U $598063
`
` 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: 9,629,965
`ISSUE DATE: April 25, 2017
`
`
`
`
`fficer
`
`
`
`Under Secretary of Commerce for Intellectual Property
`and Director of the United States
`tent and Trademark Office
`
`By Authority of the
`
`)7?
`
`P. SWAIN
`
`Certifyin
`
`Nalox I 001
`
`Nalox—l Pharmaceuticals, LLC
`
`Page 1 01°37
`
`

`

`lllilllllliilllilllliiilililllllllillilllllllllllliilli
`U 5009629965 B2
`
`(12) United States Patent
`(10) Patent No.:
`US 9,629,965 B2
`Crystal 01 al.
`(45) Date of Patent:
`*Apr. 25, 2017
`
`(54) NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`(71) Applicant: Opiant Pharmaceuticals, lne.. Santa
`Monica, CA (US)
`
`[72)
`
`Inventors: Roger Crystal. Santa Monica, CA
`(US); Michael Brenner Weiss, New
`York. NY (US)
`
`(73) Assignee: Opiant Pharmaceuticals, [1110, Santa
`Monica. CA (US)
`
`( “ ) Notice:
`
`Subject to an).1 disclaimer. the term of this
`patent is extended or adiustod under 35
`U.S.C. 1540:) by 0 days.
`This patent is subject to a terminal dis—
`claimer.
`
`(21) Appl. No.: 15/335,145
`
`(22)
`
`01100;
`
`Oct. 20. 2010
`
`(65)
`
`Prior Publication Data
`
`US 201710043107 A]
`
`Feb. 16, 2017
`
`Related US. Application Data
`
`(63) Continuation of application No. 141942344, filed on
`Nov. 16. 2015, now Pat. No, 9,480.644, which is a
`continuation-in-part of application No. 141659.472,
`filed on Mar. 16, 2015, now Pat. No. 9,211,253.
`(60) Provisional application No. 611953.379. filed on Mar.
`14, 2014.
`
`(2000.01)
`(2000.01)
`(2000.01)
`(2000.01)
`(2000.01)
`(2000.01)
`(2000.01)
`(2000.01)
`(2012.01)
`(2000.01)
`(2000.01)
`
`(51)
`
`(52)
`
`1m. (:1.
`A0101 31/00
`A0101 5/00
`A01F 13/00
`AME 11/50
`A0101 11/00
`A0111 0/00
`A61K 51/405
`A0111 47/02
`A010 42/13
`A0110 0/00
`Aéi‘M 15/00
`11.3. c1.
`(:01:
`......... A0101 11/000 (2014.02); A0111 9/0043
`(2013.t11);/161K 9/08 (2013.01); .1de 31/435
`(2013.01); 1461114002 (2013.01): A61K4'7/18
`(2013.01); A0111 42/1115 (2013.01); A0111
`42/100 (2013.01); A0101 15010901301);
`A6111! 31/00 (2013.01)
`(58) Field of Classification Search
`None
`
`
`
`4.987.136 1‘\
`5.366.154 A
`9.192570 32
`9.2I1.253 132
`9.468.747 B2
`9.480.644 132
`2003-0011300 111
`20061000967 .o’tl
`200910017102 A]
`2010-0113495 Al
`201010168147 Al
`201030331354 Al
`201l-"0046172 Al
`20120270895 A]
`2013;003:125 01]
`201610008277 A]
`201630303041 AI
`
`].-'199| Kreek cl :lI.
`21199 Bahal at 21].
`1192015 Wyse el al.
`1252015 Crystal et al.
`1012016 Crystal et a1.
`11/2016 Crystal et a1.
`4.1200: Wermelirig
`612006 Narnburi et a1.
`132009 Stinchcomb ei 81.
`512010 W'ct‘meiing et al.
`712010 (Ihapleo el al.
`I2320|0 Wcrmeling
`212011 Chaplco el :11.
`10.12012 Wermeling
`112013 Edwards et aI.
`11'20I6 Crystal at al.
`iii-"20115 Keegan el 31.
`
`(N
`F.P
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
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`W0
`W0
`\V0
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`W0
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`W0
`W0
`
`FOREIGN PA‘i‘EN'i‘ DOCUM] iNTS
`1575793
`2-"2005
`1681057 Bl
`812008
`W0 8203768 A1
`1131982
`W0 9830211 Al
`71"]998
`W0 0062757 Al
`1012000
`W0 0074652 A1
`12-2000
`W0 0158447 Al
`812001
`W0 0182931 Al
`1152001
`W0 02li778 Al
`2-"2002
`WO 03084520 A2
`1012003
`WO 2004054511 112
`732004
`W0 2005020906 A2
`3-‘2005
`WO 2006089973 A2
`812006
`WO 2007083073 Al
`7:200?
`WO 2009040595 A1
`212009
`W0 2012026963 A2
`3112012
`W0 201256317 :12
`11-"20l2
`W0 201308447 A1
`92013
`W0 2014016653 A1
`112014
`W0 2015095644 Al
`612015
`WO 2015136373 Al
`912015
`WO 2015136373 «\3
`912015
`W0 20|6007729 Al
`132016
`WO 2016007729 A3
`["2016
`
`OTHER PUBLICATIONS
`
`Aptar UnitDosc and BiDose product information sheet. available at
`wweptar.com-'docsr'pl1arma-prestcriptionr'uds-bds-dataaheetpdf.
`publication date unknown. last accessed Mar. 26. 2015.
`(Continued)
`
`Primary Examioer — Jeffrey T Palenik
`(74) Atrome): Agent, or Firm— Dennis A. Bennett;
`Cynthia Hathaway,r
`
`(57)
`
`ABSTRACT
`
`Drug products adapted for nasal delivery. comprising a
`tare-primed device filled with a pharmaceutical composition
`comprising an opioid receptor antagonist. are pmvided.
`Methods of treating opioid overdose or its symptoms with
`the inventive drug products are also provided.
`
`.10 Claims, 7 Drawing Sheets
`
`Soc application file for complete search history.
`References Cited
`
`(56)
`
`US. PA'l'EN'T DOCUMENTS
`4.131.726 A
`131930 Bernstein
`4.464378 A
`311984 [lussain
`
`Cop),r provided by USPTO from the PIRS Image Database on 10-23-2018
`
`Naioxl 001
`
`Naiox-i Pharmaceuticals, LLC
`
`Page 2 QB?
`
`

`

`US 9,629,965 B2
`Page 2
`
`[55}
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Ashton H et al.. “Best evidence topic report. Lntranasa] naloxone in
`suspected opioid overdose." Enters Med J 23:3. 221—23 (published
`Mar. 2006).
`Bailey A M et al.. “Naloxone for opioid overdose prevention;
`pharmacists'
`role in community—based practice settings." Arm.
`Phannacother 48:5. 1501-06 (published May 20M).
`Barton E D et al.. “Efficacy ofintranasal naloxone as a needleless
`alternative for treatment of opioid overdose in the prehospital
`setting." J Emerg Med 29:3. 265-2] (published Oct. 2005).
`Barton E D et al.. "Intranasal administration of naloxone by
`paramedics" Prehosp Emerg Care 6: 1. 54-58 (published Jan. 2002).
`Crystal r. ct al.. Nasal drug products and methods of their use.
`Lighllalte Therapcmics, Inc. U.S. Pat. No. 9.211.253, Notice of
`Allowanucfict. 9. 2015.
`Cryslal r. at al.. Nasal drug products and methods of their use.
`Lightlake Therapeutics. Inc.. US. Pat. No. 9.211.253. Notice of
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`Crystal r. or al., Nasal drug products and methods of their use.
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`Crystal r. et al., Nasal drug products and methods of their use,
`Lightlake Therapwtics. 1.1m. U.S. Pat. No. 9.468.742. Notice of
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`Crystal 1'. er al.. Nasal drug products and methods of their use.
`Lighllake 'l'herapeutics, Inc., US. Pat. No. 9.480.644. Examiner
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`DoeSirnlrins M et al., "Saved by the nose: Wenadministercd
`intranasal naloxone hydrochloride for opioid overdose." Am 1
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`Bowling 1 el al.. “Population pharmacokinctics of intravenous.
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`Heard C et al., “Intranasal
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`Kelly A M et al., “Intranasal naloxone for life threatening opioid
`toxicity." Emerg Med 1 19:4. 375 (published Jul. 2002).
`Kelly A M ct al.. “Randomised trial ofintranasal versus intramus—
`cular naloxone in prehospital treatment for suspected opioid over-
`dose.” Med J Ans! 182:1 24-21r (published Jan. 3. 2005).
`Kerr D et al.. “Randomized controlled trial comparing the efl’ec-
`tivcncss and safety of intranasal and intramuscular na10xone for the
`treatment of suspected heroin overdose." Addiction 104:12, 206’?-
`?4 (Epuh Nov. 9. 2009).
`Krieter P. eta1.. Pharmacokinetic Properties and Human Use Char-
`acteristics of an FDAApproved Intranasal Naloxone Product for the
`Treatment of Opioid Overdose, J Clin i‘harmcol. 2016. pp.
`l—ll.
`Loirner N ct al.. "Nasal administration of naloxone for detection of
`opiate dependence." J Psychiatr Res 26: 1. 39-43 (published Jan.
`1992].
`Loimer N et al.. “Nasal administration of naloxone is as efl’ective as
`the intravenous route in opiate addicts." Int J Addicl 29:6. 8l9-27
`(published Apr. 1994).
`Merlin M A et al., "lniranasal mloxone delivery is an alternative to
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`Robertson T M. "Intranasal naloxonc is a viable alternative to
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`Emerg Care 13:4. 512-15 (Published Oct. 2009).
`Walley A Y et al.. "Opioid overdose prevention with intranasal
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`
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`efi'ectively by emergency medical services for suspected opioid
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`20:1).
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`Teva Pharmaceuticals USA. Inc.. “Notice of ANDA No. 209522
`nalcnrone hydrochloride nasal spray. 4mgl‘spray, with paragraph IV
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`Krieler P et, al., Phannacolcinelic Properties and Human Us: Char-
`acteristics of an FDA-Approved Intranasal Naloxone Product for
`the Troamient of Opioid Overdose. 1 Clin Pharmacol. Oct. 2016:56
`[10]1243-1253.
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`variables on deposition pattern of nasal spray prmrps evaluated
`using. a nasal. Pharm. Res. (2011) 28:1895-1904.
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`pgs.
`'l'b'VA Pharmaceuticals USA. Inc.. Nolicc of ANDA No. 209522
`naloxone hydrochloride nasal spray. 4mgi'spray. with paragraph IV
`certification concerning U.S. Pat. No. 9.463.747. dated Dec. 29.
`2016.
`'
`
`U.S.App1. No, 151268.066. filed Sep. 16. 20l6. Nasal drug products
`and methods of their use. Keegan F. et al.
`L'.S. App}. No, 151415.221. filed Jan. 25. 2017. Nasal dmg products
`and methods of their use. Keegan l-‘. et al.
`US. Appl. No. 151428.105. tiled Feb. 9. 201‘? Nasal drug products
`and methods of their use. Kocgan F. ct a1.
`
`Copy provided by USPTO from thr: PIRS image Database on 10—23-201 8
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`Naloxl 001
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`Page 3 of 37
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`

`

`U.S. Patent
`
`Apr. 25, 2017
`
`Sheet] of 7
`
`US 9,629,965 32
`
`FIGJ
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`NaloxlOOl
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`Page 4 0f 37
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`

`US. Patent
`
`Apr. 25, 2017
`
`SheetZ of?
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`US 9,629,965 B2
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`Page 5 of 37
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`US. Patent
`
`Apr. 25, 2017
`
`Sheet 3 of 7
`
`US 9,629,965 B2
`
`FIG.3
`
`10—
`
`3A
`
`
`
`
`
`
`
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`
`SJ
`
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`
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`
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`+ 2 x 20 mglml.
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`+ 1 x 20 mg/mL
`+ 0.4 mg IM
`
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`
`
`0
`
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`
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`
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`
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`+ 2 x 20 mgimL
`
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`
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`+ 1 x 20 mglmL
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`----«.
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`
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`NaloxlOOl
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`Page 6 0f 37
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`US. Patent
`
`Apr. 25, 2017
`
`Sheet 4 of 7
`
`US 9,629,965 B2
`
`FIG. 4
`
`10-
`
`
`
`
`
`
`
`NaloxonePiasmaConcentration(ngimL)
`
`
`
`
`4A
`
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`
`+ 2 x 20 mgImL
`1- 1 x 40 ”19me
`+ 1 x 20 1119me
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`
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`3.5
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`
`4B
`
`Concentration(ngz‘mu
`
`
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`
`
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`
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`
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`Copy provided by USPTO from [he PIRS Image Databasc on 1033-2018
`
`NaloxlOOl
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`Page 7 0f 37
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`US. Patent
`
`Apr. 25, 2017
`
`Sheet 5 or 7
`
`US 9,629,965 B2
`
`FIG. 5
`
`0.4 mg IM
`
`_|. b
`
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`
`F3 o
`
`
`
`NatoxonePlasmaCcncentration(ngImL)
`
`99.09I‘d-503m
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`
`
`
`NaioxonePlasmaConcentration(ngfmu
`
`One Spray 20 mglmL
`
`Copy provided by USPTO From the PIRS Image Database on 10-23-2018
`
`NaloxlOOl
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`Page 8 0f 37
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`U.S. Patent
`
`Apr. 25,2017
`
`Sheet 6 of 7
`
`US 9,629,965 132
`
`FIG. 6
`
`Two Sprays 20 mgx’mL
`
`on
`
`SA
`
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`
`
`
`
`
`
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`
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`Copy provided by USP’I'O [firm the PIRS Image Database on 10-23-2018
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`NaloxlOOl
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`Page 9 of 37
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`US. Patent
`
`Apr. 25, 2017
`
`Sheet 7 of 7
`
`US 9,629,965 B2
`
`FIG. 7
`
`Two Sprays 40 mgme
`
`
`
`NaioxonePlasmaConcentration(nglmL)
`
`
`
`
`
`Copy pruvided by USPTD I‘Tom lhe PIRS Image Databasc on 10-23—201 8
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`NASA]. DRUG PRODUCTS AND METHODS
`OF THEIR USE
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`L. reuse in the rate ofdtug overdose over the 16 years of the
`study was driven entirely by overdoses of typical analgesics.
`Over the same time period, methadone overdoses remained
`stable, and overdoses from heroin declined. Whites were
`more likely than blacks and Latinos to overdose on these
`analgesics, and deaths mostly occurred in neighborhoods
`with lower rates of poverty, suggesting difl'erential access to
`doctors who can write painkiller prescriptions may be a
`driving force behind the racial disparity. (Gerda et al. “Pre—
`scription opioid mortality trends in New York City,
`I990-
`2006: Examining the emergence Qf‘arr epidemic,” Drug and
`Alcohol Dependence Volume 132, Issues 1—2,
`I Sep. 2013,
`53-62.)
`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 efforts to expand its use by providing the drug to some
`patients with take-home opioid prescriptions and these who
`inject illicit drugs, potentially facilitating earlier administra—
`tion of the drug. The UN Commission on Narcotics Drugs
`“encourages all Member States to include etTective elements
`for the prevention and treannent of drug overdose, in par-
`ticular opioid overdose, in national drug policies, where
`appropriate, and to share best practices and information on
`the prevention and treatment of drug overdose, in particular
`opioid overdose,
`including the use of opioid receptor
`antagonists such as naloxone."
`U.S. Pat. No. 4,464,328 describes a method for eliciting
`an analgesic or osmotic antagonist response in a warm-
`blooded animal, which comprises administering intranttsally
`(IN) to said animal to elicit a narcotic antagonist response,
`a narcotic antagonist efi‘ective amount of naloxone, W0
`8303768 discloses a composition that contains 1 mg of
`naloxone hydrochloride per 0.1 ml of solution adapted for
`nasal administration used in the treatment of narcotic
`induced respiratory depression (overdose) at a dosage
`approximately the same as that employed for intravenous
`(IV), intramuscular (IM) or subcutaneous (SQ) administra-
`tion. W0 00rt62757 teaches pharmaceutical compositions for
`IN 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 suf—
`fering from opioid over—dosage, wherein the spray applica—
`tor is capable of delivering single or multiple doses and
`suitable dosage units are in the range of 0.2 to 5 mg.
`The use of nasal naloxone is not without controversy. For
`instance. Loimer et al. (International Journal of Addictions,
`29(6). 319-827, 1994) reported that the nasal administration
`of mloxone is as efl'ective as the intravenous route in opiate
`addicts, however, Dowling ct al. (Ther Drug Monit. Vol 30,
`No 4, August 2008) reported that naloxone administered
`intranasally displays a relative bioavailahility of 4% only
`and concluded that the IN absorption is rapid but does not
`maintain measurable concentrations for more than an hour.
`One early study of 196 consecutive patients wilh sus-
`pected opioid overdose conducted in an urban ont-of-hos-
`pitai setting, had shown the mean interval from mergency
`medical services (EMS) arrival to a respiratory rate ofle
`breathsr'min was 9314.2 rrrin with administration of union—
`one 0.4 mg l'v'. versus 95:41.58 min with administration of
`naloxonc 0.8 mg SQ. The authors concluded that the slower
`rate of absorption Via the SQ route was ofiset by the delay
`in establishing an IV line. (Wangcr et al., Intravenous vs
`
`
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`This application is a continuation of US. application Ser.
`No. 14t942,344, filed Nov. 16, 2015, now Us. Pat. No.
`9,430,644, which is a continuation-in-part of U.S. applica-
`tion Ser. No. 14l659,4?2. filed Mar. 16, 2015. now US. Pat.
`No. 9,211,253, which claims the benefit of US. Provisional
`Application No. 6U953,3?9. filed Mar. 14, 2014, the dis-
`closures of which are hereby incorporated by reference as if
`written herein in their entirety.
`Provided are drug products adapted for nasal delivery
`comprising a pre—primed device and a pharmaceutical com-
`position comprising an opioid receptor antagonist. pharma-
`ceutical compositions comprising an opioid receptor antago-
`nist, and methods of use thereof.
`Opioid receptors are G protein-coupled receptors (GP-
`CRs) 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 3-opioid receptor, the K-opioid receptor, and the
`p—opioid receptor. Opioids depress respiration, which is
`controlled principally through medullary respiratory centers
`with peripheral
`input
`lrom chemoreceptors and other
`sources. Opioids produce inhibition at the cbemoreceptors
`via u—opioid receptors and in the medulla via u— and b-opioid
`receptors. While there are a number of neurotransmitters
`mediating the control of respiration, glutamate and y—amin-
`obutyric acid (GABA) are the major excitatory and inhibi—
`tory neurotransmitters, respectively. This explains the poten-
`tial
`for interaction of opioids with benzodiachines and
`alcohol: both benzodiazepines and alcohol facilitate the
`inhibitory efiect of GABA at the GABAA receptor, while
`alcohol also decreases the excitatory efiect of glutamate at
`N'M1)A receptors. Oxycodone and other opioid painkillers,
`as Well as heroin and methadone are all implicated in fatal
`overdose. Heroin has three metabolites with opioid activity.
`Variation in the lormation of these metabolites due to
`genetic factors and the use of other drugs could explain
`difl'erential sensitivity to overdose. Metabolites of metha-
`done contribute little to its action. However, variation in rate
`of metabolism due to genetic factors and other drugs used
`can modify methadone concentration and hence overdose
`risk. The degree oftolerancc also determines risk. Tolerance
`to respiratory depression is less than complete. and may be
`slower than tolerance to euphoric and other elfects. One
`consequence of this may be a relatively high risk of overdose
`among experienced opioid users. While agonist administra-
`tion modifies receptor function, changes (usually in the
`opposite direction) also result from use of antagonists, for
`example, supersensitivity to opioids following a period of
`administration of antagonists such as naltrexone.
`In the United States, mortality rates closely correlate with
`opioid sales.
`In 2008, approximately 36,450 people died
`from drug overdoses. At
`least 14,800 of these deaths
`involved prescription opioid analgesics. Moreover, accord—
`ing to the Substance Abuse and Mental Health Services
`Administration, the numberr’rate of Americans 12 years of
`age and older who currently abuse pain relievers has
`increased by 20 percent between 2002 and 2009. In New
`York City, between 1990 and 2006, the fatality rate from
`prescription opioids increased seven-told, front 0.39 per
`100,000 persons to 2.2. Drugs classed as prescription opi-
`oids in the study include both typica} analgesics, such as
`OxyOontin® (oxycodonc HC]
`controlled—release)
`and
`methadone (used in the treatment of dependence on other
`opioids such as heroin and also prescribed for pain), but the
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`subcutaneous naloxone for out—ofinospita! management
`ofiaresumea’ opioid overdose. Acad Emerg Med. 1998 April;
`5(4):293—9).
`The Denver Health Paramedic system subsequently
`investigated the efficacy and safety of atomized intranasal
`naloxone for the treatment of suspected opiate overdose
`(Barton, et al., Efficacy ofintranaml onlosone as a needle-
`less alternative for treatment of opioid overdose in tire
`prehorpitai setting. J Emerg Med, 2005. 29(3): p. 265—71).
`All adult patients encountered in the prehospital setting as
`suspected opiate oVerdose. found down. or with altered
`mental status who met the criteria for naloxone administra—
`tion were included in the study. 1N naloxone (2 mg) was
`administered immediately upon patient contact and before
`IV insertion and administration of 1V naloxone (2 mg).
`Patients were then treated by EMS protocol. The main
`outcome tneasures were: time of IN naloxone administra-
`tiun, time ofIV naloxone administration, time of appropri ate
`patient response as reported by paramedics. Ninety—five
`patients received IN oaloxone and were included in the
`study. A total of 52 patients responded to naloxone by either
`IN or IV, with 43 (83%) responding to [N naloxone alone.
`Seven patients (16%) in this group required further doses of
`[V naloxone. The median times from arrival at patient side
`to awakening and from administration of the IN naloitone to
`patient awakening were 8.0 minutes and 3.0 minutes respec-
`tively.
`The Drug Overdose Prevention and Education (DOPE)
`Project was the first naloxone prescription program (NPP)
`established in partnership with a courtly health depanment
`(San Francisco Demrtment of Public Health), and is one of
`the longest running N'PPs in the USA. From September 2003
`to December 2009, 1,942 individuals were trained and
`prescribed naloxone through the DOPE Project, of whom
`24% returned to receive a naloxone refill, and 11% reported
`using naloxorte during an overdose event. Of 399 overdose
`events where naloitone was used, participants reported that
`89% were reversed. In addition. 83% of participants who
`reported overdose reversal attributed the reversal to their
`administration of naloxone. and fewer than 1% reported
`serious adverse effects. Findings from the DOPE Project add
`to a growing body of research that suggests that intravenous
`drug users (lDUs) at high risk ot‘witnessing overdose events
`are willing to be trained on overdose response strategies and
`use lake-home naloxone during overdose events to prevent
`deaths (Burden, ct al.. Overdose prevention and natoxrme
`prescription for opioid users in San Francisco. J Urban
`Health. 2010 December; 8?(6):931-41).
`Another reported study reviewed EMS and hospital
`records before and alter implementation of a protocol for
`administration of intranasal naloxone by the Central Cali—
`fornia EMS Agency in order to compare the prehospital time
`intervals from patient contact and medication administration
`to clinical response for IN versus intravenous IV naloxone
`in patients with suspected narcotic overdose. The protocol
`for the treatment of opioid overdose with intranasal nalox-
`one was as follows: “Inlranasal (iN)—Adn1inister 2 mg
`intranasaily (1 mg per noslril) using mucosa] atomirer
`device (W) if suspected oat-colic intoxication and
`respiratory depression (rate 3 or less). This dose may be
`repeated in 5 minutes if respiratory depression persists.
`Respirations should be supported with a bag valve mask
`until respiratory rate is greater than 8. Intramuscular (1M)—
`Administer 1 mg if unable to administer intranasally (sec
`special considerations). May repeat once in 5 minutes.
`Intravenous (1V) —Admioister 1 mg slow IV push if no
`response to intranasal or [M administration after 10 minutes.
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`Pediatric dose— 0.1 mgfkg intranasally, if less than 10 kg
`and less than I year old“. Patients with suspected narcotic
`overdose treated in the prehospital setting over 13" months,
`between March 2003 and July 2004 were included. Para-
`medics documented dose, route of administration. and posi-
`tive response times using an electronic recrird. Clinical
`response was defined as an increase in respiratory rate
`(breathsfmin) or Glasgow Coma Scale score of at least 6.
`Main outcome variables included time from medication to
`clinical response and time fiom patient contact to clinical
`response. Secondary variables included numbers of doses
`administered and rescue doses given by an alternate route.
`Between-group comparisons were accomplished using
`Heats and chi-square tests as appropriate. One hundred
`filly-four patients met the inclusion criteria. including 104
`heated with IV and 50 treated with IN naloxone. Clinical
`response was noted in 33 (66%) and SB (56%) of the ]N and
`IV groups. respectively (p —-0.3). The mean time beuvecn
`naloxone administration and clinical response was longer for
`the IN group (12.9 vs. 8.] min. p=0.02). However, the mean
`times from patient contact to clinical response were not
`significantly dilihrent between the IN and IV groups (20.3
`vs. 20.? min, p=0.9). More patients in the IN group received
`two doses of naloxone (34% vs. 18%, p20.05). and three
`patients in the IN group received a subsequent dose oil)? or
`IM naloxone. (Robertson et al., l’ntranosoi naloxone is a
`viable alternative to intravenous noioxone jor prekospitol
`narcotic owrdose. Prehosp litnerg Care. 2009 October—
`December', 13(4):512—S).
`In August 2006. the Boston Public Health Commission
`passed a public health regulation that authorized an opioid
`overdose prevention program that included intranasal halos-
`one education and distribution of the spray to potential
`bystanders. Participants were instructed by trained stafl‘ to
`deliver I mL (1 mg) to each nostril of the overdose victim.
`After 15 months, the program had provided training and
`intranasal naloxone to 385 participants who reported 74
`successful overdose reversals (Doe-Simkins et al. Overdose
`prevention education with distribution ofintmnusae’ notor-
`one is ofeorioie public health intervention to address opioid
`overdose. Am J Public I-leallh. 2009; 99:?88-291).
`Overdose education and nasal naloxone distribution
`(OEND) programs are community—based interventions that
`educate people at risk for overdose and potential bystanders
`on how to prevent. recognize and respond to an overdose.
`They also equip these individuals with a naloxone rescue kit.
`To evaluate Ihe impact of UEND programs on rates of opioid
`related death from overdose and acute care utilization in
`Massachusetts. an intermpted time series analysis of opioid
`related overdose death and acute care utilization rates from
`2002 to 2009 was performed comparing cormnunily-year
`strata with high and low rates of OENl) implementation to
`those with no implementation. The setting was nineteen
`Massachusetts communities [geographically distinct cities
`and towns) with at least five fatal Opioid overdoses in each
`of the years 2004 to 2006. ()END was implemented among
`opioid users at risk for overdose, social service agency stalf,
`family, and friends of opioid users. OEND programs
`equipped people at risk for overdose and bystanders with
`nasal naloxone rescue kits and trained them how to prevent,
`recognize, and respond to an overdose by engaging emer—
`gency medical services. providing rescue breathing. and
`delivering naloxone. Among these communities, OEND
`programs trained 2,912 potential byswnders who reported
`32? rescues. Both community-year strata with 1-100 enroll-
`ments per 100,000 population (adjusted rate ratio 0.?3. 95%
`confidence interval 0.5? to 0.91) and community-year strata
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`with greater than 100 enrollments per 100.000 population
`(0.54, 0.39 to 0.?6) had significantly reduced adjusted rate
`ratios compared with communities with no implementation.
`Differences in rates of acute care hospital utilization were
`not significant. Opioid overdose death rates were reduced in
`communities where OEND was implemented. This study
`provides observational evidence that by training potential
`bystanders to prevent, recognize, and respond to opioid
`overdoses, Ol-iND is an efiective intervention (Walley et al..
`Opioid overdose rates and implementation of (Mrdose
`education and nasal Hfliflmfle distribution in Massachu-
`setts:
`interrupted time series analysis. BMJ 2013; 346:
`m4).
`Naloxone prescription programs are also oflered by com-
`munity-based organizations in L. A. and Philadelphia. Pro—
`grams in both cities target IDUs. Studies which rtxruited
`150 IDUs across both sites for in-deplh qualitative inter-
`views compared two groups of IDUs,
`those who had
`received naloxone prescriptions and those who had never
`received naloxone prescriptions. In both LA. and Philadel—
`phia, IDUs reported successfully administering naloxono to
`reverse recently witnessed overdoses. Reversals often
`occurred in public places by both housed and homeless
`lDUs. Despite these successes, IDUs frequently did not have
`ualoxone with them when they witnessed an overdose. Two
`typical reasons reported were naloxone was confiscated by
`police, and lDUs did not feel comfortable carrying naloxone
`in the event of being stopped by police. Similarly, some
`untrained “3le reported discomfort with the idea of carry-
`ing naloxone on them as their reason for not gaining a
`prescription.
`A randomized trial comparing 2 mg naloxone delivered
`intranasally with a mucosal atomizer to 2 mg intramuscular
`naloxone was reported by Kelly et at, in 2005 (Med J Aust.
`2005 Jan. 3; 182(1 )124-7}. The study involved 155 patients
`(Tl IM and 84 TN) requiring treatment for suspected opiate
`overdose and attended by paramedics of t