Exhibit 1001
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1001
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01800
`
`

`
`(12) United States Patent
`Kottayil et al.
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 8,486,972 B2
`Jul. 16, 2013
`
`US008486972B2
`
`(54) SUBLINGUAL FENTANYL SPRAY
`
`(75)
`
`Inventors: S. George Kottayil, Long Grove, IL
`(US); Venkat R. Goskonda, Gurnee, IL
`(US); Zhongyuan Zhu, Vernon Hills, IL
`(US); Neha Parikh, Chicago, IL (US);
`Linet Kattookaran, Mount Prospect, IL
`(US)
`
`(73) Assignee:
`
`Insys Therapeutics, Inc., Phoenix, AZ
`(US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1188 days.
`
`(21) Appl. No.: 11/698,739
`
`(22) Filed:
`
`Jan. 25, 2007
`
`(65)
`
`Prior Prrblication Data
`
`US 2007/0261695 A1
`
`Nov. 15, 2007
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/762,057, filed on Jan.
`25,2006.
`
`(51)
`
`Int. Cl.
`A01N43/40
`AOIN37/00
`A61K31/445
`A61K31/21
`A6IM 11/00
`A61K9/00
`A613 19/00
`(52) U.S.Cl.
`USPC .... .. 514/329; 128/200.14; 424/400; 514/506;
`604/407
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(58) Field of Classification Search
`USPC ........................................................ .. 514/329
`
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
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`20 2/ 055496 A1
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`20 3/ 082107 A1
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`20 3/ 095925 A1
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`5/2003 Dugger, III
`20 3/ 095927 A1
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`20 3/ 190290 A1* 10/2003 Ross ............................. .. 424/45
`20 4/ 092428 Al
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`20 4/ 120895 A1
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`7/2004 Dugger, III et al.
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`7/2004 Dugger, III et al.
`
`.................. .. 424/400
`
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`12/2004 Dugger, III et a1.
`2005/0002867 A1
`1/2005 Dugger, III et al.
`2005/0163719 A1
`7/2005 Dugger, III et al.
`2005/0180923 A1
`8/2005 Dugger. III et al.
`2005/0281752 A1
`12/2005 Dugger, III
`2005/0281753 A1
`12/2005 Dugger, III
`2005/0287075 A1
`12/2005 Dugger, III
`3/2006 Ross et al.
`2006/0062812 A1*
`2009/0124554 A1
`5/2009 Dugger, III
`2009/0162300 A1
`6/2009 Dugger, III et al.
`7/2009 Koltayil et al.
`............. .. 514/329
`2009/0176834 A1*
`FOREIGN PATENT DOCUMENTS
`2156126
`9/2000
`RU
`2232580
`7/2004
`RU
`W0 90/07333
`7/1990
`W0
`W0 00/47203
`8/2000
`W0
`W0 01/97780 A2
`12/2001
`W0
`W0 W0 2004/016243 A2
`2/2004
`W0 W0 2004/080382
`9/2004
`W0 W0 2004/075 877
`10/2004
`W0 W0 2007-007059
`I/2007
`
`OTHER PUBLICATIONS
`
`Smyth, et al, 2003, AAPS PharmSciTech 2003; 4 (3): 1-11.*
`Srrryth & Hickey (2003) Multirrrodal Particle Size Distributions
`Emitted From HFA- 134a Solution Pressurized Metered-Dose Inhal-
`ers. AAPS PharmSciTech 2003; 4 (3) Article 38. pp. 1-11.*
`International Search Report and Written Opinion dated Jul. 11, 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 Sep. 4, 2008
`from corresponding Int’l Application No. PCT/I IS07/02163.
`Examination Report dated Aug. 6, 2009 from corresponding Austra-
`lian Application No. 2007208229.
`Examination Report dated May 5, 2010 from corresponding Cana-
`dian Application .\Io. 2,637,672.
`Examination Report dated Mar. 18, 2010 from corresponding New
`Zcaland 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.
`Int”l Preliminary Report on Patentability from related Int’l Applica-
`tion No. PCT/US08/09359 dated Feb. 2, 2010.
`
`(Continued)
`
`Primary Examiner — Robert Landsman
`(74) Attorney, Agent, or Firm — Wood, Phillips, Katz, Clark
`& Mortimer
`
`(57)
`
`ABSTRACT
`
`The present invention is directed to sublingual formulations
`containing fentanyl, a pharmaceutically acceptable salt
`thereof, or dcrivativc thcrcof, suitable for administration to a
`patient, and methods for treatment with the formulations.
`
`3 Claims, 7 Drawing Sheets
`
`

`
`US 8,486,972 B2
`Page 2
`
`OTHER PUBLICATIONS
`Lejus, et a1., “Fentanyl Versus sufentanilz plasma concentrations dur-
`ing continuous epidural postoperative infusion in children,” British
`Journal ofAnaesthesia, vol. 85, Issue 4, Oct. 2000, pp. 615-617.
`Office Action on Patent Application No. 200780003555.X dated Jul.
`9, 2010.
`
`Examination Report for corresponding European Patent Application
`N0. 077525499, mailed 011 NOV 30, 2010
`Supplementary Search RGPOIT f0I corresponding EUIOPGAII Patent
`Application No. 977625499, mailed on Nov. 30, 2010.
`
`* cited by examiner
`
`

`
`U.S. Patent
`
`Jul. 16, 2013
`
`Sheet 1 017
`
`US 8,486,972 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
`
`Time (min)
`
`I
`
`80
`
`I
`
`1 00
`
`I’
`
`1 20
`
`I
`
`1 40
`
`Conoentration(nglml)
`
`I
`
`'60
`
`Mean (:I:S.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
`
`
`
`Mean (:tS.E.) plasma concentration—time profiles following sublingual administration of
`Fentanyl (n=3)
`
`

`
`U.S. Patent
`
`Jul. 16, 2013
`
`Sheet 2 of7
`
`US 8,486,972 B2
`
`Figure 3: Formula of Example 2, 80 pg 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 pg SL dose
`
`F#2 SL Dose Time Concentration Profile
`
`:7
`
`EE
`
`Time (min)
`
`l5I
`
`:
`_O
`
`80
`
`l 6
`
`0
`
`E8C 8
`
`Mean (iS.E.) plasma concentration—time profiles following sublingual administration of
`Fentanyl (n=3)
`
`

`
`U.S. Patent
`
`Jul. 16, 2013
`
`Sheet 3 of7
`
`US 8,486,972 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
`
`O
`
`
`
`Concentration(nglml)
`
`O
`
`20
`
`40
`
`60
`
`80
`
`100
`
`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
`
`3E3
`
`55C
`
`‘EC
`
`8C
`
`8
`
`Time (min)
`
`60
`
`80
`
`Mean (iS.E.) plasma concentration—time profiles following sublingual administration of
`Fentanyl (n=3)
`
`

`
`U.S. Patent
`
`Jul. 16, 2013
`
`Sheet 4 of7
`
`US 8,486,972 B2
`
`Figire 7: Formula of Example 4, 50 pg IV dose
`
`F4-IV Dose Concentration Profile
`
`1 000
`
`800
`
`600
`
`400
`
`200 Concentration
`(ngImL)
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`120
`
`140
`
`Time (min)
`
`
`Mean (iS.E.) plasma concentration—time profiles following intravenous administration of
`Fentanyl (n=3)
`
`Figure 8: Formula of Example 4, 50 pg SL dose
`
`
`
`Concentration(ngImL)
`
`_L CO C
`
`CO00
`
`ono0
`
` F4-SL Dose Concentration Profile
`
`
`
`40
`
`60
`
`80
`
`100
`
`120
`
`140
`
`Time (min)
`
`Mean (d:S.E.) plasma concentration—time profiles following sublingual administration of
`Fentanyl (n=3)
`
`

`
`U.S. Patent
`
`Jul. 16,2013
`
`Sheet 5 of7
`
`US 8,486,972 B2
`
`Figure 9: Formula of Example 5, 50 pg IV dose
`
`F-5 IV Dose Time Concentration Profile
`
`1400
`
`E
`
`I
`
`E
`
`£
`
`0
`
`20
`
`40
`
`60
`
`so
`
`100
`
`C
`120
`
`140
`
`Time (min)
`
`:7 1200
`%
`5 1000
`E 800
`E
`600
`3
`400
`
`E 3
`
`200
`0
`
`Mean (d:S.E.) plasma concentration—time profiles following intravenous administration of
`Fentanyl (n=3)
`
`Figure 10: Formula of Example 5, 50 ug SL dose
`?__ ___fi
`
`F-5 SL Dose Time Concentration Profile
`
`\lOO
`
`who-no:oooooooo
`Concentration(nglmL) 8o
`
`
`
`NO0
`
`0
`
`O
`
`i%?l
`
`I
`
`20
`
`PH
`
`i
`
`I—-O—i
`
`I
`
`40
`
`l—o——-i
`
`I
`
`i
`
`I
`
`i
`
`I
`
`80
`60
`Time (min)
`
`100
`
`120
`
`I
`
`140
`
`Mean (iS.E.) plasma concentration—time profiles following sublingual administration of
`Fentanyl (n=3)
`
`

`
`U.S. Patent
`
`Jul. 16,2013
`
`Sheet 6 of7
`
`US 8,486,972 B2
`
`Figure 11: Vignetting Results Dv10, Dv50, Dv9O vs. Distance from Range Lens
`
`0 Hum: Records
`
`I D10 (urr-.)
`
`A [50 (pm)
`
`' D90 (pm)
`
`100
`
`so
`60
`40
`20
`
`0
`
`'
`:
`*
`s
`
`-
`'
`I
`I
`
`I
`I
`.
`
`I
`|
`:
`E
`
`:
`
`.
`
`o
`
`5
`
`1o
`
`is
`
`distance (cm)
`
`Figure 12: Exhaust Results Dvl0, Dv50, Dv90 vs. Distance to Exhaust at 4 cm Device to
`Laser Beam
`
`dcm
`
`Ofiurm Racatdf I Dwlprnl A D6DIum) Ifilwm
`
`90
`80
`70
`60
`50
`40
`30
`20
`10
`
`D—O
`
`-DOII
`
`I
`
`IDO’OI
`
`IIIf
`
`0
`
`2
`
`4
`
`8
`
`8
`
`10
`
`12
`
`exhuast distance (cm)
`
`Note: 10 cm distance used for plotting of results with no exhaust fan present.
`Refbrcrxcez Notebook I, LDR H38
`
`

`
`U.S. Patent
`
`Jul. 16, 2013
`
`Sheet 7 of 7
`
`US 8,486,972 B2
`
`Figure 13: Exhaust Results Dv10, DVSO, Dv90 vs. Distance to Exhaust at 7 cm Device to
`Laser Beam
`
`Ten
`
`oP|urne Records‘ IDIOW-'rI> LC50(um] ID90lv"\1
`
`80
`
`70
`
`60
`
`50
`40
`
`30
`
`20
`10
`0
`
`DOOI
`
`O
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`Nose: [0 cm distance used for plotting of IC3lllIS with no exhaust fan present.
`Reference: Notebook !. LDR I08
`
`Figure 14: Device to Laser Beam Placement Results, Dv10, DVSO, Dv90 vs. Distance to
`Laser Beam
`
`9 Flume Records
`
`I 010 (pm;
`
`Ammum)
`
`I0‘30(W\l
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`IIO6
`
`DD
`
`A
`
`'
`
`3
`
`2
`
`A
`
`I
`
`4
`distance (cm)
`
`

`
`US 8,486,972 B2
`
`1
`SUBLINGUAL FENTANYL SPRAY
`
`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
`
`is a p.-opioid receptor agonist with analgcsic
`Fcntanyl
`potency approximately 80-100 times that of morphine. In
`clinical settings, fentanyl exerts its principal pharmacologic
`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 n1u-receptor agonists, including fenta11yl, 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 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®), and as a trar1sdern1al system (e.g.,
`Duragesic® 25, 50, 75, and 100 ug of fentanyl per hour).
`Duragesic® provides continuous systemic delivery of fenta-
`nyl for approximately 72 hours. Duragesic® is indicated in
`the management ofchronic pain in patients requiring continu-
`ous opioid analgesia for pain that is not optimally managed
`with lesser means such as acetaminophen—opioid combina-
`tions, 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 absorp-
`tion of the fentanyl through the patch, or postoperative pain
`because serious or life-threatening 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 pai11. Actiq® is con-
`traindicated in the management of acute or postoperative
`pain.
`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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`2
`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
`
`t is an object of the invention to provide a fentanyl formu-
`lation suitable for sublingual administration for cffcctivc 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 which minimize the underdosing and/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 cor11positior1s 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
`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-r11er1tioned 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 fron1 about 20 to about 200 microns.
`In certain embodiments, the present invention is directed to
`a subli11gual fentanyl formulation comprising discrete liquid
`droplets of fentanyl, a pharmaceutically acceptable salt
`thereof, or derivative thereof; in a pharmaceutically accept-
`able liquid carrier; said droplcts 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
`dose comprising discrete liquid droplets of fentanyl, a phar-
`maceutically acceptable salt thereof, or derivative thereof;
`and a pharmaceutically acceptable liquid carrier; said drop-
`
`

`
`US 8,486,972 B2
`
`3
`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 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, morc prcfcrably 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 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 i11 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
`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 phannaceutically 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 from about 20 to about 200 microns. Preferably,
`he 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,
`oreferably from about 10 microns to about 200 microns,
`areferably from about 20 microns to about 100 microns, more
`oreferably 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 fcntanyl, 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
`ofthe liquid formulation in 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
`fror11 about 20 to about 200 microns. Preferably, the device
`delivers a therapeutically effective dose of the liquid formu-
`lation in the form of liq11id 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 l 00 microns, more preferably from
`about 30 microns to about 70 microns.
`
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`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 ofliquid 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 fron1 about 20 to about
`200 microns.
`
`In ccrtain cmbodimcnts, the present invcntion 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, r11ore preferably fror11 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 ir1 a pl1an11a-
`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 r11icror1s, 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
`admini stcring to a human paticnt cxpcricncing 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
`organic solvent which is included in an amount suitable for
`dissolving the fentanyl, a pharmaceutically acceptable salt
`thereof, or derivative thereof.
`
`

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`US 8,486,972 B2
`
`5
`In certain preferred embodiments the formulations of the
`present 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
`humans.
`
`In certain preferred embodiments the formulations of the
`present invention provide a mean maximum plasma concen-
`tration (Cmx) of fentanyl of about 127 pg/ml to about 213
`pg/ml per 100 ug fentanyl after sublingual administration to
`humans.
`
`In certain preferred embodiments of the present invention
`thc formulations of the present invention do not includc 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-
`r11aceutically acceptable salt thereof, or derivative tl1ereofwill
`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 pl1an11aceutically 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% oftl1e 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.
`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,
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`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.
`hi still other embodiments, the formulation provides a respi-
`rable dose ofnot more than about 5% ofthe total fentanyl dose
`contained.
`
`Many patients with 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 ir1 a patier1t’s activity level. Attempts to
`counteract this type ofpain by increasing the dose of long-
`acting formulations of analgesics often produce slow onset of
`analgesia a11d unwanted 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, potcnt analgcsic 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 cognizable discomfort wherein the pain experienced
`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 iii 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.
`Chrome 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 an 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
`
`7IG. 1 depicts the mean (:S.E.) plasma concentration-time
`profiles following intravenous administration of Fentanyl of
`Example l (11:33) in the study of Example 6.
`7IG. 2 depicts the mean (:S.E.) plasma concentration-time
`profiles following sublingual administration of Fentanyl of
`Example 1 (n:3) in the study of Example 6.
`
`

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`US 8,486,972 B2
`
`7
`FIG. 3 depicts the mean (:SE.) olasma concentration-time
`orofiles following intravenous administration of Fentanyl of
`Example 2 (n:3) in the stucy of Example 6.
`FIG. 4 depicts the mean (:S.F,.) alasma concentration-time
`orofiles following sublingual administration of Fentanyl of
`Example 2 (n:3) in the stucy of Example 6.
`FIG. 5 depicts the mean (:SE.) olasma concentration-ti ne
`orofiles following intravenous administration of Fentanyl
`Example 3 (n:3) in the stucy of Example 6.
`FIG. 6 depicts the mean (:SE.) olasma concentration-ti ne
`orofiles following sublingual administration of Fentanyl
`Example 3 (11:3) iii the stucy of Example 6.
`FIG. 7 depicts the mean (:SE.) olasma concentration-ti ne
`arofiles following intravenous admin