`
`mgmmmmm magma
`
`U TSSBUGB
`
`
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`
`
`October 25,2018
`
` THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`THE RECORDS OF THIS OFFICE OF:
`
`
`
`
`
`U.S. PATENT: 9,775,838
`
`
`ISSUE DATE: October 03, 201‘ 7
`
`
`
`
`
`By Authority of the
`Under Secretary of Commerce for Intellectual Property
`
`and Director of the United States atent and Trademark Office
`
`Cerfifyin Officer
`
`
`
`
`NaloxlOOl
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 1 of 43
`
`

`

`(12) Unite States Patent
`US 9,775,838 32
`(10) Patent No.:
`0!
`
`(451 Date 0. Patent: “.301. 3, 201?
`
`USU-3977583832
`
`(54) NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`(71} ApplicanlsrAdapt Pharma Limited. Dublin (ll-l):
`Opiant Pharmaceuticals. Santa
`Monica. CA (US)
`
`('12)
`
`Inventors: Fintan Keegan. Dublin (IE); Robert
`Gerard Befl, Clean/eater. FL (US);
`Roger Crystal. Santa Monica, CA
`(US); Michael Brenner Weiss, New
`York, NY (U S)
`
`{73) Assignees: ADAPT PEARL/IA LIMITED, Dublin
`(IE): OPIANT
`-
`PHARRIACEUTICALS, Santa
`Monica. CA (US)
`
`( “ ) Notice:
`
`Subject to any disclaimer, the term oftliis
`patent,
`is extended or adjusted under 35
`u.s.c. 154(b) by 0 days.
`This patent is subject to a terminal dis—
`claimer.
`
`(2111 Appl. No.; 151589.090
`
`(22)
`
`111.36:
`
`May a, 2017
`
`(65)
`
`Prior Publication Data
`
`US 201710239241111
`
`Aug. 24, 2017
`
`Related US. Application Data
`(63) Continuation of application No. 1514] 5,221, filed on
`Jan. 25, 2017, which is a continuation of application
`No. 151183,441, filed on 11.10.15, 2016, now Pa1.No.
`9,561,177, and a continuation-in-part of application
`No. 141950.707, filed on Nov. 24, 2015, now Pat. No.
`9368.747, which is a continuation of application No.
`14/942,344, filed on Nov. 16. 2015. now Pat. No.
`9,480,644. which is
`a
`continuation-impart of
`application No. 141659,472. filed on Mar. 16, 2015,
`now Pat. No. 9.211253.
`
`(60)
`
`Provisional application No. 62/274,536, filed on Jan.
`4, 2016, provisional application No. 621219.055, filed
`on Sep.
`1'1, 2015, provisional application No.
`611953.379. filed on Mar. 14. 2014.
`
`(51)
`
`Int. Cl.
`A6111! 31/00
`461.11! 5/00
`A61F 13/00
`.1611; 31/50
`A6111 31/435
`A61K 9/00
`AME 47/13
`A6111! 15/03
`A61." 11/00 .
`(521 US. (.1.
`CFC .......... A61K 31/485 (2013.01); A61K 9/0043
`(2013.01); A611; 47/186(2013.01);/161M
`11/007 (2014.02); 461.11 15/011 (2013.01)
`
`(2006.01)
`(2006.01 )
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2012.01)
`(2006.01)
`(2006.01)
`
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4.l31,72fi A
`4.464.378 A
`5.866.154 A
`7.977.376 B2
`9.192.570 B2
`9.211.253 15:
`9.468514? 32
`9.400.644 B2
`9.561.171 112'
`0.629.965 02‘
`2003-0077300 Al
`200610009447 A]
`2006-‘0l20967 A1
`20091'00l7102 A]
`20|0101l3495 A]
`201010168147 A]
`201010331354 A]
`201110046172 A]
`2012-0270895 A1
`201310023325 A]
`201550174061 11]
`201510258019 A]
`2016-0008277 Al
`
`....... 4241260
`. 4241260
`.. 4241423
`
`[119110 Bernstein
`811984 llussain
`211999 13111131 01 a].
`5141450
`7120l1 Singh 1:1 3.].
`..... 514/23
`I1.-'20|5 Wyse et a1.
`12/2015 Crystal e131.
`.
`361K910043
`
`10/2016 Crystal et a1.
`.
`111615131100
`1112016 Cursed et at.
`AfilK 9.10043
`232017 Keegau
`A61K 9/0043
`412017 Ciystnl
`42414-00
`412003 Werrncling
`112006 Markus ......
`514/221
`
`..
`. 424/45
`
`1512006 Namhuri et a.
`424/449
`112009 Stinchcombetal.
`514/282
`512010 Wermeling et al.
`
`.. 514/282
`7120l0 Chaplet) at al.
`514/282
`1212010 \Verrneling
`514/232
`2120“ Chaplet) et :11.
`5141282
`10120l2 Wermeling
`604/143
`112013 Edwards at al.
`6120l5 Wyse at al.
`AfilK 910043
`.
`912015 Crystal et a].
`.. AfilK 910043
`l.-"2016 Crystal at al.
`....... AolK 9.-'0043
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`157 5795
`CN
`1681057
`EP
`WO 32/03768
`W0
`W0 98130211
`W0
`WO 00162757
`W0
`WO 00174652
`WC
`WO 00176474
`W0
`WO 01158447
`W0
`wo 01132931
`W0
`WO 02111778
`WI.)
`W0 031084520
`W0
`WU 200410545511
`WO
`W0 Wt) 20051020906
`W0 W0 20061058022
`W0
`WO 2006089973
`
`212005
`712006
`1111982
`711998
`1012000
`1212000
`1212000
`812001
`11/2001
`232002
`1012003
`72004
`312005
`512006
`832006
`(Continued)
`
`OTHER PUBLICATIONS
`
`Aplar UnilDose and BiDose product information sheet. available at
`ww.apm.com"docse'plianna-prescription.-'uds-bds-datasheet.pdf.
`publication date unknown, inst. accessed Mar. 20, ml 5.
`[Continued]
`
`Primary Examiner — Jefli'ey T. Palcnik
`(74) Attorney, Agent. or Firm — Harness, Dickey &
`Pierce, P.L.C.
`
`ABSTRACT
`(5'1)
`Drug products adapted for nasal delivery, comprising a
`pro-primed device filled with a pharmaceutical composition
`comprising an opioid receptor antagonist, are provided.
`Methods of treating opioid overdose or its symptoms with
`the inventive drug products are also provided.
`
`46 Claims, 7 Drawing Sheets
`
`Copy provided by USPTO from the PlRS Image Database on 10-23—20 | B
`
`NaloxlOOl
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 2 of 43
`
`

`

`US 9,775,838 BZ
`Page 2
`
`(56)
`
`References Cited
`
`FOREI GN PATliN'l‘ DOCUMENTS
`
`W0 W0 20071183073
`W0 W0 20109-040595
`W0 W0 20121026963
`W0 W0 20121094283
`W0 W0 2012-"156317
`W0 W0 20141016653
`W0 W0 20151095644
`WU
`WO 2015136373
`W0 W0 20161007729
`
`7Q00’i‘
`2.12009
`3i'2012
`732012
`11.12012
`112014
`632015
`9-"2015
`112016
`
`.. AGIK 9.112
`.. A61K 9.300
`
`AfiiK 311485
`AfilK 47.512
`
`
`OTHER PUBLICATIONS
`
`TEVA Pharmaceulicals USA. Inc.. "Notice of ANDA No. 209522
`naloxone hydrochloride nasal spray 4mgi'spray. with paragraph IV
`certification concerning US. Pat. No. 9.468.747". dated Doc. 29,
`2016.
`Barton E D el al., “Efficacy of intranasal naluxune as a noedlclcss
`alternative for treatment of opioid overdose in the prehospital
`setting," J Emerg Med 29:3. 265-71 (published Oct. 2005).
`Barton E D et a].. "lntranasal administration of nnloxone by
`paramedics." Prebosp Emerg Care 6: 1. 54—58 (published Jan. 2002).
`Beletsky, 1.. et al.. “Physicians_K.now1edge of and Willingness to
`Prescribe Naloxone to Reverse Accidental Opiate Overdose: Chal—
`lenges and Oppomtnities." Joumal of Urban Health: Bulletin of the
`New York Academy ofMedicine. 84(1):l26—l36 (published 2006).
`Djupcsland. P.. (2013)., "Nasal drug delivery devices: characteris-
`tics and pcd‘on'nance in a clinical perspective-a review". Drug
`Deir'v. and Trmsi. Res. 3:42-62.
`Doe-Simltins M et at. “Saved by the nose: bystander-administered
`intranasal naloxone hydrochloride for opioid overdose." Am J
`Public Health 99:5. 738-91 (published May 2009).
`Dowling J et
`al.._ "Population pharrnacokinetics of intravenous.
`intramuscular. and intranssal naloxone in human volunteers." The:
`Dnrg Monil 30:4 490—96 (published Aug. 2008).
`Heard C et
`211.. "lnlranasal fiurnazenil and naloxoine to reverse
`over-sedation in a child undergoing dental restorations.“ Paediatr
`Anaesth 19:8 795-99 (published Aug. 2009).
`Kelly A M et a1.. "lntranasal nalottone for life threatening Opioid
`toxicity." Emerg Med 1 19:4, 375 (published Jul. 2002).
`Kelly A M et al.. “Randomised 0131 of intranasa1 versus intramus-
`cular naloxone in prehospital treatment for suspected opioid over-
`dose.” Med J Aust 182:1 24-27 (published Jan. 3. 2005).
`Kerr D et a1.. "Randomirred controlled trial comparing the effec-
`livcness and safety of intranasal and intramuscular naloxone for the
`treatment of suspected heroin overdose." Addiction 104:12. 206?-
`74 (Epub Nov. 9. 2009).
`Kundoor. V.. et al. (2011). Etfect of fonnulation- and administra-
`tion-related variables on deposition pattern of nasal spray pumps
`evaluated using naan cast. Pharm, Res. 28.189501904.
`Krieter P. or 31.. Phan'nscokinctic Properties and Human Use Char-
`acteristics of an FDA Approved Intranasal Naloxone Product for the
`Treatment of Opioid Overdose, J Clin Pharmacol. 2016. pp. 1-11.
`Loimer N ct ah. “Nasal administration of naloxone for detection of
`opiate dependence.” J Psychiatr Res 26:1. 3943 (published Jan.
`1992).
`Loimer N cl a1.. “Nasal administration ofnaloxone is as efl'ective as
`the intravenous route in opiate addicts." Int J Addict 29:6. 819-27
`(published Apr. 1994).
`Makidon el al.
`(2010). “(Characterization of stability and nasal
`delivery systems for inumtnization with nanoci-nulsion-based vac—
`cines” Journai ofAerosoi Medicine and Puimonmy Drug Deliv-
`ery23(2):77-89.
`Merlin M A ct 81.. “lntranasal naloxone delivery is an alternative to
`intravenous naloxone for opioidoverclosos." Am J Emerg Med 28:3.
`296-303 (lipub Jan- 28, 2010,).
`Robertson T M. "lntranasal naloxone is a viable alternative to
`intravenous naloxone for prehospital narcotic overdose." Preliosp
`Emerg Care 13:4. 512-15 (Published Oct. 2009).
`
`Walley A Y et al.. “Opioid overdose prevention with intranasal
`naloxone among people who take methadone," J Subst Abuse Treat
`44:2. 241417 (Epub Sop. 12.2012).
`Walley. A Y et a1. "Opioid overdose rates and implementation of
`overdose education and nasal naloxone distribution in Massachu—
`setts: interrupted time series analysis." BM} 3413:1174. (Published
`Jan. 31. 2013).
`Weber .1 M at al.. “Can nebulized naluotone be used safely and
`efl'octively by emergency medical services for suspected opioid
`overdose?" Prehmp Emerg Care 1622. 239-92 (1".pr DOC. 22.
`2011).
`Wermeling D P :1 a1. “Aresponse to the opioid overdose epidemic:
`naloitone nasal spray." Drug Delivery Transi. Res. 3:1, 63-74
`(published Feb. 1, 2013).
`Wermeling I) P et a1.. "Opioid harm reduction strategies: focus on
`expanded access to intranasal naloxone.” Pharmacothcrapy 30:7.
`627-31. 2010.
`Teva Pharmaceuticals USA. lnc.. "Notice of ANDA No. 209522
`naloxone hydrochloride nasal spray. 4mgi‘spray. with paragraph [V
`certification concerning US. Pat. No. 9.211.253". dated Sep 13.
`2016.
`International Search Report (15R). dated Sep. 2. 2015 in Interna—
`tional Application No. PCT.’IE.2015.-'00094l. 4 pgs.
`international Search Report (ISR) and Written Opinion (W0). dated
`Aug. 25. 2014 in International Application No. PCT.-’F.P2014f
`064032 (W0 20151000941) 11 pgs.
`Notice ofAllowancc and Fees Due. dated Oct. 9. 2015 in L‘- .S. App].
`No. 14-"659.472, 9 pgs.
`Notice of Allowance and Foes Due. dared Dec. 21. 2016 in Us.
`App]. No. 15.183.441. 15 pgs.
`Corrected Notice of Allowance and Foes Duo. dated Nov. 9. 2015
`in US. Appl. No. 141659.472. 9 pgs.
`Oflice Action (Non—final). dated Aug. 22. 2016. issued in U.S. App].
`NO. 151321.441.
`and
`pbamtacndynamic
`“The
`(2011)
`a].
`Middleton
`ot
`pharmacokineiic profile of iniIanasa] crushed bupirenorphine and
`buprenorphinefnaloxono tablets in opioid abusers". Addiction
`106(8): 1460-1473.
`Third party observer oommenls from corresponding UKApplication
`No. GB 1616616.7 dated Apr. 21. 2017.
`cha Pbamacwticals USA. Inc.. Notice of ANDA No. 209522
`naioxone hydrochloride nasal spray. 4mgn'spray, with paragraph IV
`certification concerning Us. Pat. No. 9.561.177.‘ dated Mar. 17.
`2017.
`Ashton H a 211.. "Best evidence topic report. Intranasai naloxone in
`suspcxlcd opioid overdose." Emerg Med J 23:3. 221-23 (published
`Mar. 2006).
`Bailey A M at 31., “Naloxonc for opioid overdose prevention:
`pharmacisls'
`role in communitybased practice settings." Ann.
`Pharmacother 48:5. 601-06 (published May 2014).
`ADAPTPharma Operations Limited, er at v. The Pharmacmimts
`USA. Inc.. et at. U.S. District Court for the District ochw Jersey.
`Civ. Action No. 2:16-cv-07721 (Oct. 2l. 2016); Exhibit AUS. Pat.
`No. 9.2l1.253.
`ADAPTPhar-ma Opemtious Limiter}, e: at. v. rm Pharmaceuticais
`US4.1'M.. (’1 at. US. District Court for the District ofNew Jersey.
`Civ. Action No. 2:33-cv—00001 (Feb. 8. 2017): Exhibit A 113. Pat.
`No. 9.468.747.
`Notice ofAllowance and Fees Due dated Oct. 9. 2015 now L'.S. Pat.
`No. 9.211.253.
`Notice ol‘Alloviancc and Fees Due dated Nov. 9. 2015 now US. Pat.
`No. 9.211.253.
`Notice of Allowance and Fees Due dared Apr. 12. 2016 now U.S.
`Pat. No. 9.468.247.
`Notice ofAllowance and Fees Due dated Jul. 26. 2016 now US. Pat.
`No. 9.468.747.
`Examiner initiated interview wnu'nary datod Mar. 31. 2016 now
`U.S. Pat. No. 9.480.644.
`Notice ofAllowancc and Foes Due dated Mar. 3]. 2016 now 11.5.
`Pat. No. 9.480.644.
`Notice ofAllowancc and Foes Due dated Jul. 7. 2016 now US. Pat.
`No. 9.480.644.
`
`* cited by examiner
`
`Copy provided by USP'l'O from the PIRS Image Database on 10-23-2018
`
`Nalox 1 001
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`
`
`U. S. Patent
`
`Oct. 3, 2017
`
`Sheet 1 of 7
`
`US 9,775,838 .32
`
`:.. .. . ¢.x«mw ., .
`
`. 4. m,
`
`m\w-xu:.n>.v¢v+w+_.........M
`
`
`
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`
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`
`W2 mg IN
`
`rmaamé mg m
`
`(mg/mL}
`
` Nainxane
`
`
`
`Time Post Administration {hr}
`
`FIG. 1
`
`Copy provided by USPTO from the PIRS Image Dalahase on 10-23-20] 8
`
`NaloxlOOl
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`Page 4 of 43
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`

`..______‘
`
`U.S. Patent
`
`Oct. 3, 2011‘r
`
`Sheet 2 of?
`
`US 9,775,838 132
`
`m n. n. . .. . .. . n . u .M. Wm. . v . .. . . . w Wm.” 'rw
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`i
`12.0
`
`Time Post Administratian {hr}
`
`.:_
`
`Ef
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`
`FIG. 2
`
`
`
`Copy provided by USPTO from the PIRS Image Database on 10-23—2013
`
`NaloxlOOl
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`Page 5 0f 43
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`

`

`:
`
`US. Patent
`
`Oct. 3, 2017
`
`Sheet 3 of 7
`
`Us 9,775,838 32
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`
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`NaloxonePfasmaComentrafior:{ngfmu
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`+ 2 X 40 mgme
`+ 2 x 20 mgimL
`1- 1 x 40 mgme
`+ 1 x 20 mgimL
`4" 0.4 mg $M
`
`
`
`Hours Postdose
`
`FIG. 3A
`
`i
`
`10
`
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`
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`
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`4
`a
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`HoursPostdose
`
`\\ Elk—~—
`
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`
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`
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`12
`
`FIG. 33
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`Copy provided by USP’TO from the PIRS Image Database on 10-23-20l8
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`NaloxlOOl
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`Page 6 01°43
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`

`

`US. Patent
`
`Oct. 3, 2017
`
`Sheet 4 of 7
`
`US 9,775,838 B2
`
`10
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`
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`
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`
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`
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`
`+ 2 x 20 mglmL
`"t" 1 x 40 mg/mL
`+ 1 x 20 mgme
`+ 0.4 mg M
`
`
`
`0.0
`
`.
`
`.
`
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`
`2.5
`.
`Hours Posidose
`
`3.0
`
`3.5
`
`4.0
`
`FIG. 4A
`
`10
`
`CI
`
`”A
`
`9......
`
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`
`4- 2 x 40 mgimL
`+ 2 x 20 mglmL
`1— 1 x40 mglmL
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`4» 0.4ngM
`
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`
`(ng/mL)
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`oNaloxonePlasmaConcentraiion
`
`.......,._,,,.W,fw___1
`‘oz]—.1__.fi__.w_,
`2.5
`3.0
`3.5
`4.0
`2.0
`0.5
`1.0
`1.5
`HoursPostdose
`
`.0 c:
`
`FIG. 4B
`
`Copy provided by USPTO from the PIRS Image Database on ”LES-2018
`
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`Page 7 of 43
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`

`

`
`
`US. Patent
`
`Oct. 3, 201'.lr
`
`Sheet 5 of 7
`
`US 9,775,838 BZ
`
`04 mg EM
`
`
`
`
`
`
`
`NaloxonePiasmaConcentration(nglmL)
`
`
`
`
`
`NaloxonePlasmaConcentration(ngrmL)
`
`
`
`.h.
`
`One Spray 20 mgme
`
`M00
`
`O
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`
`
`
`
`Copy provided by USPTO from [he PIRS Image Database on 1023-2018
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`Naloxl 001
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`

`
`
`US. Patent
`
`Oct. 3, 2017
`
`Sheet 6 of?
`
`US 9,775,838 B2
`
`03
`
`Two Sprays 2O mgfrnL
`
`
`
` N NaloxonePlasmaConcentration(nglmL) .h
`
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`
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`
`
`
`
`
`0
`
`2
`
`4
`
`6
`Hour
`
`FIG. 6A
`
`8
`
`10
`
`12
`
`One Spray 40 mgme
`
`!
`5
`
`.E
`
`.
`
`3 8:
`g
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`E 6
`
`E 8 '
`
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`0
`3
`9
`CL 2
`<1)
`
`+ Male
`an Female
`
`o
`
`0
`
`2
`
`4
`
`8
`
`10
`
`12
`
`8
`Hour
`
`FIG. SB
`
`Cnpy provided by USPI'O from the Pl R5 Image Database on 10—23—20] 8
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`m £
`
`COX2 g
`
`

`

`US. Patent
`
`Oct. 3,2017
`
`Sheet 7 of 7
`
`Us 9,775,838 32
`
`
`
`Two Sprays 40 mglmL
`
`
`
`NaloxonePlasmaConcentration(nglmL)
`
`
`
`
`
`Copy provided by LISPTU from The PIRS Imagc Database on 10-23-2018
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`US 9,7?5338 BZ
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`NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
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`CROSS-REI-‘ERENCE 'I‘O RELATEI)
`APPLICATIONS
`
`This application is a continuation of Ser. No. 15M] 5,221,
`filed on 25 Jan. 2011'. which is a continuation of Ser. No.
`15083341, filed on Jun. 15, 2016, now US. Pat. No.
`9,561,172, which is a continuation—in-part application of Ser.
`No. 14850302, filed on Nov. 24, 2015, now U.S. Pat. No.
`9,468,741, which is a continuation of Ser. No. 14l942,344,
`filed on Nov. 16, 2015, now US. Pat. No. 9,480,644, which
`is a continuation—in-part application of Ser. No. 14l659,4'r’2,
`filed on Mar. 16, 2015, now U.S. Pat. No. 9.211.253, which
`claims benefit of Ser. No. 61l953,379, filed on Mar. 14,
`2014. This application also claims benefit of Ser. No.
`621219.955, filed on 1? Sep. 2015 and Ser. No. 62l2?4,536,
`filed on 4 Jan. 2016. The entire disclosures of the applica—
`tions identified in this paragraph are incorporated herein by
`reference-s.
`
`JOINT RESEARCH AGREEMENT
`
`The subject matter disclosed and claimed herein was
`developed by or on behalf of LightLake Therapeutics Inc.
`and Adapt Pharma Operations Ltd, as parties to a joint
`research agreement, and as a result of activities undertaken
`within the scope of the joint research agreement. The joint
`research agreement was in effect on or before the effective
`filing date of the present claims.
`FIELD
`
`This disclosure generally relates to pharmaceutical com-
`positions comprising an opioid receptor antagonist, medical
`devices for delivery of the pharmaceutical compositions,
`and methods of using the compositions and the medical
`devices.
`
`BACKGROUND
`
`This section provides background information related to
`the present disclosure which is not necessarily prior art.
`Opioid receptors are G protein-coupled receptors (GP-
`CR5) that are activated both by endogenous opioid peptides
`and by clinically important alkaloid analgesic drugs such as
`morphine. There are three principal types of opioid recep-
`tors: the b—cpioid receptor, the tit-opioid receptor, and the
`p-opioid receptor. Opioids depress respiration, which is
`controlled principally through medullary respiratory centers
`with peripheral
`input
`from chemoreccptors and other
`sources, Opioids produce inhibition at the chemoreceptors
`via u-opioid receptors and in the medulla via p- and d-opioid
`receptors. While there are a number of neurotransmitters
`mediating the control of respiration, glutamate and y-amin—
`ohutyric acid (GABA) are the major excitatory and inhibi-
`tory neurotransmitters, respectively. Oxycodone and other
`opioid painkillers, as well as heroin and methadone are all
`implicated in fatal overdose.
`In the United States, mortality rates closely correlate with
`opioid sales. In 2014,
`there were 4105 drug overdose
`deaths in the United States, representing a 6.5% increase
`from 2013 as reported by Rudd et al. (20163 Morbidity &
`Mortality Weekly Report 64(50):]373-82 {starting at page
`10} “Increases in Dmg and Opioid Overdose Deaths —
`United States, 2000-2014." Over 23,000 of those were
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`overdoses of herein or prescription opioids, which repre-
`sents nearly a four—fold increase since l999. Drugs classed
`as prescription opioids include both typical analgesics, such
`as OxyContin® (oxycodone lIC] controlled-release) and
`methadone (used in the treatment of dependence on other
`opioids such as heroin and also prescribed for pain), but the
`increase in the rate ofdrug overdose in recent years has been
`driven mainly by overdoses of prescription analgesics.
`Naloxone is an opioid receptor antagonist that is approved
`for use by injection for the reversal of opioid overdose and
`for adjunct use in the treatment of septic shock.
`It
`is
`currently being used mainly in emergency departments and
`in ambulances by trained medical professionals. There have
`been efl‘orts to expand its use by providing the drug to some
`patients with take-home Opioid prescriptions and those who
`inject illicit drugs potentially facilitating earlier administra-
`tion of the drug.
`US. Pat. No. 4,464,328 to Hussein reports a method for
`eliciting an analgesic or narcotic antagonist response in a
`wann-blooded animal, which comprises administering intra-
`nasalIy UN")
`to said animal to elicit a narcotic antagonist
`rcSponse, a narcotic antagonist efl‘ective amount of nalox—
`one.
`
`WO 82f03't‘68 to Hussein reports a composition that
`contains 1 mg of naloxone hydrochloride per 0.] m] of
`solution adapted for nasal administration used in the treat—
`ment of narcotic induced respiratory depression (overdose)
`at a dosage approximately the same as that employed for
`intravenous (IV), intramuscular (IM) or subcutaneous (SQ)
`administration.
`
`W0 03(6275? to Davies reports pharmaceutical compo-
`sitions for [N or oral (P0) administration which comprise an
`opioid antagonist, such as naloxone for application by spray
`in the reversal of opioid depression for treatment of patients
`suflcring from opioid over-dosage, wherein the spray appli—
`cator is capable of delivering single or multiple doses and
`suitable dosage units are in the range of 0.2 to 5 mg.
`The use ofnasa] naloxone is not without controversy. For
`instance, Bowling et a1. (Ther Drug Monit. Vol 30, No 4.
`August 2008) reported that naloxone administered intrana-
`sally displays a relative bioavailability of 4% only and
`concluded that
`the IN absorption is rapid but does not
`maintain measurable concentrations for more than an hour.
`US. Pat. No. 9,192,570 to Wyse reports naloxone formu-
`lations for intranasal administration, Wysc reports (column
`2?, lines 29-3?) that benzalkonium chloride is not suitable in
`such formulations, because it facilitates unacceptable deg-
`radation of the naloxone. Wyse recommends (lines 4143)
`benzyl alcohol and paraben preservatives in place of hen-
`zalkonium chloride.
`
`there remains a need for durable, easy-to—use,
`Thus,
`noedleleSS devices with storage—stable formulations, that can
`enable untrained individuals to quickly deliver a therapeu—
`tically effective dose of a rapid-acting opioid antagonist to
`an opioid overdose patient. The therapeutically eflective
`dose should be sufficient
`to obviate the need for the
`untrained individual
`to administer an alternative medical
`intervention to the patient. and to stabilize the patient until
`professional medical care becomes available.
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`SIJMIMARY
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`This section provides a general summary of the disclo-
`sure= and is not a comprehensive disclosure of its fiil] scope
`or all of its features.
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`This diseiosure provides an improved single-use. pre-
`primed device adapted for nasal delivery of a pharmaceuti-
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`cal solution to a patient comprising: at least about 4% (wiv)
`naloxonc hydrochloride or a hydrate thereof, wherein the
`improvement comprises that the device is adapted to spray
`a round plume with an ovality ratio less than about 2, for
`example less than about 1.5.
`In another embodiment, there is provided a mist compris-
`ing droplets ofau at least 4% (wr’v) naloxone hydrochloride
`solution, wherein no more than about 10%, for example no
`more than about 5%, of the droplets have a diameter less
`than 10 pm.
`In yet another embodiment. there is provided an improved
`single-use. pro-primed device adapted for nasal delivery of
`a pharmaceutical solution to a patient comprising: at least
`about 4% (wt'v) naloxouc hydrochloride or a hydrate thereof;
`and between about 0.2% and about 1.2% (wr'v) of an
`isotonicity agent, wherein the improvement comprises that
`the device is adapted to Spray a round plume with an ovality
`ratio less than about 2.0.
`In yet another embodiment, there is provided an improved
`single—use. pro—primed device adapted for nasal delivery of
`a pharmaceutical solution to a patient comprising: at least
`about 4% (wtv) naloxone hydrochloride or a hydrate thereof;
`and between about 0.005% and about 0.015% (wiv) of a
`preservative, wherein the improvement comprises that the
`device is adapted to spray a round plume with an ovality
`ratio less than about 2.0.
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`BRJEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the mean (:SD) naloxone plasma concen-
`tration following administration of 0.4 mg intramuscular
`(1M), 2 mg intranasal
`(IN). and 4 mg IN in 14 human
`subjects.
`FIG. 2 shows the mean (:SD) naloxone plasma concen-
`tration with logarithmic transformation following adminis-
`tration of 0.4 mg intramuscular (1M), 2 mg intramural (IN)1
`and 4 mg IN in i4 human subjects.
`FIGS. 3A and 3B show the mean naloxone plasma con-
`centration following single inlranasal administrations (FIG.
`3A) and intramuscular injections (FIG. 3B) of naioxone to
`healthy subjects (N=28) over a twelve-hour period.
`FIGS. 4A and 4B show the mean naioxone plasma con-
`centration following single intranasal administrations (FIG.
`4A) and intramuscular injections (FIG. 4].!) of naloitone to
`healthy subjects (N=28) over a four—hour period.
`FIGS. 5A and SB show the mean naloxone plasma con-
`centration following intramuseular injection of 0.4 mg
`naloxone (FIG. 5A, top) and one spray of 20 mg/mL (i.e..
`2% wiv) naloxone (FIG. 5B, bottom) to healthy male
`(N—clo) and female (N=]2) subjects over a twelve—hour
`period.
`FIGS. 6A and 6B show the mean naloxone plasma con-
`centration following two sprays of 20 mglrnL- (i.e., 2% wtv.
`FIG. 6A, top] and one spray ol‘40 mgtmL (i.e., 4% wlv, FIG.
`SB, bottom) to healthy male (N=]6) and female (N=l2)
`subjects over a twelve-hour period.
`FIG. 1' shows the mean naloxone plasma concentration
`following two sprays of40 mgl’mL (i.e., 4% wtv) to healthy
`male (N=16] and female (N= 1 2) subjects over a Melve—liour
`period.
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`DETAILED DESCRJI’IION
`
`Dcfi nition
`
`For clarity and consistency, the following definitions will
`be used throughout this patent document.
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`The term "active ingredient" or “pharmaceutically active
`compound" is defined in the content of a “pharmaceutical
`composition“ and is intended to mean a component of a
`pharmaceutical composition that provides the primary phar-
`macological efl'ect, as Opposed to an “inactive ingredient"
`which would generally be unopposed as providing no phar-
`maceutical benefit.
`
`The term “actuation," as used herein. refers to operation
`of the device such that the pharmaceutical composition is
`delivered therefrom.
`The term “agonist,” as used herein, refers to as used
`herein refers to a moiety that interacts with and activates a
`receptor. and thereby initiates a physiological or pharmaco-
`logical responsc chruactcristic of that receptor. The term
`“antagonist," as used herein, refers to a moiety that com—
`petitively binds to a receptor at the same site as an agonist
`(for example, the endogenous ligand), but which does not
`activate the intracellular response initiated by the active
`form of the receptor and can thereby inhibit the intracellular
`responses by an agonist or partial agonist. An antagonist
`does not diminish the baseline intracellular response in the
`absence of an agonist or partial agonist. The term “inverse
`agoni st” refers to a moiety that binds to the endogenous form
`of the receptor or to the constitutively activated form of the
`receptor and which inhibits
`the baseline intracellular
`response initiated by the active form of the receptor below
`the nonnal base level of activity which is observed in the
`absence of an agonist or partial agonist.
`The term “antimicrobial preservative,“ as used herein,
`refers to a phannaccutically acceptable excipient with anti-
`microbial properties which is added to a pharmaceutical
`composition to maintain microbiological stability.
`The term “AUG,“ as used herein, refers to the area under
`the drug plasma concentration—time curve. The term
`“AUCMI as used herein, refers to the area under the drug
`plasma concentration-time curve tiom r- 0 to the last mea-
`surable concentration. The term "AUC¢,_,,,” as used herein.
`refers to the area under the drug plastna concentration—time
`curve extrapolated to as. The term “AUCD_,_.,,.“ as used
`herein,
`refers to the AUCM normalized to 0.4 mg IM
`naloxone. The term "AIJC0_,,,,D," as used herein, refers to the
`AUCUM normalized to 0.4 mg IM naloxone
`The term "bioavailability (F),” as used herein. refers to
`the fraction of a dose of drug that is absorbed from its site
`of administration and reaches, in an unchanged form, the
`systemic circulation. The term "absolute bioavailability" is
`used when the fraction of absorbed drug is related to its IV
`bioavailability.
`It may be calculated using the following
`formula:
`
`Dmttme MM
`_ A. UCwmnm,
`A Urdu-mm. Doseunemm
`
`The term relative bionvailahility (Fm!) is used to compare
`two diflerent extravascular routes ofdr'ug administration arid
`it may be calculated using the following formula:
`
`rel
`
`_ dUCmmmmwr
`— AUCmmva-ur-rv‘:
`
`DORmmnm-mrr
`I: C Stmmml'flb'l
`
`The term "clearance (CL)," as used herein, refers to the
`rate at which a drug is eliminated divided by its plasma
`concentration, giving a volume of plasma from which drug
`is completely removed per unit of time. CL is equal to the
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`elimination rate constant (A) multiplied by the volume of
`distribution (Vd), whcrein "Va" is the fluid voltune that
`would be required to contain the amount of drug present in
`the body at the same concentration as in the plasma. 'lhe
`term “apparent clearance (CUP)? as used herein, refers to
`clearance that does not take into account the bioavailabilily
`of the drug. It is the ratio of the dose over the AUC.
`The term “CW3,“ as used herein, refers to the maximum
`observed plasma concentration. The term “CmmD.” as used
`herein. refers to Cm, normalized to 0.4 mg 1M nalortonc.
`The term “coefficient of variation (CV)," as used herein.
`refers to the ratio of the sample standard deviation to the
`sample mean. It is ofien expressed as a percentage.
`The term “confidence interval." as used herein, refers to
`a range of values which will include the true average value
`of a parameter a specified percentage of the time.
`The term "device," as used herein, refers to an apparatus
`capable of delivering a drug to patient in need thereof.
`The term "delivery time,“ as used herein. refers to the
`amount of time that elapses between a determination made
`by a healthcare professional. or an untrained individual that
`an individual
`is in need of nasal delivery of an opioid
`antagonist and completion of the delivery.
`The term "elimination rate constant 0.)," as used herein,
`refers to the l'raclicml rate of drug removal from the body.
`This rate is constant in first-orderkinetics and is independent
`of drug concentration in the body. it is the slope of the
`plasma concentration-time line (on a logarithmic 1 scale).
`The term “AR," as used herein, refers to the terminal phase
`elimination rate constant. wherein the “terminal phase” of
`the drug plasma concentration-time curve is a straight line
`when plotted on a semilogarithmic graph. The terminal
`phase is often caiied the “elimination phase“ because the
`primary mechanism for decreasing drug concentration dur—
`ing the terminal phase is drug elimination from the body.
`The distinguishing characteristic of the terminal elimination
`phase is that the relative proportion of drug in the plasma
`and peripheral volumes of distribution remains constant.
`During this "terminal phase” drug returns from the rapid and
`slow distribution volumes to the plasma, and is permanently
`removed fiom the plasma by metabolism or renal excretion.
`The term “equivalent," as used herein refers to a weight
`of an opioid antagonist selected from naloxone and phari
`maceuticaliy acceptable salts thereof that is equimolar to a
`specified weight oi'nalortone hydrochloride. For example. 8
`mg of anhydrous naloxone hydrochloride (molecular
`weight, 363.34) is equivalent to about 12 mg of naloxone
`freebase (molecular weight, 3273?), and to about 8.3 mg of
`naloxone hydrochloride dihydrate
`(molecular weight
`399.8?)
`The term "filled.” as used herein, refers to an association
`between a device and a phannaceutical composition,
`for
`example. when a pharmaceutical composition described
`herein comprising a therapeutically efl'ective amount of an
`opioid antagonist is present within a reservoir that forms a
`part of a device described herein.
`The term "hydrate,” as used herein. refers to an opioid
`antagonist described herein or a salt thereof that firrther
`includes a stoichiometrie or non-stoicbiometric amount of
`water bound by non-covalent intermolecular forces.
`The term “in need of treatment" and the term “in need
`thereof" when referring to treatment are used interchange—
`ably and refer to a judgment made by a caregiver (eg.
`physician, nurse, nurse practitioner) that a patient will
`benefit from treatment.
`As used herein, two embodiments are "mutually exclu-
`sive" when one is defined to be something which is different
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`than the other. For example, an embodiment wherein the
`amount of naloxone hydrochloride is specified to be 4 mg is
`mutually exclusive with an embodiment wherein the amount
`of naloxonc hydrochloride is specified to be 2 mg. However.
`an embodiment wherein the amount of naloxone hydrochlo-
`ride is specified to be 4 mg is not mutually exclusive with an
`embodiment in which less than about 10% of said pharma-
`ceutical composition leaves the nasal cavity via