as
`100
`120
`149 ‘
`
`Time (m in}
`
`Mean (:tS.Ei.) piasma concentratis:m—time profiies following intmveneus administration of
`Fentanyl (n.=3}.
`
`Figure 2: Fonnula offixampke 1, 50 pg Sublinguai dose
`
`
`
`Mean ($3.3) piasrna cont-entrationmtime profiies following sublinguai administration Of
`Fentany} (:2=3)
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 2 of 10
`
`US 8,835,459 B2
`
`Figure 3: Forrnula 0fExample 2, 80 pg IV dose
`
`{-'-’#2 IV Dose Time Concentration Profiie
`
`Time (min)
`
`_........_..........‘_:_:_.._,,:..._......m..._.!
`
`50
`
`80
`
`H30
`
`120
`
`140
`
`Mean ($8.13.) plasma cczncentration-time pmfilcs foilowing intravenous administration of
`Fentany} {n==3}.
`
`Figure 4: Fonnuha of Example 2, 88 gig SI, dense
`
`F#2 SL Dose Time Cancentration Profite
`
`:3
`
`E‘
`
`a;
`E.
`
`Time (min)
`
`‘IC.)0
`U)
`
`01
`Jan
`
`5E
`
`31:.
`
`8
`
`Mean (£235.) piasma concentratiamtinma profiles foliowing subiingual adminisrraiien of
`Fentanyl (n:=3)
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 3 of 10
`
`US 8,835,459 B2
`
`Figure 5: Formula of Exampla 3, 30 pg {V dost:
`
`F#3 iv Dose time concentration profile
`
`I
`
`1200
`
`.4 C*3D
`
`Mean ($5.13.) piasma concentratian-—time profiles foilewing intravenous administration of
`Fentanyi {n#3)
`
`Figure: 6: Fonnula cf Example 3, 50 pg SL dose
`
`F#3 SL Dose Time Concentration Profile
`
`E E % E 8
`
`80
`
`100
`
`120
`
`Time (min)
`
`Mean (-.L~S,E.) plasma concent‘ration—time prafiies folloxsublingual administration of
`Fentanyl {n=3)
`
`
`
`
`
`Concentraiiongnglmf}
`
`800
`
`600
`
`400
`
`260
`
`Time (min)
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 4 of 10
`
`US 8,835,459 B2
`
`Figure 7: Formuia of Example 4, 50 pg IV dose
`
`
`
`Figure 8: Fomluia of Exetnapkz 4, 50 pg Si, dose
`
`(ngimu
`Conoentrafian
`
`C}
`
`20
`
`40
`
`60
`
`80
`
`‘£00
`
`1 20
`
`‘S 40
`
`1
`
`Time (min)
`
`Mean (.-1:S.E.} plasma concentrationwtime profiles following sublingual administration of
`Fentanyi {n=3}
`
`
`
`1 000
`
`800
`
`600 -
`
`400
`
`209
`
`(ng!mL)
`Concentration
`
`0
`
`20
`
`40
`
`60
`
`BO
`
`1 O0
`
`1 20
`
`140
`
`Time (min)
`
`Maan {.~::S.E..} plasma concentraiiunwtime profiles following intravenous administratian of
`Faniany! (n$3}
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 5 of 10
`
`US 8,835,459 B2
`
`Figure: 9: Formuia cf Example 5, 50 pg IV dose
`
`F-5 IV Dose Time Concentration Profiie
`
`1400
`
`E
`
`I
`
`:g 1200
`‘g: 1000
`"E
`50::
`3g 50:3
`g
`40:3 ~
`3 2004!
`O
`
`o
`
`20
`
`40
`
`E
`
`{
`
`E
`
`3
`E
`E
`""""""""4'""""""""""""r""""— “ww““% é
`so
`as
`me
`-:20
`mo
`Time (min)
`__...,...,,§,.$.,,_,“.w_ ______¢
`
`_l___‘_‘_
`
`'
`
`Mean (:I:S.E.) plasma concentratienwtime profiies following intravenous administration of
`Fenian}/1 92:3)
`
`Figure 10: Formuia of Exampie 5, 50 gg SL dose:
`
`‘*1C3C3
`
`‘£355330000
`
`--8M:2caCO
`
`C3
`
`
`
`Cancentration(ngImL)
`
`
`
`F~5 SL Base Time Concentration Profile
`
`s———-~—+
`
`H”!
`
`:~—-+-——-s
`
`:--4’:
`
`
`
`Mean {:t:S.E.) plasma concentrationviime pmfiies foliowing subiingual administration of
`I-‘entanyi {n=3)
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 6 of 10
`
`US 8,835,459 B2
`
`* PLUME RECORDS - D1G{;1.m) * D50(um) - D90(;1.m)
`
`
`
`DESYANCE (cm)
`
`F I G. 1 1
`
`- D9D(p.m)
`
`4 cm
`90 -PLUME RECORDS -mom) I-D50(pm)
`80
`..
`70
`60-
`58
`40
`30
`20
`10
`
`G
`
`0
`
`2
`
`4
`
`6
`
`8
`
`we
`
`12
`
`EXHAUST nasTAwcE (cm)
`
`F|G.12
`
`

`
`U.S. Patent
`
`Sep. 16, 2014
`
`Sheet 7 of 10
`
`US 8,835,459 B2
`
`7 cm
`
`1» PLUME RECORBS - Dfflmm) *D5G(;¢m) - D90{pm)
`
`
`
`-mums RECORDS -D1U(_u.m) AD50(;.Lm)
`
`-D9D(;1.m)
`
`as
`
`78
`
`- 0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`5
`
`‘i
`
`8
`
`DISTANCE (cm)
`
`FlG.14
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 8 of 10
`
`US 8,835,459 B2
`
`
`
`
`
`
`
`MEANFENTANYiGONG(ngimuMEANFENTANYLsome(ngfmL)
`
`
`
`
`
`
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 9 of 10
`
`US 8,835,459 B2
`
`E
`
`§‘
`
`Figure 17
`
`‘£0
`
`PreliminaryMean Fantanyi Concentralécns From Periods 1 ~ 5
`
`l
`
`tnglml.)
`
` Femany!
`
`:€
`
`3 E
`
`‘
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 10 of 10
`
`US 8,835,459 B2
`
`Figure 13
`
`Preliminary Mean Fentanyi Cancentrafions From Pericd$ 1 - S
`-—
`
`1.-:
`
`12 -
`
`i
`...- 1 —«---«H---—«»—~H~««.«-««~«-~«-~«««+»»««-~
`
`as I?
`
`T
`
`A
`
`-
`
`1.0 a ~——-m—~———-—-~_~—~—— -
`3; FA
`Wm.--..........................
`
`--
`
`
`
`Femtanyi(nglmu
`
`
`
`
`
`Time {II}
`
`
`
`zoo
`
`W -t- am,-mg?
`
`«--«A--—6{1G“.,_§'$_w“m-3::-—_—;"£EflGM4?‘
`
`An expanded X-axis time scale. Natice that concentratians are genemliy at ~60% ofpcak
`by 10 minutas. The peak is approximmeiy 100 minutes broad.
`
`

`
`1
`SUBLINGUAL FENTANYL SPRAY
`
`US 8,835,459 B2
`
`2
`
`This application is a continuation of U.S. patent applica-
`tion Ser. No. 12/221,333 filedAug. 1, 2008 (now U.S. Pat. No.
`8,486,973 issued Jul. 16, 2013), which claims the benefit of
`U.S. Provisional Application Nos. 60/963,076, filed onAug.
`2, 2007 and 60/963,253 filedAug. 3, 2007; the disclosures of
`which are hereby incorporated by reference in their entireties.
`
`FIELD 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
`
`Fentanyl is a p.-opioid receptor agonist with analgesic
`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 effective 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 who 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 fentanyl is subject to first pass effect
`metabolism as upwards of 50% or more of orally adminis-
`tered fentanyl is not absorbed. Other forms of delivery such a
`parenteral, buccal, and transdermal have been utilized to
`decrease or avoid this first pass effect for fentanyl.
`Fentanyl is currently available in injectable form, 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 acetami-
`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 in 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 purportedly to allow the Actiq® unit to be removed 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 pain. Actiq® is con-
`traindicated in the management of acute or postoperative
`pain.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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-
`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 of a 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
`
`It is an object of the invention to provide a fentanyl formu-
`lation suitable for sublingual administration for effective pain
`management.
`It 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.
`It is a further object of certain embodiments of the inven-
`tion to provide methods and compositions for fentanyl admin-
`istration which minimize the underdosing and/or overdosing
`of a patient in need of fentanyl therapy.
`It 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.
`It 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
`which can be administered sublingually in a manner which
`will cause substantial sublingual absorption without substan-
`tial risk of the dose passing into the lungs of the recipient.
`The above-mentioned objects and 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 an effective amount of fentanyl, a phar-
`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 from about 20 to about 200 microns.
`In certain embodiments, the present invention is directed to
`a sublingual fentanyl formulation comprising discrete 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.
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`US 8,835,459 B2
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`In certain preferred embodiments, none of the particles
`have a diameter which would allow the fentanyl, pharmaceu-
`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 5
`a unit 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-
`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.
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`10
`
`In certain embodiments, the present invention is directed to
`a unit 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-
`lets 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.
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`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 of 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.
`
`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 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
`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 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 amount of 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.
`
`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 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 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 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
`
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`
`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 from 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 formulation comprising 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 45
`a device which includes a reservoir containing a unit dose of
`a liquid formulation comprising an effective amount of fen-
`tanyl, a pharmaceutically acceptable salt thereof, or deriva-
`tive thereof in a pharmaceutically acceptable liquid carrier;
`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,
`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 formulation in the form of 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.
`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 pharrnaceu-
`tically acceptable liquid carrier; the device having an actuator 65
`which when actuated delivers a therapeutically effective dose
`ofthe liquid formulation in the form of liquid droplets having
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`US 8,835,459 B2
`
`5
`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 forrnu-
`lation further includes a pharmaceutically acceptable solvent.
`Preferably the pharmaceutically acceptable solvent is an
`organic solvent which is included in an amount suitable for
`dissolving the fentanyl, a pharmaceutically acceptable salt
`thereof, or derivative thereof.
`In certain preferred embodiments the formulations of the
`present invention provide a mean time to maximum plasma
`concentration (Tmax) of fentanyl at from about 5 minutes to
`about 120 minutes, after sublingual administration to
`humans.
`
`In certain preferred embodiments the formulations of the
`present invention provide a mean maximum plasma concen-
`tration (Cmax) of fentanyl of about 127 pg/ml to about 213
`pg/ml per 100 pg fentanyl after sublingual administration to
`humans.
`
`In certain preferred embodiments of the present invention
`the formulations of the present invention do not include a
`propellant.
`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 pharmaceutically acceptable salt thereof, or derivative
`thereof, 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
`not be passed into the lungs ofthe patient. In certain preferred
`embodiments, the transmucosal area is the buccal area of a
`human.
`
`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
`treatment of acute pain and/or breakthrough pain, as an anes-
`thetic premedication, for the induction of anesthesia, as a
`sedative and/or for the treatment of anxiety.
`The invention is also directed to a sublingual fentanyl
`formulation comprising discrete liquid droplets of an effec-
`tive amount of fentanyl, a pharmaceutically acceptable salt
`thereof, 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
`patient, 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 effective 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.
`
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`6
`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
`thereof, or derivative
`thereof in a pharmaceutically acceptable liquid carrier; and
`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.
`
`In accordance with the above objects, the invention is also
`directed to a sublingual spray formulation comprising an
`effective amount of fentanyl and at least one pharrnaceuti-
`cally acceptable excipient, the formulation providing a mean
`Tmax of about 1.28+/-0.60 hours when a dose is adminis-
`
`tered sublingually to humans. In certain other embodiments,
`the sublingual formulation has a concentration of fentanyl
`from about 1 mg/mL to about 8 mg/mL. In certain preferred
`embodiments,
`the concentration of fentanyl
`is about
`1
`mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL or
`about 8 mg/mL.
`In accordance with certain of the above objections, the
`invention is also directed to a sublingual formulation exhib-
`iting a mean Cmax of about 0.813 ng/ml+/-0.252 based on a
`sublingual dose of about 400 mcg fentanyl when adminis-
`tered to humans.
`
`In certain other embodiments, the sublingual formulation
`provides a dosage amount of fentanyl selected from the group
`consisting of about 100 mcg, about 200 mcg, about 600 mcg
`and about 800 mcg, and provides a mean Cmax which is
`substantially dose proportional to the sublingual formulation
`containing 400 mcg fentanyl dosage amount, when adminis-
`tered to humans.
`
`In still other embodiments, the sublingual formulation pro-
`vides a substantially dose proportional mean Cmax based on
`a mean Cmax of about 0.813 ng/ml+/-0.252 for a 400 mcg
`fentanyl dose when administered to humans.
`The present invention also provides a sublingual formula-
`tion which provides a mean Tmax when administered to
`humans selected from the group consisting of: about 1.12
`hours when the formulation provides a 100 mcg dose, about
`1.04 hours when the formulation provides a 200 mcg dose,
`about 0.97 hours when the formulation provides a 400 mcg
`dose, about 0.987 hours when the formulation provides a 600
`mcg dose, and about 1.06 hours when the formulation pro-
`vides a 800 mcg dose.
`In accordance with the above objects, it is a further object
`of the invention to provide a sublingual fentanyl formulation
`which provides a plasma concentration after administration
`to humans selected from the group consisting of: about 60%
`of the mean Cmax in about 10 minutes, about 86% of the
`mean Cmax by about 20 minutes and a combination thereof.
`In other embodiments, the invention is directed to a sub-
`lingual
`fentanyl
`formulation that when administered to
`humans provides a plasma concentration that is greater than
`about 80% of the mean Cmax for about 2 hours.
`
`In still other embodiments, the sublingual formulation
`comprises 400 mcg of fentanyl, providing one or more mean
`pharrnacokinetic values selected from the group consisting
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`US 8,835,459 B2
`
`7
`of: AUClast 4.863+/—l.7082l hr*ng/mL, AUCinf 5.76l+/—
`1.916 hr*ng/mL, and AUCextrap l0.26+/-5.66%, when
`administered to humans.
`In even s