(12) United States Patent
`Kottayil et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,835,459 B2
`*Sep. 16, 2014
`
`US008835459B2
`
`SUBLINGUAL FENTANYL SPRAY
`
`Applicant: Insys Therapeutics, Inc., Phoenix, AZ
`(1 IS)
`
`hiventorsz S. George Kottayil, Long Grove, IL
`(US); Venkat R. Goskonda, Phoenix,
`AZ HIS); Zhongyuan Zhu, Vernon
`Hills, IL (US); Linet Kattookaran,
`Mount Prospect, II, (IIS); Neha Parikh,
`Chicago, II, (US)
`
`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 0 days.
`This patent is subject to a terminal dis-
`claimer.
`
`13/895,111
`
`May 15, 2013
`
`Prior Publication Data
`
`US 2013/0296368 A1
`
`Nov. 7, 2013
`
`Related U.S. Application Data
`
`Continuation of application No. 12/221,333, filed on
`Aug. 1, 2008, now Pat. No. 8,486,973.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Provisional application N o. 60/963,076, filed on Aug.
`2, 2007, provisional application No. 60/963,253, filed
`on Aug. 3, 2007.
`Int. Cl.
`A 01N 43/40
`A 61K 31/445
`A 61M 11/00
`A 61K 31/435
`A 61K 31/4468
`A61K 9/00
`U.S. Cl.
`CPC ......... .. A61K 31/4468 (2013.01); A61K 31/435
`(2013.01); A61M 11/00 (2013.01); A61K
`31/445 (2013.01), A61K 9/006 (2013.01);
`A61K 9/0056 (2013.01)
`.... .. 514/329; 128/200.14
`USPC
`Field of Classification Search
`None
`See application file for complete search history.
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,244,478
`5,219,033
`5,958,379
`5,976,504
`6,759,059
`6,946,150
`3,436,972
`
`1/ 1981 Handman
`6/1993 Licbcrt ct al.
`9/1999 Regenold et al.
`11/1999 Russell
`7/2004 Pettersson et al.
`9/2005 Whittle
`7/2013 Kottayil et al.
`
`2002/0055496 A1
`2002/0160991 A1
`2003/0039680 A1
`2003/0077228 A1
`2003/0077229 A1
`2003/0082107 Al
`2003/0095925 A1
`2003/0095926 Al
`2003/0095927 Al
`2003/0190286 Al
`2003/0190290 Al ‘
`2004/0092428 A1
`2004/0120895 A1
`2004/0136‘) 3 A1
`2004/01369 4 A1
`2004/01369 5 A1
`2004/0141923 A1
`2004/0265239 A1
`2005/0002867 A1
`2005/01637 9 A1
`2005/0180923 A1
`2005/0281752 Al
`2005/0281753 Al
`2005/0287075 Al
`2006/00628 2 Al
`2007/0071806 Al *
`2007/0261695 A1
`2009/0124554 Al
`2009/0162300 A1
`2012/00352 6 A1*
`
`5/2002 McCoy et al.
`10/2002 Shao
`2/2003 Dugger, 111
`4/2003 Dugger, III
`4/2003 Dugger. III
`5/2003 Dugger. III
`5/2003 Dugger. III
`5/2003 Dugger. III
`5/2003 Dugger. III
`10/2003 Dugger. III
`10/2003 Ross ............................. .. 424/45
`5/2004 Chen ct al.
`6/2004 Duggcr, III
`7/2004 Duggcr. III ct al.
`7/2004 Dugger, III et al.
`7/2004 Dugger, III et al.
`7/2004 Dugger, III et al.
`12/2004 Dugger, III et al.
`1/2005 Dugger. III et al.
`7/2005 Dugger. 111 et al.
`8/2005 Dugger. 111 et al.
`12/2005 Dugger, III
`12/2005 Dugger. III
`12/2005 Dugger. III
`3/2006 Ross et al.
`3/2007 McCarty ..................... .. 424/451
`1 1/2007 Kottayil et al.
`5/2009 Dugger. III
`6/200‘) Dugger, III
`2/2012 Palmer et al.
`
`............... .. 514/326
`
`FOREIGN PATENT DOCUMENTS
`
`2156126
`2232580
`VVO 90/07333
`VVO 00/47203
`VVO 01/97780 A2
`VVO 2004/016243 A2
`VVO 2004/080382
`VVO 2004/075877
`VVO 2007-007059
`VVO 2007/087431
`
`9/2000
`7/2004
`7/1990
`8/2000
`12/2001
`2/2004
`9/2004
`10/2004
`1/2007
`8/2007
`
`OTHER PUBL1CA'1'1()N S
`
`lnt’l Preliminaiy Report 011 Patentability from related h1t’l Applica-
`tion No. PCTIUS08/09359 dated Feb. 2, 2010.
`Lejus, et al., “Fentanyl versus sufe11ta11il: plasma concentrations dur-
`ing continuous epidural postoperative infusion in children,” British
`Journal ofAnaesthesia. vol 85, Issue 4, Oct. 2000, pp. 615-617.
`Examination Report for corrcspond ing Au stralian Patent Application
`No. 2008282743, mailed on Feb. 9. 2011.
`Smyth, et al., 2003, AAPS Pl1armSci‘1'ech 2003; 4 (3):l-11.
`
`(Continued)
`
`Robert Iandsman
`Primary Examiner
`(74) Attorney, Agent, orFirm — Wood, Phillips, Katz. Clark
`& Mortimcr
`
`(57)
`
`ABSTRACT
`
`The present invention is directed to sublingual formulations
`containing fentanyl,
`6: pharniaceutically acceptable sale
`thereof, or derivative thereof, suitable for administration to a
`patient, and methods for treatment with the formulations.
`
`6 Claims, 10 Drawing Sheets
`
`Page 1 of 46
`
` Insys Exhibit 2018
`CFAD v. Insys
`IPR2015-01800
`
`

`
`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. 077625499, mailed 011 Sep. 30, 2010.
`Supplementary European Search Report, 2 pages, for corresponding
`European Patent Application No. 07762549.9, mailed on Sep. 30,
`2010.
`Office 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: pharrnacokinetic analysis ol‘ 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 of the Russian Examination Report datedAug.
`2009 from corresponding Russian Application No. 2008130763.
`ISR and Written Opinion from related Lnt’l Application ho. PC'l'/
`US08/09359 dated Jan. 9. 2009.
`
`"‘ cited by examiner
`
`Page 2 of 46
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 1 of 10
`
`US 8,835,459 B2
`
`Plasma concentrationnfime curves after EV &. SL doses af Fentgggg
`
`Figure 1: Formuia. of Exampie I, 50 pg W dose
`
`F1-IV Dose Time Concentration Profile
`
`SS0
`890
`700
`800
`590
`400
`330
`
`=
`
`29:: i
`100
`0 ‘“ *‘~u-
`o
`20
`40
`so
`50
`100
`no
`140
`
`I
`
`Time {min}
`
`W...
`
`1
`
`
`
`Comentrafion(nglml)
`
`E
`
`L
`
`Mean (:tS.E.) piasma conce11traiiun—time pmfiies following, intravenous administration of
`’Fcntax1yl (n=3),
`
`Figure 2: Formula offixampke 1, 50 pg Sublinguai dose
`
`Mean (:E:S.E.) plasma concentrationmtime profiies fcxilowing sublingual administration of
`Fe-many‘! (:2=3)
`
`Page 3 of 46
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 2 of 10
`
`US 8,835,459 B2
`
`Figure 3: Formula of Example: 2, 80 pg EV dose
`
`F#2 IV Dose Time Concentration Profiie
`
`160
`
`Time (min)
`
`Mean (iS.E,) plasma ccmcentrationutimsz pmfilcs foilowing intravenous administration of
`Fenianyi {n==3}.
`
`Figure 4: Formuia of Example 2, 88 gag SI, dense
`
`F#2 SL Dose Time Concentration Profits’.-
`
`
`
`Conceantmfion(ngImL)
`
`Time (min)
`
`Mean (-.lc:S.E.) piasma concentratiarrwtinme pmfiles foiiowing subiingual administration of
`Fcntany] (rz=3)
`
`Page 4 of 46
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 3 of 10
`
`US 8,835,459 B2
`
`Figure 5: Formula of Example 3, 50 pg [V dost:
`
`Ff.‘-3 IV Dose time concentration profile
`
`E30 D
`
`
`
`Crmcentraziongnglmf)
`
`40
`
`Time (min)
`
`Mean (:tS.§?1.) piasrna conccniraiisnntinxe profiles foiicswing intravenous administratimz of
`Fcntanyi (n=-=3)
`
`Figure 6: Formula of Example 3, Si} pg SL dose
`
`F#3 SL Dose Time Concentration Profile
`
`
`
`Cancentratizzn{nglmL.}
`
`80
`
`180
`
`120
`
`Time (min)
`
`Mean {i-3.5.) piasma c0nc£:ntrati(>z‘.«—time pmfiies folimving subiingual administration of
`Fentanyl {n=3}
`
`Page 5 of 46
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 4 of 10
`
`US 8,835,459 B2
`
`Figure 7: Formula c>fBxampIe 4, SC! pg IV dose
`
`F4-W Dcse Concentration Profile
`
`1000
`
`800 -
`
`500 -
`
`400
`
`200
`
`
`
`Concentration(ng!mL)
`
`ED
`
`80
`
`100
`
`120
`
`‘MG
`
`Time (min)
`
`Mea;1{:£:S.E.} plasma wnucsntraliumtime profiles following intravenous aclministration of
`Fetllanyi (.n==3}
`
`Figur 8‘ Fommia ofiixanlpic 4, 50 pg Si, dose
`
`é\
`
`F4$L Dose Concentraticm Profile
`
`
`
`Conoentrafion(nglmL)
`
`E56
`
`Time (min)
`
`plasr;;;:;ncentr2;;::;c::;~v1;;$';);;.les foilowing sublingual administration of
`Fentanyi {n=3}
`
`Page 6 of 46
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 5 of 10
`
`US 8,835,459 B2
`
`: Formuia of Example 5, SD ;1gIV dose
`
`
`
`Concentration(ng!mL)
`
`1400
`
`1200
`
`2::
`
`200 4,
`G
`
`D
`
`F-5 EV Dose Time Concentration Profuse
`
`1;
`
`E
`
`E
`
`;
`
`29
`
`40
`
`BO
`
`100
`
`1 20
`
`"""'
`
`,,,,,N
`
`w .
`
`Time (min)
`
`Mean (nES.E.) plasma concemratienwtime profiies following intravenaus administraiicm of
`Fantasy! {r:—"=3)
`
`Figure 10: Formuia ofExampIe 5, 50 pg SL dose
`
`‘-5C)O
`
`G‘!OO
`
`U!DO
`
`AO0
`
`£410O
`
`-4MOC!C!(D
`
`C3
`
`
`
`Concentrafion(ngimu
`
`F-5 SL Dcsse Time Concentration Profile
`
`“7"“' *—-1
`
`{
`
`46
`
`BB
`60
`Time (min;
`
`106
`
`120
`
`140
`
`Mean {:t:S.E.) piasma concentrationwtimc pmfiics foiiowing subiingual administration 0?
`Fentanyi 01:3)
`
`Page 7 of 46
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 6 of 10
`
`US 8,835,459 B2
`
`- PLUME RECORDS - D1{1(p.m) 4» E}50(;1m) - D9{3(g.1.,m)
`
`10
`
`DISTANCE (cm)
`
`F|G.1’|
`
`4 cm
`
`-PLUME RECORDS -D§6(pm) sD50{;xm)
`i
`
`- D90(;.zm)
`
`
`
`--I-Fv-Jt'.aJ-15-U"IO'§"-JC20(O
`
`4
`
`6
`
`8
`
`EXHAUST DiSTANCE (cm)
`
`F|G.12
`
`Page 8 of 46
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 7 of 10
`
`US 8,835,459 B2
`
`7 cm
`
`- PLUME RECORDS - DfD(;.1m) ~D5£}(;1m) - D9D(;zm)
`
`- PLUME RECORDS I D10(;Lm) - D5{}(g1m) - D9D(;1.m)
`
`O
`
`3
`
`5
`
`DlSTfi\NCE (cm)
`
`FlG.14
`
`Page 9 of 46
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 8 of 10
`
`US 8,835,459 B2
`
`CT
`§0)
`«$3
`(.32
`C)
`(.3
`__J
`3*‘
`
`§F‘
`2LL!
`LL.
`
`§§
`
`
`
`MEANFENTANYLCONC{ngimij
`
`Page 10 of 46
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 9 of 10
`
`US 8,835,459 B2
`
`Figure 15
`
`Praliminary Mean Femanyl Clancenftalions From Periods 1 - 5
`
`35 EE
`
`‘
`§:5.’
`
`P
`
`
`
`Fem:-zny!tnglmi.)
`
`Page 11 of 46
`
`

`
`U.S. Patent
`
`Sep. 16,2014
`
`Sheet 10 of 10
`
`US 8,835,459 B2
`
`Figu re 1 8
`
`Preliminary Mean Femanyi Concentrations From Periods 1 - 5
`
`2;
`
`2E
`
`“
`E
`
`0
`
`3
`
`6
`
`Q
`
`12
`
`‘£3
`
`18
`
`Tune (In)
`
`?_:a—.zoo
`
`W -—¢—~ Aoapm-3
`
`-o-- soo‘,_,_L%'""'”"-‘-as-:__z3uo,,E._%
`
`An ex panded X-axis time scale. Nmicc that cozicentratiuns are gemirally at ~60% ofpcak
`by 10 minutes. The peak is approximately EGG minutes broad.
`
`Page 12 of 46
`
`

`
`US 8,835,459 B2
`
`1
`SUBLINGUAL FENTANYL SPRAY
`
`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
`
`5
`
`Tl1e invention is directed to sublingual fon11ulatio11s con-
`taining fentanyl, a phamiaceutically 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 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 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 fer1ta11yl, 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 ofdelivery such a
`parenteral, buccal, and transdermal have been utilized to
`decrease or avoid this first pass effect for fentanyl.
`Fer1ta11yl is currently available in injectable fonn, 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 p.g of fentanyl per hour;
`Duragesic is a registered trademark of Johnson & Johnson
`Corporation). Duragesic® provides continuous systemic
`delivery of fe11tanyl for approximately 72 hours. Dura gesic®
`is indicated in the management of chronic pain in patients
`requiring continuous opioid analgesia for pai11 that is not
`optimally managed with lesser means such as acetami— ,
`nopl1er1—opioid combinations, nor1—steroidal analgesics, or
`pn1 (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 i11 patients witl1 malignancies wl1o
`are already receiving a11d who are tolerant to opioid therapy
`for their underlying persistent cancer pai11. Actiq® is con-
`traindicated in the management of acute or postoperative
`pain.
`
`2
`Sublingnal tablets a11d lozenges (e.g., Actiq®) whicl1 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.
`SUMIVIARY 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 a11d compositions capable ofrapidly induc-
`ing a state of sedation, analgesia, and/or anesthesia.
`t is a further object ofcertain embodiments of the inven-
`tion to provide methods and compo si tions for fentanyl admin-
`istration which minimize the ur1derdosir1g and’or overdo sing
`of a patient in need of fentanyl therapy.
`t is a further object of certain embodiments of the inven-
`tion to provide methods a11d compositions suitable for the
`treatment of breakthrough pain in patients receiving chronic
`pain treatment.
`t is a filrther 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 call be administered sublingually ir1 a n1a1mer which
`will cause substantial sublingual absorption without 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 phanna-
`ceutically acceptable salt thereof, or derivative thereof, to
`provide fast—acting relief in a formulation in which a substan-
`tial portion of the fenta11yl, 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 a11 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; ir1 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.
`
`Page 13 of 46
`
`

`
`US 8,835,459 B2
`
`3
`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
`a unit dose of a sublingual fentanyl formulation, said unit
`dose comprising discrete liquid droplets of fentanyl, a phar-
`maceutically acceptable salt thereofl 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 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 fiom 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 ofdiscrete 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 ofdiscrete liquid , ,
`droplets having a size distribution of from about 5 microns to
`about 500 microns, preferably from about l0 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
`thereofi 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-
`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 eifective dose of the
`liquid fonnulation in the form of liquid droplets having a size
`distribution of fiom 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 i1iulti—dose device which includes a reservoir containing a
`liquid fomiulation comprising fentanyl, a phannaceutically
`acceptable salt thereof, or derivative thereof in a pham1aceu-
`tically acceptable liquid carrier; the device having an actuator
`which when actuated delivers a therapeutically effective dose
`ofthe liquid formulation in the form of liquid droplets having
`
`4
`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 forniu—
`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 fonnulation
`comprising fentanyl,
`a phannaceutically acceptable salt
`thereof, or derivative thereof in a phannaceutically 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 fonnulation
`comprising fentanyl,
`a phannaceutically acceptable salt
`thereof, or derivative thereof; and a pharmaceutically accept-
`able liquid carrier; and an actuator which upon actuation
`delivers a therapeutically effective amount ofliquid 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 oresent 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 tiereof, dispersed in a pharma-
`ceutically acceptable liquid carrier to a human patient to treat
`breakthrough pain experiencec by said human patient.
`In certain embodiments, the aresent 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 tiereof, dispersed in a phanna-
`ceutically acceptable liquid carrier to a human patient who is
`receiving chronic pain treatment, and is experiencing break-
`through pain.
`ln certain embodiments, the aresent 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 phannaceutically 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.
`ln 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 phannaceutically acceptable salt thereof, or
`derivative thereof, and a pharmaceutically acceptable liquid
`carrier said liquid spray formulation being administered as
`
`Page 14 of 46
`
`

`
`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 fom1u—
`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 fe11tanyl, 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 (T,,,,u) of fentanyl at from about 5 minutes to
`about 120 minutes, after sublingual administration to
`humans.
`n certain preferred embodiments the fomrulations of the
`present invention provide a mean maximum plasma concen-
`tra ion (Cmax) of fentanyl of about 127 pg/ml to about 213
`pg/ml per 100 ug fe11tanyl after sublingual administration to
`humans.
`11 certain preferred embodiments of the present invention
`the formulations of the present invention do 11ot include a
`propellant.
`n certain embodiments, the formulations of the present
`invention are suitable for
`transmucosal administration,
`including, for example, bueeal administration.
`n certain embodiments, the present invention is further
`directed to a method of transmucosally administering fe11ta—
`ny , a pharmaceutically acceptable salt thereof, or derivative
`thereof, to a human to provide fast-acting relief in a fonnu-
`lation in which a substantial portion of the fentanyl, a phar-
`maceutically acceptable salt thereof, or derivative thereofWill
`no be passed into the lu11gs ofthe patient. In certain preferred
`embodiments, the transmucosal area is the buccal area of a
`human.
`n certain embodiments, the present invention is further
`directed to tl1e 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 tl1e treatment of anxiety.
`Tl1e invention is also directed to a sublingual fe11tanyl
`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% oftlie 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 r11ore than about 5% of tl1e total fer1ta11yl dose contained.
`Tl1e 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
`um 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 r11ore than about
`5% of the discrete liquid droplets l1ave a mean diameter less
`than 9 pm. In other embodiments, the fonnulation provides a
`respirable dose ofnot more than about 5% ofthe total fentanyl
`dose contained.
`
`,
`
`,,
`
`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 a11 effective amount of fentanyl, a
`phannaceutically acceptable salt
`thereof, or derivative
`thereof in a phamraceutically acceptable liquid carrier; and
`the device having an actuator Wl1ieh 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 tl1e discrete liquid droplets l1ave 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 um.
`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 pharrr1aceuti—
`cally acceptable excipient, the formulation providing a mean
`Tmax of about 128+/-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 fomiulation exhib-
`iting a mean Cmax of about 0.813 ng/n1l+/ -0.252 based on a
`sublingual dose of about 400 mcg fentanyl when adminis-
`tered to humans.
`In certain other embodiments, tl1e sublingual fonnulation
`provides a dosage amount offentanyl selected from the group
`consisting ofabout 100 meg, about 200 meg, about 600 mcg
`and about 800 mcg, and provides a mean Cmax which is
`substantially dose proportional to the sublingual formulation
`containing 400 meg fentanyl dosage amount, when adminis-
`tered to humans.
`In still other embodiments, the sublingual fonnulation 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 close 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 tl1e formulation provides a 400 mcg
`dose, about 0.987 hours when tl1e fonnulation provides a 600
`mcg dose, and about 1.06 hours when the fon11ulatio11 pro-
`vides a 800 mcg dose.
`In accordance with the above objects. it is a further object
`of the invention to provide a sublingual fe11tanyl fonnulation
`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 tl1e mean Cmax for about 2 hours.
`In still other embodiments, the sublingual fonnulation
`comprises 400 mcg of fe11tanyl, providing one or more mean
`pl1arrnacokinetie values selected from the group consisting
`
`Page 15 of 46
`
`

`
`US 8,835,459 B2
`
`7
`of: AUClast 4863+/'—l.70821 hr"‘ng/mL, AUCinf 5761+/—
`L916 hr*ng/ml., and /\UCextrap 1026+/-5.66%, when
`administered to hL1ma11s.
`the
`ln even still further embodiments of the invention,
`sublingual fentanyl formulation provides a do sage amount of
`fentanyl when administered to humans which is substantially
`dose proportional to the dosage which contains about 400
`meg fentanyl selected from the group consisting of about 100
`mcg, about 200 mcg,