U 7598058
`
`-;'"‘.-{\.5 K
`
`THE. UNITED STATES OF AMERICA
`a“ mwmmwwm meow-.8
`
`
`October 25, 2018
`
`
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`
`THE RECORDS OF THIS OFFICE OF:
`
`U.S. PATENT: 9,211,253
`
`
`ISSUE DATE: December 15, 205
`
` By Authority of the
`Under Secretary of Commerce for Intellectual Property
`
`and Director of the United States tent and Trademark Office
`
`
`
`Certify' g Officer
`
`
`
`
`
`Nalox'lOOl
`
`Nalox—l Pharmaceuticals, LLC
`
`Page 1 of 38
`
`

`

`(12) Umted States Patent
`(10} Patent No.:
`US 9,211,253 132
`
`Crystal et al.
`(45) Date of Patent:
`Dec. 15, 2015
`
`USOO921 1253B2
`
`(54) NASAL DRUG PRODUCTS AN D METHODS
`OF THEIR USE
`
`-
`_
`-
`.
`-
`(T1) Applicant. L1ghtlalte Therapeutics, 1110., London
`{00)
`
`(?2)
`
`Inventors: Roger Crystal, London (GB); Bflchael
`Brenner Weiss, New York, NY (US)
`.
`.
`(73) Asstgnee: Lightlake Therapeutics Inc., New York,
`NY (US)
`_
`_
`_
`( " ) Notice:
`Subject to any disclaimer, the tens-1 of this
`patent is extended or adjusted under 35
`.
`,
`..
`U'S'C'154mb3 ““35"
`(21) Appl- No: 140559.472
`(22) Filed:
`Mar. 16, 2015
`
`(65)
`
`Prior Publication Data
`US 201550258019 A1
`Sep. 17: 2015
`
`Related U.S. Application Data
`_
`_
`_
`l’rovtstonal application No. 61f953.379. filed on Mar.
`14, 2014‘
`
`(60)
`
`(5})
`
`Int. Cl.
`A6IM3I/00
`A5135?“
`A 6‘” 13/00
`A 61K 3156
`AGIK 9/00
`A 613' 31/435
`AdlK 4.17/32
`A 61K 42/???
`A613, 9/08
`A 61M II/02
`A61.” 15x03
`Z
`‘
`(52) U Q, CI
`( P(.
`
`(2006 01)
`(2005101)
`(200501)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006 01)
`‘
`(2006.01)
`(2005-01)
`(2006.01)
`(2006.01)
`
`A64”: 9/9043 (2013.01); AtflK 9/08
`(2013.01): A 61K 3 M4335 (2013.01); A 6.1K
`4 7/02 (20] 3.01 ); A61K 4' 7/183 (2013.01);
`Almr 4 7/136 (2013.01); A61M 11/02
`(2013 .01 ), A6IM 152198 (2013.01) A6IM3L’00
`(201301)
`
`(58) Field of Classification Search
`None
`See application file for complete scorch history.
`
`(56)
`
`References Cited
`US. l-‘x—‘(l'liN'l‘ DOCUMENTS
`4.181.726 A
`I-’l930 Bernstein
`4.454378 A
`80984 Hussain
`5.865.154 A
`2fl999 Bahal et at.
`200330073300 Al
`41'2003 Wermeling
`2006.1'0l2096? A I
`6.0006 Namburi el al.
`33:33: (13133 R:
`333:3 Effiel‘? a“; 31-
`20 I 03.033 [3 54 A1
`121'20l0 Wearfneling
`201110040172 A1
`2.12011 Chaplet:- et 211.
`201250270895 Al
`10321.” 2 Wcmmling
`20I 5-"0I74061 A1
`62015 Wyse at a].
`
`A6IK 9,0043
`
`__
`
`FOREIGN PATENT DOCUMENTS
`I 575 795
`2.32005
`“581057 Bl
`8:"2008
`W0 2009;.040595 Al
`4",2009
`wo 8203768 Al
`11-1982
`wo 0830211 A1
`70993
`W0 0062757 Al
`1032000
`W0 0074652 Al
`12.32000
`W00158447 Al
`1'2001
`"
`,"3
`$3 $1323; t:
`125%:
`wo 03084520 A2
`10.32003
`WO 2004054511 A2
`712004
`WO 2005020906 A2
`3.0.005
`W0 2006039913 A2
`812006
`2007083073 A1
`73200?
`\‘L’OEDI2026963 :12
`31-2012
`WO 20125631? 2—12
`1132012
`WO 2013128447 A]
`912013
`2015095644 Al
`612015
`20151363713 A]
`91'2015
`
`(N
`EP
`Gt!
`wo
`wo
`W0
`W0
`W0
`
`$8
`wo
`W0
`W0
`W0
`WO
`we
`W0
`wo
`WT)
`W0
`
`OTHER PUBLICATIONS
`L35- Paim mcmcnts—NW’
`SciFinder starch results; downloaded Sep. 25. 2015.‘
`Walk-y. A Y et a1. “Opioid overdose rates and implementation of
`overdose education and nasal naloxone distribution in Massachu-
`sctts: interrupted time series analysis." BM] 346:1'174. (Published
`Jan, 31. 2013),
`Walley A ‘1’ cl 211., "Opioid overdose prevention with intranasal
`naloxone among people who take meLhadone," J Subst Abuse Treat
`44:2. 241—4? (Fl-rub Sep. 12. 2012).
`'
`Weberl Metal..“Ca.n nebulized naloxoncbcused safely and etl‘ee-
`tively by emergency medical services {or suspected opiod overdose?"
`Prehosp Emerng 15:2. 209-92 (Epub Dec. 22. 2011).
`Merlin M A et at. “Lnlrmsal naloxonc delivery is an alternative to
`intravenous naloxnne for opioid overdoses," Am J Emerg Med 23:],
`395-303 {th 1311- 291 20 101-
`_
`.
`.
`Kerr L) d 11.1.. “Randomized controlled trial comparing the effective-
`ness and safety of iritrariasaj and intramuscular naloxone for the
`treatment ot‘snspected heroin overdose." Addiction 104: 12. 2067-74
`(Epub Nov. 9, 2009).
`Robertson T M. “Intruasal mloxonc is a viable alternative to intra-
`venous naloxone for prehospitnl narcotic overdose.“ Prehosp Hmcrg
`Care 13:4. 5l2-15 (Published Oct. 2009).
`intranas'
`oxonch drochlori e or 0 101' over
`se."AmJ Pu
`ic
`Doe-5021101115]; M et al.. "Saved 1:13: [the nosehbystaététer-administngpd
`Health 995‘ 788—918published May géjogy
`Heard C et al.. "[ntranasal flumazcnil and naloxone to reverse over-
`sedation in a child undergoing dental restorations," Paediatr Anaesth
`19:8 ”695—99 (published A_us- 2009).
`_
`_
`Dowhng J et at, “Population phannacokmetics ofintravcnous. intra-
`muscular. and inn-3.1121301 naloxone in human volunteers," Ther Dru _
`Monit 30:4 490-96 (published Aug. 2003).
`g
`Ashton 11 et at, “Best evidence mpic report. Lntranasal naloxone i.n
`suspected opioid overdose." Emerg Med .1 23:3. 221—23 (published
`MB:- 2005)-
`
`(Continued)
`
`Primary Examiner — Jeffrey T Palcnik
`(74) Afrorm'y, Agent, or Fir-1!: — Dennis A. Bennett
`
`(57)
`
`ABSTRACT
`_
`.
`_
`Drug products adapted for nasal delivery, comprismg a pre-
`primed device filled with a pharmaceutical composition com—
`prising an opioid receptor antagonist, are provided. Methods
`oftreating op1oid overdose or its symptoms vi 1th the inventive
`drug Pmducts are also prowdcd‘
`29 Claims. 7 Drawing Sheets
`
`Copy provided by USPTO from the PIRS Image Database on 10-23—201 8
`
`Nalox'lOOl
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 2 of 38
`
`

`

`US 9,211,253 32
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`Barton E D et al., “Efficacy of intranasal naloxonc as a needlelcas
`alternative for treatment of opioid overdose in the prehospital setv
`ting.“J Emerg Med 29:3. 265-7]. (published Oct 2005).
`Kelly.r A M net 211.. “Randomised trial of inuanasal versus intramuscu-
`lar naloxono in prehospital treatment for suspected opioid overdose."
`Med J Aust 182: I 24—2? (published Jan. 3. 2005).
`Kelly A M el al_, “lntramsal naloxone for life threatening opioid
`toxicity." Emerg Med] 19:4, 3?5.(puhlishod Jul. 2002].
`Barton E D et a1.. “lntranasal adminislmtion of naloxone by para—
`medics." Prchosp Emerg Care 6: 1. 54-58 (published Jan. 2002).
`Lo'uner N at al.. “Nasal administration of naloxone is as effective as
`the intravenous route in opiate addicts." Int J Addict 29:6. 819—27
`(published Apr. 1994).
`
`Loimer N et al., “Nasal administration of naloxorie for detection of
`opiate dependence." J Psychiatr Res 26:l. 3943 (published Jan.
`1992).
`Bailey A M at al.. “Naloxone for opioid overdose prevention: phar-
`macisls‘
`role in
`communiqrvbaaed practice
`settings." Ann.
`Phamacothcr 4815. 6014.16 (published May 20 I4).
`Wermeling D P et 3].. "A response to the opioid overdose epidemic:
`nalmcone nasal spray." Drug Delivery Transl. Res. 3:1. 63—?4 (pub
`lished Feb. 1,2013).
`Wermeling D P or a1.I “Opioid harm reduction strategies: focus an
`expanded access lo intranasal naloxone.” Pharmacotherapy 30:1
`62‘?-31.
`Apta: UnitDose and BiDose product information sheet. available at
`wwwaptamcomtdocs.‘pha.rrna-presc.ription-’uds—bd.s-datasheet.pd£
`publication date unknown, last acccsmi Mar. 26. 2015.
`Intonation al Search Report and Written Opinion for Application No.
`mizulsmotmr; 52p 2. 2015; 11 pages.
`
`" cited by examiner
`
`
`
`Copy provided by USPTO from Ll1e PIRS Image Database on “1-23-2013
`
`NaioxlOOl
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 3 of 38
`
`

`

`US. Patent
`
`Dec. 15, 2015
`
`Sheet 1 on
`
`US 9,211,253 32
`
`
`
`I
`
`i
`
`FIGURE 1
`
`7 0 -
`
`+0.4mg [M
`
`
`
`-
`
`g 3.0
`
`K 2
`
`'2' 2.0
`
`1.0
`
`0.0
`
`0.0
`
`0.5
`
`1.0
`
`1.5
`
`2.0
`
`2.5
`
`3.0
`
`Time Post Administration (hr)
`
`__
`
`6.0 -1
`
`3 5 0 _,
`
`E
`
`B . _
`E 4'”
`
`I
`
`I
`
`+2 mg IN
`
`W4 mg IN
`
`
`
`Copy providbd by USPTO from the PIRS Image Database on ”3-23-2018
`
`NaloxlOOl
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 4 0f38
`
`

`

`US. Patent
`
`Dec. 15, 2015
`
`Sheet 2 of 7
`
`US 9,211,253 B2
`
`FIGURE 2
`
`
`
`10.0
`
`
`
`
`8.0
`
`10.0
`
`12.0
`
`
`
`Malamute{malmL}
`
`4.0
`
`6.0
`
`
`
`_..-uni-rmnm—w-r.:
`
`
`
`Time Post Administration {hr}
`
`I
`
`Copy providcd by USP‘TO from the PIRS Image Database on 10-23-2018
`
`NaloxlOOl
`
`Nalox-l Phannaceuticals, LLC
`
`Page 5 0f 38
`
`

`

`——N
`
`US. Patent
`
`Dec. 15, 2015
`
`Sheet 3 of?
`
`US 9,211,253 B2
`
`FIGURE 3
`
`FIG. 3A
`
`_| C
`
`m
`
`
`
`2 x 40 mglmL
`2 x 20 mgimL
`1 x 40 mgimL
`1 x 20 mgImL
`0.4 mg IM
`
`
`
`
`
`NalomnePlasmaConcentration[ngz‘mL} m
`+++++
`
`
`E!E73 m Ed
`
`Hours Postdose
`
`9 d
`
`0-01 + 2 x 40 mgImL
`+ 2 x 20 mgfrnL
`
`(nglmL}
`NalnxonePlasmaConcentration
`
`
`
`{1001
`
`+ ‘1 x 40 mgh‘nL
`+ 1 x 20 mgme
`+ 0.4 mg IM
`
`Hours Postdose
`
`Copy provided by USPTD from [he PIRS Image ”alabasc on 10-23-20 | 3
`
`NaloxlOOl
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 6 of 38
`
`

`

`US. Patent
`
`Dec. 15, 2015
`
`Sheet 4 of?
`
`US 9,211,253 132
`
`FIG. 4A
`
`10
`
`FIGURE 4
`
`8
`
`6
`
`
`
`4:.
`
`
`
`
`
`NaloxonePlasmaConcentration(ngimL) M
`
`
`
`
`-"- 2 x40 rngme
`+ 2 x 20 mgimL
`+ 1 x 40 mgme
`+ 1 x 20 mgln'lL
`+ 0.4 mg IM
`
`
`
`.0
`
`0.5
`
`1.0
`
`2.5'
`2.0
`1.5
`Hours Postdose
`
`3.0
`
`3.5
`
`4.0
`
`FICA“?-
`
`10
`
`(Flam)
`
`.a.
`
`+ 2 x 40 mglmL
`+ 2 x 20 mglmL
`+ 1 x 40 mgimL
`+ 1 x 20 1119me
`+ 0.4 mg IM
`
`
`
`13 .—l oNaloxonePlasmaConcentration
`
`
`
`.01
`0.0
`
`"_'_'_""I
`0.5
`1.0
`
`"_'—'—l_1r[r—-I—l—I—r—u-u—1—1—4-r—I—|—I—I—|—y—‘
`1.5
`2.0
`2.5
`3.0
`3.5
`4.0
`Hours Postdose
`
`Copy provided by USPTO from the PIRS Image Database on 10-23-20I3
`
`Nalox 1 001
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 7 of38
`
`

`

`US. Patent
`
`Dec. 15, 2015
`
`Sheet 5 on
`
`US 9,211,253 82
`
`FIG. 5A
`
`.3. D
`
`FIGURE 5
`
`0.4 mg IM
`
`
`
` NaloxonePlasmaConcentration(ngme)
`
`
`
`
`
`Hour
`
`One Spray 20 mgme
`
`4 C
`
`opy prm-idtd by LISPTO frIJrn [he PIRS Image Dambase on 10—23-20l8
`
`NaloxlOOl
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 8 0f 38
`
`FIG. SB
`
`3‘
`E“‘5‘,
`o:
`E-I:
`.Q
`E4—.
`
`§:2
`
`OUm EU
`
`) ED
`
`.
`[Dc
`
`32t
`
`n2
`
`

`

`U.S. Patent
`
`Dec. 15, 2015
`
`Sheet 6 of7
`
`US 9,211,253 B2
`
`FIG. 6A
`
`FIGURE 6
`
`Two Sprays 20 mglmL
`
`O!CO
`
`NaloxonePiasmaConcentration(ngme) J}.
`
`
`
`2
`
`0
`
`
`
`
`
`+ Mala
`
`+ Female
`
`0
`
`2
`
`4
`
`6
`Hour
`
`8
`
`1 0
`
`12
`
`FIG. 63
`
`03
`
`One Spray 40 mgme
`
`
`
`NaloxonePlasmaConcentration(nglmL)
`
`I
`
`
`
`
`
`Copy provided by LISPTO from the PIRS Image Dambasc on 10-23-2018
`
`NaloxlOOl
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 9 of 38
`
`

`

`US. Patent
`
`Dec. 15, 2015
`
`Sheet 7 of?
`
`US 9,211,253 32
`
`FIGURE 7
`
`Two Sprays 40 mglmL
`
`J:-D')03
`
`
`
`NaloxonePlasmaConcentration(nglmL)
`
`
`
`
`
`|\J
`
`Copy provided by USPTO from the PIRS Image Damtmse on 10-23-20”:
`
`NaloxlOOl
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 10 0f 38
`
`

`

`US 9,211,253 32
`
`2
`
`NASAI. DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`This application claims the benefit of 1.1.3. Provisional
`Application No. 61953379, Fried Mar. 14, 2014, the disclo—
`sure ol'whi ch is hereby incorporated by reference as ifwritten
`herein in its entirety.
`Provided are drug products adapted for nasal delivery co m-
`prising a pro-primed device and a pharmaceutical composi-
`tion comprising an opioid receptor antagonist, pharmaceuti-
`cal compositions comprising an opioid receptor antagonist,
`and methods ofusc thereof.
`Opioid receptors are G protein-coupled receptors (GPt .‘R s)
`that are activated both by endogenous opioid peptides and by
`clinically important alkaloid analgesic drugs such as mor-
`phine. There are three principal types of opioid receptors: the
`lit-opioid receptor. the K-opioid receptor, and the tr-opioid
`receptor. Opioids depress respiration. which is controlled
`principally through medullary respiratory centers with
`peripheral
`input
`li'om chemoreccptors and other sources.
`Opioids produce inhibition at
`the chemorcceptors via
`n—opioid receptors and in the medulla via u- and fi~opioid
`receptors. While there are a number of neurotransmitters
`mediating the control of respiration. glutamate and v—ami-
`nobutyric acid [GABA) are the major excitatory and inhibi-
`tory neurotransmitters, respectively. This explains the poten-
`tial for interaction of opioids with benzodiazepirres and
`alcohol: both benzodiazepines and alcohol
`facilitate the
`inhibitory effect of GABA at the GAHAA receptor, while
`alcohol also decreases the exeitatory effect of glutamate at
`NM] )A receptors. Oxycodonc and other opioid painkillers, as
`well as heroin and methadone are all implicated in fatal over—
`dose. Heroin has three metabolites with opioid activity. Varia-
`tion in the formation of these metabolites due to genetic
`factors and the use of other drugs could explain differential
`sensitivity to overdose. Metabolites of methadone contribute
`little to its action. However, variation in rate of metabolism
`due to genetic factors andother drugs used can modify metha-
`done concentration and hence overdose risk. The degree of
`tolerance also determines risk. Tolerance to respiratory
`depression is less than complete. and may be slower than
`tolerance to euphoric and other effects. One consequence of
`this may be a relatively high risk of overdose among experi—
`enced opioid users. While agonist administration modifies
`receptor function, changes (usually in the opposite direction)
`also result from use of antagonists. for example, superscnsi-
`tivity 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. according to the
`Substance Abuse and Mental Health Services Administra—
`tion, the nrunberr’rate of Americans 12 years of age and older
`who currently abuse pain relievers has increased by 20 per-
`cent between 2002 and 200 9. In New York City, between 1990
`and 2006. the fatality rate from prescription opioids increased
`seven-fold. from 0.39 per 100,000 persons to 2.7. Drugs
`classed as prescription opioids in this study include both
`typical analgesics, such as OxyContin® (oxycodorre 11C 1
`controlled-release) and methadone (used in the treatment of
`dependence on other opioids such as heroin and also pre-
`scribed l'or pain), but the increase in the rate ofdrug overdose
`over the 16 years of the study was driven entirely by over-
`doses of typical analgesics. Over the same time period,
`methadone overdoses remained stable. and overdoses from
`heroin declined. Whites were more likely than blacks and
`
`[atinos to overdose on these analgesics, and deaths mostly
`occurred in neighborhoods with lower rates of poverty, sug—
`gesting differential access to doctors who can write painkiller
`prescriptions may be a driving force behind 1he racial dispar-
`ity. (Gerda et al. “Prescription opioid nmrmlr'tv trends in New
`York City, 1990—2006: Examining the emergence of an epi-
`denrt'c," Drug atrd Alcohol Dependence Volume 132, Issues
`1—2,
`1 Sep. 20]3, 53-62.)
`Naloxone is an opioid receptor antagonist that is approved
`for use by injection for the reversal ol‘opioid overdose and for
`adjunct use in the Lreatment of septic shock. I: is currently
`being used mainly in emergency departments and in ambu-
`lances by trained medical professionals.
`'lhere have been
`efforts 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. The UN Commission on Narcotics Drugs
`“encourages all Member States to include effective elements
`for the prevention and treatment of drug overdose, in particu—
`lar opioid overdose. in national drug policies, where appro-
`priate= 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 antago-
`nists such as naloxone.“
`US. Pat. No. 4,464,373 describes a method for eliciting an
`analgesic or narcotic antagonist response in a warm—blooded
`animal, which comprises administering irrtrarrasally (IN) to
`said animal to elicit a narcotic antagonist response, a narcotic
`antagonist effective amount of naloxone. W0 Sztm'r'és dis-
`closes a composition that contains 1 mg of naloxone hydro—
`chloride pcr 0.1 ml of solution adapted for nasal administra-
`tion used in the treatment of narcotic induced respiratory
`depression (overdose) at a dosage approximately the same as
`that employed for intravenous (IV). intramuscular (TM) or
`subcutaneous (SQ) administration. W0 00f6275? teaches
`pharm accu ticai compositions tor IN or oral (P0) admini stra-
`tion which comprise an opioid antagonist. such as naloxone
`for application by spray in the reversal of opioid depression
`for treatment of patients sulTering from opioid over-dosage,
`wherein the spray applicator is capable ot‘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 louma] of Addictions,
`29(6), 819-327. 1994) reported that the nasal administration
`of naloxorre is as effective as the intravenous route in opiate
`addicts. however, Bowling ct. al. (Ther Drug Monit, Vol 30,
`No 4. August 2008) reported that naloxone administered
`intranasally displays a relative bioavailability ol'4% only and
`concluded that the IN absorption is rapid but does not main—
`tain measurable concentrations for more than an hour.
`One early study of I 96 consecutive patients with suspected
`opioid overdose conducted in an urban out-of-hospital set-
`ting, had shown the mean interval from emergency medical
`services (EMS) arrival to a respiratory rate of :10 breaths.»r
`min was 9. 3:4 2 min with administration of nnloxone 0.4 mg
`1V, versus 9.6:4.58 rrrin with administration of naloxorre 0.8
`mg SQ. The authors concluded that the slower rate of absorp-
`tion via the SQ route was offset by the delay in establishing an
`IV line. (Wanger e1 3]., Intravenous vs strlrutaneorrs nofox—
`oneforom—cf—hmpr'mf management! QIPresumea' opioid over—
`dose. Acad Emerg Med. 1998 April; 5(4):293—9).
`The Denver Health Paramedic system subsequently inves—
`tigated the efficacy and safety of atomired intranasal nalox-
`one for the treatment of suspected opiate overdose (Barton. et
`31.. Efiicacyofr'rttmnosor' nafoxone as a needle-less alternar‘i me
`for treatment ofopfor'd overtime in the prekmpr‘rar’ setting. .1
`
`10
`
`15
`
`20
`
`30
`
`35
`
`40
`
`4S
`
`SEI
`
`Si
`
`60
`
`65
`
`Copy provided by USPTO From the PIRS Image Database on 10-23-2018
`
`Nalox l 001
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 11 of 38
`
`

`

`3
`Emerg Med. 2005. 29(3): p. 265-?1). 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 administration were included in the
`study. IN naloxone (2 mg) was administered immediately
`upon patient contact and before IV insertion and administra—
`tion of 1V italoxone (2 mg), Patients were then treated by
`EMS protocol. The main outcome measures were: time of IN
`naioxonc administration, time efIV naloxone administration.
`time of appropriate patient response as reported by paramed-
`ics. Ninety-five patients received 1N naloxonc and were
`included in the study. A total of 52 patients responded to
`naloxone by either IN or IV, with 43 (83%) responding to IN
`naloxone alone. Seven patients (I 6%) in this group required
`further doses of IV naloxoue. The median times from arrival
`at patient side to awakening. and from administration ofthe [N
`naloxone to patient awakening were 8.0 minutes and 3.0
`minutes respectively.
`The Drug Overdose Prevention and Education (DOPli)
`Project was the first ualoxone prescription program (NP?)
`established in partnership with a county health department
`(San Francisco Department of Public Health), and is one of
`the longest running NPPs in the USA. From September 2003
`to December 2009, 1,942 individuals were trained and pre-
`scribed naloxone through the DOPE Project, of whom 24%
`returned to receive a naloxone refill, and 11% reported using
`ualexone during an overdose event. Of 399 overdose events
`where naloxone was used, participants reported that 89%
`were reversed. In addition, 83% of participants who reported
`overdose reversal attributed the reversal to their administra-
`tion ol‘naloxone, and fewer than 1% reported serious adverse
`effects, Findings from the DOPE Project add to a growing
`body or research that suggests that intravenous drug users
`(IDUs) at high risk of witnessing overdose events are willing
`to be trained on overdose response strategies and use take-
`home naloxone during overdose events to prevent deaths
`(Enteen, ct al., Overdose prevention and naioxoneprescrip—
`rionfor opioid users in San Francisco. J Urban Health. 2010
`December; 87(6):931—41)_
`Another
`reported study reviewed EMS and hospital
`records before and afier implementation of a protocol for
`administration of intranasal naloxone by the Central Califor-
`nia EMS Agency in order to compare the prehospital time
`intervals iron: patient contact and medication administration
`to clinical response for IN versus inn-avenous IV naloxone in
`patients with suspected narcotic overdose. The protocol for
`the treatment of opioid overdose with intranasal naloxone
`was as follows: “lntranasal (IN )—.~‘\drninister 2 mg intrane-
`sally (1 mg per nostril) using mucosa] atomizer device
`(MADTM) if suspected narcotic intoxication and respiratory
`depression (rate 8 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 (IM)—r\dminislcr 1 mg
`if unable to administer intranasally (see special consider-
`ations). May repeat once in 5 minutes. Intravenous (IV)
`—
`Administer 1 mg slow 1V push if no response to intranasal or
`[M administration afier 10 minutes. Pediatric dose -0.I
`mgfltg intranasally, il‘less than 10 kgand less than 1 yearold“.
`Patients with suspected narcotic overdose treated in the pre-
`hospital setting over 17 months, between March 2003 and
`July 2004 were included, Paramedics documented dose, route
`of administration, and positive response times using an elec~
`Lronic record. Clinical response was defined as an increase in
`respiratory rate (breathsr'min) or Glasgow Coma Scale score
`of at least 6. Main outcome variables included time from
`medication to clinical response and time from patient contact
`
`(IL?
`
`65
`
`US 9,211,253 BZ
`
`10
`
`15
`
`25
`
`30
`
`35
`
`40
`
`4S
`
`50
`
`55
`
`4
`to clinical response. Secondary variables included numbers
`ofdoscs administered and rescue doses given by an alternate
`route. Between-group comparisons were accomplished using
`Hosts and chivsquare tests as appropriate. One hundred fifty-
`four patients met the inclusion criteria, including 104 treated
`with IV and 50 treated with 1N naloxone. Clinical response
`was noted in 33 (66%) and 58 (56%) ofthe 1N anlegroups,
`respectively (p '—0.3). The mean time between naloxone
`administration and clinical response was longer for the IN
`gmup (12.9 vs. 8.1 min, p 0.02). However, the mean times
`from patient contact to clinical response were not signifi-
`cantly dilTerenl. between the IN and IV groups (20.3 vs. 20.1'
`min. p 0.9). More patients in the IN group received two doses
`ot‘naloxene (34% vs. 18%, p' 0.05), and three patients in the
`IN group received a subsequent dose of IV or IM naioxone.
`(Robertson el al., Inn-armor! ndioxone is a viabie alternative
`to intravenous automate for prehospirnl narcotic overdose.
`Prehosp Emerg Care. 2009 October—December, 13(4):5]2—
`5).
`in August 2006, the Boston Public Health Commission
`passed a public health regulation that authorized an opioid
`overdose prevention program that included intranasal nalox—
`one education and distribution of the spray to potential
`bystanders. Participants were instructed by trained stand to
`deliver 1 ml. (1 mg) to each nostril of the overdose victim.
`After 15 months,
`the program had provided training and
`intranasal naloxonc to 385 participants who reported 74 suc-
`cessful overdose reversals (l )oe—Simkins et al. Overdosepne-
`ventiorr education with distribution oft'mranasal naioxone is
`afiasihr‘epubiie freak}: intervention to address opioid over—
`dose. Am J Public Health. 2009'. 99: 788-?91).
`Overdose education and nasal naloxone distribution
`(BEND) 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 naloxene rescue kit.
`To evaluate the impact ol‘OEN'D programs on rates of opioid
`related death from overdose and acute care utilization in
`Massachusetts, an interrupted time series analysis of opioid
`related overdose death and acute care utilization rates from
`2002 to 2009 was performed comparing community-year
`strata with high and low rates of OEND implementation to
`those wi lh no implementation. The setting was nineteen Mas-
`sachusetts communities (geographically distinct cities and
`towns) with at least five fatal opioid overdoses in each of the
`years 2004 to 2006. (JEN!) was implemented among opioid
`users at risk for overdose, social service agency staff. family,
`and friends ofopioid users. OEND programs equipped people
`at risk for overdose and bystanders with nasal nalexone res—
`cue kits and trained them how to prevent, recognize, and
`respond to an overdose by engaging emergency medical ser—
`vices. providing rescue breathing, and delivering naloxone.
`Among these communities, OFN‘D programs trained 2,912
`potential bystanders who reported 32? rescues. Both commu-
`nity-year strata with 1-100 enrollments per 100,000 popula—
`tion (adjusted rate ratio 0.?3, 95% confidence interval 0.57 to
`0.9] ) and community-year strata withgreater than 100enroll-
`ments per 100,000 population (0.54, 0.39 to 0.76) had sig-
`nificantly reduced adjusted rate ratios compared with com-
`munities with on 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,
`recegnine, and respond to opioid overdoses, ()ENI) is an
`etl'ective intervention (Walley et ah. Opioid overdose rares
`and impfememarion ofoverdose education and name! Jmi'ox—
`
`(Topy provided by USPTO from the PIRS Image Database on 10-23—20] El
`
`Nalox l 00 1
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 12 of 38
`
`

`

`US 9,211,253 132
`
`imermpted time series
`
`
`
`5
`one distribution in Massachusetts:
`nual’yst‘r. BM} 2013; 3461f174).
`Naloxone prescription programs are also offered by cont—
`munity—based organisations in Los Angeles and Philadelphia.
`Programs in both cities target IDUs. Studies which recruited
`1501DUS across both Sites for in—depth qualitative interviews
`compared two groups ofIDUs, those who had received nalox—
`one presc riptions and those who had never rec eived naloxone
`prescriptions. In both LA. and Philadelphia, IDUS rcportcd
`successfully adminislcring nalottone Io reverse recently wit-
`nessed overdoses. Reversals often occurred in public places
`by both housed and homeless lDUs. Despite these successes.
`IDUs frequently did not have naloxone with them when they
`witnessed an overdose. Two typical reasons reported were
`naloxone was confiseated by police. and IDUs did not feel
`comfortable carrying naloxone in the event ofbeing stopped
`by police. Similarly, some untrained [Dlls repnned discom—
`fort With the idea ofcanying nalox one on them as their reason
`for not gaining a prescription
`A ranchimived trial comparing 2 mg naloxone delivered
`intranasally with a mucosa] atomizer to 2 mg intramuseular
`nalnxone was reported by Kelly et al.. in 2005 (Med J Aust.
`2005 Jan. 3; 182(1):24-7). The study involved 155 patients
`(ill IM and 34 IN) requiring treatment for suspected opiate
`overdose and attended by paramedics of the Metropolitan
`Ambulance Service (MAS) and Rural Ambulance Victoria in
`Victoria, Australia. The 1M group had more rapid response
`titan the IN group. and were more likely to have more than 10
`spontaneous respirations per minute within 8 minutes (82% v.
`63%;P=0.0173}.Thcre was no statistically signifiea nt dir'er—
`ence between the 1M and IN groups for needing rescue nalox—
`one (13% [1M group] v. 26% [IN group]; P=0.0558). "he
`authors concluded thal IN naloxone is effective in treating
`opiate-induced respiratory depression. but is not as effective
`as [M naioxone.
`Kerr el al. (Addiction. 2009 Dace miter: 104(12):206?-?4)
`disclosed treatment of heroin overdose by intrunasal admin-
`istration of naloxonc constituted in a vial as a preparation of
`2 mg in l n11.. Participants received 1 mg (0.5 ml) in each
`nostril. The rate of response within l0 minutes was 6&"83
`62.3%) for 2 mg IN naloxone versus 69t89 (??.5%) for 2 mg
`1M naloxo no. The mean response times were 8.0 minutes and
`7.9 minutes for [N and IV naloxone respectively. Supplemeu‘
`tary rlnloxone was administered to fewer patients who
`received 1M naloxone (4.5%) than IN (13.1%).
`W020121 563]? describes a study in which naloxone. 8
`mg and 16 mg, was administered as 400 pL IN (200 14L per
`nostril). The adminislralion was performed as follows: The
`pump oflhe nasal spray was primed by removng the cap and
`press tug downward. This is repeated at least 6 times or until 21
`[inc spray appears; priming is done just prior to dosing. The
`subject is in a standing or upright posilion and should gently
`blow the nose to clear the nostrils. The subject should tilt the
`head forward slightly and gently close one nostril by pressing
`the outside ol‘Lhe nose with a finger on the nostril to be closed.
`The device is inserted into the open nostril and it is sprayed 2
`times into the nostril. The subject should gently breath inward
`through the nostril. the device is removed, and the steps are
`repeated for Ihc other nostril. The mean Tm, values were
`reported to be 0.34 h (20.4 min) and 03911814 min) for the
`8 and 16 mg doses respectively.
`Werrneling (Drug Deliv Transl Res. 2013 Feb. 1; 3(1):
`63 J4) teaches that the initial adult dose ofnaloxoue inknown
`or suspected narcotic overdose is 0.4 to 2 mg. which may be
`repeated to a total dose of 10 mg and that the current formu-
`lations ofnaloxone are approved for intravenous (IV), intra-
`muscular (IM) and subcutaneous (SC) administration, with
`
`6
`IV being the recommended route. Wermeling also predicts
`that a 2 mg nasal solution dose of naloxone will likely have a
`Cm, of 3—5 nglml, and a In, ot‘approximatcly 20 minutes.
`Since the onset ofaction of naloxone used in opioid over—
`dose cases should be as fast as possible, naloxonc is thus far
`mainly administered intravenously or intramuscularly by
`emergency health care personnel. Due to a high first pass
`metabolism, oral dosage fonns comprising naloxone display
`a low bioavailability and thus seem to be not suitable for such
`purposes. The administration of naloxone via injection into
`the blood stream or into the muscle requires first ofall trained
`medical personnel (for intravenous injection} or a trained
`carer (for intramuscular injection). Secondly. depending on
`the constimtion of the addict and the period of intravenous
`drug abu so, it can be particularly difficult to find access inlo a
`vein of the addict’s body for administering naloxono intrave-
`nously. Clearly, there is a risk of exposure to blood borne
`pathogens for-the medical personnel or the trained carer since
`a large population of drug addicts suffers from blood borne
`pathogen induced diseases such as HIV, hepatitis B and C,
`and the like since accidental needlestick is a serious safety
`concern. 385,000 needle— stick injuries have been estimated to
`have occurred in the year 2000 in the US alone (Wilbum,
`Needfestick and sharps injury prevention. Dnline J Issues
`Nurs 2004, Sep. 30-, 9005).
`Naloxone has a relatively short half-life of compared to
`some longer-acting opioid formulations and so after a typical
`therapeutic dose of naloxone is administered to an opioid
`overdose patient there is ofien the need to rte-administer
`naloxonc, in some cases even several times. and it is impor-
`tant to seek immediate medical attention.
`Furthermore,
`it has been suggested that in view of the
`growing opioid overdose crisis in the US, naloxone should be
`made available over-the-counter (OTC), which would require
`a device, such as a nasal spray device, that untrained consum-
`ers are able to use safely. A nasal spray device that was
`pic-tilled with a natloxone formulation would also be less
`likely to be confiscated by police than the system developed
`by some EMS programs that combines an FDA-approved
`naloxone injection product with a marketed. medical device
`called the Mucosal Alomimtion Device.
`Thus,
`there remains a need for durable. easy-lo-usc.
`needleless devices with storage—stable lbrmulations, that can
`enable untrained individuals to quickly deliver a therapeuti—
`cally effective dose of a rapid—acting opioid antagonist to an
`opioid overdose patient. The therapeutically effective dose
`should be sufficient to obviate the need for the untrained
`individual
`to administer either a second dose of opioid
`antagonist or an alternative medical
`intervention to the
`patie