I 1111111111111111 11111 1111111111 11111 11111 1111111111 111111111111111 IIII IIII
`US009211253B2
`
`c12) United States Patent
`Crystal et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,211,253 B2
`Dec. 15, 2015
`
`(54) NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`(71) Applicant: Lightlake Therapeutics, Inc., London
`(GB)
`
`(72)
`
`Inventors: Roger Crystal, London (GB); Michael
`Brenner Weiss, New York, NY (US)
`
`(73) Assignee: Lightlake Therapeutics Inc., New York,
`NY(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.: 14/659,472
`
`(22) Filed:
`
`Mar. 16, 2015
`
`(65)
`
`Prior Publication Data
`
`US 2015/0258019 Al
`
`Sep. 17, 2015
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 61/953,379, filed on Mar.
`14, 2014.
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61M31/00
`A61M5/00
`A61F 13/00
`A61K 31156
`A61K9/00
`A61K 311485
`A61K 47102
`A61K 47118
`A61K9/08
`A61M 11102
`A61M 15108
`U.S. Cl.
`CPC ................. A61K 9/0043 (2013.01); A61K 9/08
`(2013.01); A61K 311485 (2013.01); A61K
`47102 (2013.01); A61K 471183 (2013.01);
`A61K 471186 (2013.01); A61M 11102
`(2013.01); A61M 15108 (2013.01); A61M 31/00
`(2013.01)
`
`Field of Classification Search
`None
`See application file for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,181,726 A
`4,464,378 A
`5,866,154 A
`2003/0073300 Al
`2006/0120967 Al
`2010/0113495 Al
`2010/0168147 Al
`2010/0331354 Al
`2011/0046172 Al
`2012/0270895 Al
`2015/0174061 Al
`
`l/ 1980 Bernstein
`8/ 1984 Hussain
`2/1999 Bahal et al.
`4/2003 Wermeling
`6/2006 Namburi et al.
`5/2010 Wermeling et al.
`7/2010 Chapleo et al.
`12/2010 Wermeling
`2/2011 Chapleo et al.
`10/2012 Wermeling
`6/2015 Wyse et al.
`
`FOREIGN PATENT DOCUMENTS
`
`A61K 9/0043
`
`CN
`EP
`GB
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`1575795
`1681057 Bl
`WO 2009/040595 Al *
`WO 8203768 Al
`WO 9830211 Al
`WO 0062757 Al
`WO 0074652 Al
`WO 0158447 Al
`WO 0182931 Al
`WO 0211778 Al
`WO 03084520 A2
`WO2004054511 A2
`WO 2005020906 A2
`WO 2006089973 A2
`2007083073 Al
`WO 2012026963 A2
`WO2012156317 A2
`WO 2013128447 Al
`2015095644 Al
`2015136373 Al
`
`2/2005
`8/2008
`4/2009
`11/1982
`7 /1998
`10/2000
`12/2000
`8/2001
`11/2001
`2/2002
`10/2003
`7/2004
`3/2005
`8/2006
`7/2007
`3/2012
`11/2012
`9/2013
`6/2015
`9/2015
`
`OTHER PUBLICATIONS
`
`U.S. Patent Documents-None.*
`SciFinder search results; downloaded Sep. 25, 2015.*
`Walley, A Y et al, "Opioid overdose rates and implementation of
`overdose education and nasal naloxone distribution in Massachu(cid:173)
`setts: interrupted time series analysis," BMJ 346:fl 74, (Published
`Jan. 31, 2013).
`Walley A Y et al., "Opioid overdose prevention with intranasal
`naloxone among people who take methadone," J Subst Abuse Treat
`44:2, 241-47 (Epub Sep. 12, 2012).
`Weber J Met al., "Can nebulized naloxone be used safely and effec(cid:173)
`tively by emergency medical services for suspected opiodoverdose?"
`Prehosp Emerg Care 16:2, 289-92 (Epub Dec. 22, 2011 ).
`Merlin MA et al., "Intranasal naloxone delivery is an alternative to
`intravenous naloxone for opioid overdoses," Am J Emerg Med 28:3,
`296-303 (Epub Jan. 28, 2010).
`Kerr D et al., "Randomized controlled trial comparing the effective(cid:173)
`ness and safety of intranasal and intramuscular naloxone for the
`treatment of suspected heroin overdose," Addiction 104: 12, 2067-74
`(Epub Nov. 9, 2009).
`Robertson T M, "Intranasal naloxone is a viable alternative to intra(cid:173)
`venous naloxone for prehospital narcotic overdose," Prehosp Emerg
`Care 13:4, 512-15 (Published Oct. 2009).
`Doe-Simkins Met al., "Saved by the nose: bystander-administered
`intranasal naloxone hydrochloride for opioid overdose," Am J Public
`Health 99:5, 788-91 (published May 2009).
`Heard C et al., "Intranasal flumazenil and naloxone to reverse over(cid:173)
`sedation in a child undergoing dental restorations," Paediatr Anaesth
`19:8 795-99 (published Aug. 2009).
`Dowling Jet al., "Population pharmacokinetics of intravenous, intra(cid:173)
`muscular, and intranasal naloxone in human volunteers," Ther Drug
`Monit 30:4 490-96 (published Aug. 2008).
`Ashton H et al., "Best evidence topic report. Intranasal naloxone in
`suspected opioid overdose," Emerg Med J 23:3, 221-23 (published
`Mar. 2006).
`
`(Continued)
`
`Primary Examiner -
`Jeffrey T Palenik
`(7 4) Attorney, Agent, or Firm - Dennis A. Bennett
`
`ABSTRACT
`(57)
`Drug products adapted for nasal delivery, comprising a pre(cid:173)
`primed device filled with a pharmaceutical composition com(cid:173)
`prising an opioid receptor antagonist, are provided. Methods
`of treating opioid overdose or its symptoms with the inventive
`drug products are also provided.
`
`29 Claims, 7 Drawing Sheets
`
`Adapt & Opiant Exhibit 2034
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 1
`
`

`

`US 9,211,253 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`Barton E D et al., "Efficacy of intranasal naloxone as a needleless
`alternative for treatment of opioid overdose in the prehospital set(cid:173)
`ting," J Emerg Med 29:3, 265-71 (published Oct. 2005).
`Kelly AM et al., "Randomised trial of intranasal versus intramuscu(cid:173)
`lar naloxone in prehospital treatment for suspected opioid overdose,"
`Med J Aust 182:1 24-27 (published Jan. 3, 2005).
`Kelly A M et al., "Intranasal naloxone for life threatening opioid
`toxicity," Emerg Med J 19:4, 375.(published Jul. 2002).
`Barton E D et al., "Intranasal administration of naloxone by para(cid:173)
`medics," Prehosp Emerg Care 6:1, 54-58 (published Jan. 2002).
`Loimer Net al., "Nasal administration ofnaloxone is as effective as
`the intravenous route in opiate addicts," Int J Addict 29:6, 819-27
`(published Apr. 1994).
`
`Loimer Net al., "Nasal administration of naloxone for detection of
`opiate dependence," J Psychiatr Res 26: 1, 39-43 (published Jan.
`1992).
`Bailey AM et al., "Naloxone for opioid overdose prevention: phar(cid:173)
`macists'
`role
`in community-based practice settings," Ann.
`Pharmacother 48:5, 601-06 (published May 2014).
`Wermeling DP et al., "A response to the opioid overdose epidemic:
`naloxone nasal spray," Drug Delivery Transl. Res. 3:1, 63-74 (pub(cid:173)
`lished Feb. 1, 2013).
`Wermeling DP et al., "Opioid harm reduction strategies: focus on
`expanded access to intranasal naloxone," Pharmacotherapy 30:7,
`627-31.
`Aptar UnitDose and BiDose product information sheet, available at
`www.aptar.com/docs/pharma-prescription/uds-bds-datasheet.pdf,
`publication date unknown, last accessed Mar. 26, 2015.
`International Search Report and Written Opinion for Application No.
`IB/2015/000941; Sep. 2, 2015; 11 pages.
`
`* cited by examiner
`
`Adapt & Opiant Exhibit 2034
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 2
`
`

`

`U.S. Patent
`
`Dec. 15, 2015
`
`Sheet 1 of 7
`
`US 9,211,253 B2
`
`FIGURE 1
`
`7.0 ·-
`
`6.0
`
`:::i"S.O
`E
`tio E 4.0 -
`
`-QI 6 3.0
`
`,c
`0
`
`"ii z 2.0
`
`..,._0.4mg1M
`
`-2mglN
`
`-t!r-4 mg IN
`
`0.0
`
`0.0
`
`0.5
`
`1.5
`2.0
`1.0
`Time Post Administration (hr)
`
`2.5
`
`3.0
`
`Adapt & Opiant Exhibit 2034
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 3
`
`

`

`U.S. Patent
`
`Dec. 15, 2015
`
`Sheet 2 of 7
`
`US 9,211,253 B2
`
`FIGURE2
`
`-+-0.4mg IM
`
`-2mglN
`
`-.-4mg IN
`
`10.0 ..
`
`~
`E 1.0
`~
`.§.
`
`(I.I
`C
`0
`)(
`.2 0.1
`Ill z
`
`0.0 - - -~ - - -~ - - -~ - -
`8.0
`4.0
`0.0
`6.0
`2.0
`Time Post Administration (hr)
`
`10.0
`
`12.0
`
`Adapt & Opiant Exhibit 2034
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 4
`
`

`

`U.S. Patent
`
`Dec. 15, 2015
`
`Sheet 3 of 7
`
`US 9,211,253 B2
`
`FIG. 3A
`
`FIGURE3
`
`10
`:::i'
`
`E --C) .s 8
`~ -
`
`C
`0
`
`C 6
`Q)
`(.)
`C
`0
`u
`cu
`E 4
`en
`cu
`0:::
`C 2
`0 ><
`0 ro z
`
`Q)
`
`- 2 x40 mg/ml
`
`-+- 2 x 20 mg/ml
`-.- 1 x40 mg/ml
`...... 1 x 20 mg/ml
`---+--- 0.4 mg IM
`
`2
`
`4
`
`6
`Hours Postdose
`
`8
`
`10
`
`12
`
`FIG. 3B
`
`10
`
`:::?
`
`C
`0
`
`Q)
`(.)
`C
`
`1
`
`0.1
`
`E --Ol .s
`'§ ... -C
`0 u
`cu
`E 0.01
`en
`cu
`a:
`
`Q)
`C
`~ 0.001
`0
`ca z
`0.0001
`
`2x40 mg/ml
`-
`-+- 2 x 20 mg/ml
`-.- 1 x 40 mg/ml
`+- 1 x 20 mg/ml
`---+--- 0.4 mg IM
`
`0
`
`2
`
`4
`
`6
`Hours Postdose
`
`8
`
`10
`
`12
`
`Adapt & Opiant Exhibit 2034
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 5
`
`

`

`U.S. Patent
`
`Dec. 15, 2015
`
`Sheet 4 of 7
`
`US 9,211,253 B2
`
`FIGURE4
`
`_._ 2 x40 mg/ml
`----- 2 x 20 mg/ml
`----J.---- 1 x 40 mg/ml
`-+- 1 x 20 mg/ml
`---+- 0.4 mg IM
`
`FIG. 4A
`
`10
`::J'
`
`E --C')
`-S 8
`C:
`0
`... +-'
`~
`C: 6
`Q)
`(.)
`C:
`0
`0
`cu
`E 4
`(/) cu
`ii
`Q)
`C: 2
`0
`X
`0 ro z
`
`0
`0.0
`
`0.5
`
`1.0
`
`2.5
`2.0
`1.5
`Hours Postdose
`
`3.0
`
`3.5
`
`4.0
`
`FIG. 4B
`
`10 -...J
`E --O')
`-S
`C
`0
`:;:; cu 1
`.....
`+-'
`C
`Q)
`(.)
`C
`0
`0
`cu
`E
`.£20.1
`c..
`Q)
`C
`~
`0 ro
`z
`0.01
`0.0
`
`(/)
`
`_._ 2 x 40 mg/ml
`----- 2 x 20 mg/ml
`......,. 1 x40 mg/ml
`-+- 1 x 20 mg/ml
`---+- 0.4 mg IM
`
`0.5
`
`1.0
`
`2.5
`2.0
`1.5
`Hours Postdose
`
`3.0
`
`3.5
`
`4.0
`
`Adapt & Opiant Exhibit 2034
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 6
`
`

`

`U.S. Patent
`
`Dec. 15, 2015
`
`Sheet 5 of 7
`
`US 9,211,253 B2
`
`FIG. SA
`
`........
`-g 1.0
`-0)
`
`C
`.........
`
`FIG. SB
`
`::. 4
`
`E -0)
`
`C
`.........
`
`FIGURES
`
`0.4 mg IM
`
`-e-- Male
`.....- Female
`
`2
`
`4
`
`6
`Hour
`
`8
`
`10
`
`12
`
`One Spray 20 mg/ml
`
`--.- Female
`....... Male
`
`2
`
`4
`
`6
`Hour
`
`8
`
`10
`
`12
`
`Adapt & Opiant Exhibit 2034
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 7
`
`

`

`U.S. Patent
`
`Dec. 15, 2015
`
`Sheet 6 of 7
`
`US 9,211,253 B2
`
`FIG. 6A
`
`-_J 8
`E -O')
`C -C
`
`0
`:;::::; 6
`co
`,._
`+-'
`C
`Q)
`(.)
`C
`
`0 4 u
`co
`E
`(/) co
`0... 2
`Q)
`C
`0
`>< 0
`co 0
`z
`0
`
`FIG. 6B
`
`::::;- 8
`
`E -0)
`C -
`
`FIGURE 6
`
`Two Sprays 20 mg/ml
`
`-+-
`-.Ir
`
`Male
`Female
`
`2
`
`4
`
`6
`Hour
`
`8
`
`10
`
`12
`
`One Spray 40 mg/ml
`
`-+- Male
`.....,__ Female
`
`2
`
`4
`
`6
`Hour
`
`8
`
`10
`
`12
`
`Adapt & Opiant Exhibit 2034
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 8
`
`

`

`U.S. Patent
`
`Dec. 15, 2015
`
`Sheet 7 of 7
`
`US 9,211,253 B2
`
`FIGURE 7
`
`Two Sprays 40 mg/ml
`
`--- Male
`-.- Female
`
`2
`
`4
`
`6
`Hour
`
`8
`
`10
`
`12
`
`-_J 8
`E -0)
`C -C
`
`0 6
`:;:::::; co
`,._
`+-'
`C
`(I)
`(.)
`C
`0 4
`0
`co
`E
`(/) co
`a.. 2
`(I)
`C
`
`0 >< 0
`co 0
`z
`0
`
`Adapt & Opiant Exhibit 2034
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 9
`
`

`

`1
`NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`US 9,211,253 B2
`
`5
`
`This application claims the benefit of U.S. Provisional
`Application No. 61/953,379, filed Mar. 14, 2014, the disclo(cid:173)
`sure of which is hereby incorporated by reference as if written
`herein in its entirety.
`Provided are drug products adapted for nasal delivery com(cid:173)
`prising a pre-primed device and a pharmaceutical composi(cid:173)
`tion comprising an opioid receptor antagonist, pharmaceuti(cid:173)
`cal compositions comprising an opioid receptor antagonist,
`and methods of use thereof.
`Opioid receptors are Gprotein-coupledreceptors (GPCRs)
`that are activated both by endogenous opioid peptides and by
`clinically important alkaloid analgesic drugs such as mor(cid:173)
`phine. There are three principal types of opioid receptors: the
`o-opioid receptor, the K-opioid receptor, and the µ-opioid
`receptor. Opioids depress respiration, which is controlled
`principally through medullary respiratory centers with
`peripheral input from chemoreceptors and other sources.
`Opioids produce inhibition at the chemoreceptors via
`µ-opioid receptors and in the medulla via µ- and o-opioid
`receptors. While there are a number of neurotransmitters
`mediating the control of respiration, glutamate and y-ami(cid:173)
`nobutyric acid (GABA) are the major excitatory and inhibi- 25
`tory neurotransmitters, respectively. This explains the poten(cid:173)
`tial for interaction of opioids with benzodiazepines and
`alcohol: both benzodiazepines and alcohol facilitate the
`inhibitory effect of GABA at the GABAA receptor, while
`alcohol also decreases the excitatory effect of glutamate at
`NMDA receptors. Oxycodone and otheropioid painkillers, as
`well as heroin and methadone are all implicated in fatal over(cid:173)
`dose. Heroin has three metabolites with opioid activity. Varia(cid:173)
`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 and other drugs used can modify metha(cid:173)
`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(cid:173)
`enced opioid users. While agonist administration modifies
`receptor function, changes (usually in the opposite direction)
`also result from use of antagonists, for example, supersensi(cid:173)
`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(cid:173)
`tion, the number/rate of Americans 12 years of age and older
`who currently abuse pain relievers has increased by 20 per(cid:173)
`cent between 2002 and 2009. 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® ( oxycodone HCl
`controlled-release) and methadone (used in the treatment of
`dependence on other opioids such as heroin and also pre(cid:173)
`scribed for pain), but the increase in the rate of drug overdose
`over the 16 years of the study was driven entirely by over(cid:173)
`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
`
`2
`Latinos to overdose on these analgesics, and deaths mostly
`occurred in neighborhoods with lower rates of poverty, sug(cid:173)
`gesting differential access to doctors who can write painkiller
`prescriptions may be a driving force behind the racial dispar-
`ity. (Cerda et al. "Prescription opioid mortality trends in New
`York City, 1990-2006: Examining the emergence of an epi(cid:173)
`demic," Drug and Alcohol Dependence Volume 132, Issues
`1-2, 1 Sep. 2013, 53-62.)
`Naloxone is an opioid receptor antagonist that is approved
`10 for use by injection for the reversal ofopioid overdose and for
`adjunct use in the treatment of septic shock. It is currently
`being used mainly in emergency departments and in ambu(cid:173)
`lances by trained medical professionals. There have been
`efforts to expand its use by providing the drug to some
`15 patients with take-home opioid prescriptions and those who
`inject illicit drugs, potentially facilitating earlier administra(cid:173)
`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-
`20 lar opioid overdose, in national drug policies, where appro(cid:173)
`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(cid:173)
`nists such as naloxone."
`U.S. Pat. No. 4,464,378 describes a method for eliciting an
`analgesic or narcotic antagonist response in a warm-blooded
`animal, which comprises administering intranasally (IN) to
`said animal to elicit a narcotic antagonist response, a narcotic
`antagonist effective amount ofnaloxone. WO 82/03768 dis-
`30 closes a composition that contains 1 mg of naloxone hydro(cid:173)
`chloride per 0.1 ml of solution adapted for nasal administra(cid:173)
`tion 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
`35 subcutaneous (SQ) administration. WO 00/62757 teaches
`pharmaceutical compositions for IN or oral (PO) administra(cid:173)
`tion which comprise an opioid antagonist, such as naloxone
`for application by spray in the reversal of opioid depression
`for treatment of patients suffering from opioid over-dosage,
`40 wherein the spray applicator 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,
`45 29(6), 819-827, 1994) reported that the nasal administration
`of naloxone is as effective as the intravenous route in opiate
`addicts, however, Dowling et al. (Ther Drug Monit, Vol 30,
`No 4, August 2008) reported that naloxone administered
`intranasally displays a relative bioavailability of 4% only and
`50 concluded that the IN absorption is rapid but does not main(cid:173)
`tain measurable concentrations for more than an hour.
`One early study of 196 consecutive patients with suspected
`opioid overdose conducted in an urban out-of-hospital set(cid:173)
`ting, had shown the mean interval from emergency medical
`55 services (EMS) arrival to a respiratory rate of 2:l O breaths/
`min was 9 .3±4 2 min with administration of naloxone 0.4 mg
`IV, versus 9.6±4.58 min with administration ofnaloxone 0.8
`mg SQ. The authors concluded that the slower rate of absorp(cid:173)
`tion via the SQ route was offset by the delay in establishing an
`60 IV line. (Wanger et al., Intravenous vs subcutaneous nalox(cid:173)
`one for out-of-hospital management of presumed opioid over(cid:173)
`dose. Acad Emerg Med. 1998 April; 5(4):293-9).
`The Denver Health Paramedic system subsequently inves(cid:173)
`tigated the efficacy and safety of atomized intranasal nalox-
`65 one for the treatment of suspected opiate overdose (Barton, et
`al., Efficacy of intranasal naloxone as a needle less alternative
`for treatment of opioid overdose in the prehospital setting. J
`
`Adapt & Opiant Exhibit 2034
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 10
`
`

`

`US 9,211,253 B2
`
`5
`
`3
`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 administration were included in the
`study. IN naloxone (2 mg) was administered immediately
`upon patient contact and before IV insertion and administra(cid:173)
`tion of IV naloxone (2 mg). Patients were then treated by
`EMS protocol. The main outcome measures were: time ofIN
`naloxone administration, time ofIV naloxone administration,
`time of appropriate patient response as reported by paramed(cid:173)
`ics. Ninety-five patients received IN naloxone 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 (16%) in this group required
`further doses of IV naloxone. The median times from arrival
`at patient side to awakening and from administration of the IN
`naloxone to patient awakening were 8.0 minutes and 3.0
`minutes respectively.
`The Drug Overdose Prevention and Education (DOPE)
`Project was the first naloxone prescription program (NPP) 20
`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(cid:173)
`scribed naloxone through the DOPE Project, of whom 24%
`returned to receive a naloxone refill, and 11 % reported using
`naloxone 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(cid:173)
`tion 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
`(IDU s) at high risk of witnessing overdose events are willing
`to be trained on overdose response strategies and use take(cid:173)
`home naloxone during overdose events to prevent deaths
`(Enteen, et al., Overdose prevention and naloxone prescrip(cid:173)
`tion for opioid users in San Francisco. J Urban Health. 2010
`December; 87 ( 6): 931-41).
`Another reported study reviewed EMS and hospital 40
`records before and after implementation of a protocol for
`administration of intranasal naloxone by the Central Califor(cid:173)
`nia 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 45
`patients with suspected narcotic overdose. The protocol for
`the treatment of opioid overdose with intranasal naloxone
`was as follows: "Intranasal (IN)-Administer 2 mg intrana(cid:173)
`sally (1 mg per nostril) using mucosa! atomizer device
`(MAD™) if suspected narcotic intoxication and respiratory 50
`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)-Administer 1 mg
`if unable to administer intranasally (see special consider- 55
`ations). May repeat once in 5 minutes. Intravenous (IV)(cid:173)
`Administer 1 mg slow IV push if no response to intranasal or
`IM administration after 10 minutes. Pediatric dose-0.1
`mg/kg intranasally, ifless than 10 kg and less than 1 year old".
`Patients with suspected narcotic overdose treated in the pre- 60
`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(cid:173)
`tronic record. Clinical response was defined as an increase in
`respiratory rate (breaths/min) or Glasgow Coma Scale score 65
`of at least 6. Main outcome variables included time from
`medication to clinical response and time from patient contact
`
`4
`to clinical response. Secondary variables included numbers
`of doses administered and rescue doses given by an alternate
`route. Between-group comparisons were accomplished using
`t-tests and chi-square tests as appropriate. One hundred fifty-
`four patients met the inclusion criteria, including 104 treated
`with IV and 50 treated with IN naloxone. Clinical response
`was notedin33 (66%) and 58 (56%) of the IN and IV groups,
`respectively (p=0.3). The mean time between naloxone
`administration and clinical response was longer for the IN
`10 group (12.9 vs. 8.1 min, p=0.02). However, the mean times
`from patient contact to clinical response were not signifi(cid:173)
`cantly different between the IN and IV groups (20.3 vs. 20.7
`min, p=0.9). More patients in the IN group received two doses
`of naloxone (34% vs. 18%, p=0.05), and three patients in the
`15 IN group received a subsequent dose ofIV or IM naloxone.
`(Robertson et al., Intranasal naloxone is a viable alternative
`to intravenous naloxone for prehospital narcotic overdose.
`Prehosp Emerg Care. 2009 October-December; 13(4):512-
`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(cid:173)
`one education and distribution of the spray to potential
`bystanders. Participants were instructed by trained staff to
`25 deliver 1 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 suc(cid:173)
`cessful overdose reversals (Doe-Simkins et al. Overdose pre(cid:173)
`vention education with distribution of intranasal naloxone is
`30 a feasible public health intervention to address opioid over(cid:173)
`dose. Am J Public Health. 2009; 99:788-791).
`Overdose education and nasal naloxone distribution
`(OEND) programs are community-based interventions that
`educate people at risk for overdose and potential bystanders
`35 on how to prevent, recognize and respond to an overdose.
`They also equip these individuals with a naloxone rescue kit.
`To evaluate the impact of OEND 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 with no implementation. The setting was nineteen Mas(cid:173)
`sachusetts communities (geographically distinct cities and
`towns) with at least five fatal opioid overdoses in each of the
`years 2004 to 2006. OEND was implemented among opioid
`users at risk for overdose, social service agency staff, family,
`and friends of opioid users. OEND programs equipped people
`at risk for overdose and bystanders with nasal naloxone res(cid:173)
`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, OEND programs trained 2,912
`potential bystanders who reported 327 rescues. Both commu(cid:173)
`nity-year strata with 1-100 enrollments per 100,000 popula(cid:173)
`tion ( adjusted rate ratio 0. 73, 95% confidence interval 0.57 to
`0 .91) and community-year strata with greater than 100 enroll(cid:173)
`ments per 100,000 population (0.54, 0.39 to 0.76) had sig(cid:173)
`nificantly reduced adjusted rate ratios compared with com(cid:173)
`munities 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, OEND is an
`effective intervention (Walley et al., Opioid overdose rates
`and implementation of overdose education and nasal nalox-
`
`Adapt & Opiant Exhibit 2034
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 11
`
`

`

`US 9,211,253 B2
`
`5
`one distribution in Massachusetts: interrupted time series
`analysis. BMJ 2013; 346:fl 74).
`Naloxone prescription programs are also offered by com(cid:173)
`munity-based organizations in Los Angeles and Philadelphia.
`Programs in both cities target IDUs. Studies which recruited
`150 IDU s across both sites for in-depth qualitative interviews
`compared two groups ofIDUs, those who hadreceivednalox(cid:173)
`one prescriptions and those who had never received naloxone
`prescriptions. In both L.A. and Philadelphia, IDUs reported
`successfully administering naloxone to reverse recently wit(cid:173)
`nessed overdoses. Reversals often occurred in public places
`by both housed and homeless IDU s. Despite these successes,
`IDU s frequently did not have naloxone with them when they
`witnessed an overdose. Two typical reasons reported were
`naloxone was confiscated by police, and IDUs did not feel
`comfortable carrying naloxone in the event of being stopped
`by police. Similarly, some untrained IDUs reported discom(cid:173)
`fort with the idea of carrying naloxone on them as their reason
`for not gaining a prescription.
`A randomized trial comparing 2 mg naloxone delivered
`intranasally with a mucosa! atomizer to 2 mg intramuscular
`naloxone was reported by Kelly et al., in 2005 (Med J Aust.
`2005 Jan. 3; 182(1):24-7). The study involved 155 patients
`(71 IM and 84 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 IM group had more rapid response
`than 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). There was no statistically significant differ(cid:173)
`ence between the IM and IN groups for needing rescue nalox(cid:173)
`one (13% [IM group] v. 26% [IN group]; P=0.0558). The
`authors concluded that IN naloxone is effective in treating
`opiate-induced respiratory depression, but is not as effective
`as IM naloxone.
`Kerr et al. (Addiction. 2009 December; 104(12):2067-74)
`disclosed treatment of heroin overdose by intranasal admin(cid:173)
`istration of naloxone constituted in a vial as a preparation of
`2 mg in 1 mL. Participants received 1 mg (0.5 ml) in each
`nostril. The rate of response within 10 minutes was 60/83 40
`(72.3%) for2 mg IN naloxoneversus 69/89 (77.5%) for 2mg
`IM naloxone. The mean response times were 8.0 minutes and
`7 .9 minutes for IN and IV naloxone respectively. Supplemen(cid:173)
`tary naloxone was administered to fewer patients who
`received IM naloxone (4.5%) than IN (18.1 %).
`WO2012156317 describes a study in which naloxone, 8
`mg and 16 mg, was administered as 400 µLIN (200 µL per
`nostril). The administration was performed as follows: The
`pump of the nasal spray was primed by removing the cap and
`pressing downward. This is repeated at least 6 times or until a 50
`fine spray appears; priming is done just prior to dosing. The
`subject is in a standing or upright position 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 of the nose with a finger on the nostril to be closed. 55
`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 the other nostril. The mean T max values were
`reported to be 0.34 h (20.4 min) and 0.39 h (23.4 min) for the 60
`8 and 16 mg doses respectively.
`Wermeling (Drug Deliv Transl Res. 2013 Feb. 1; 3(1):
`63-7 4) teaches that the initial adult dose of naloxone in known
`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(cid:173)
`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
`Cmax of3-5 ng/mL and a tmax of approximately 20 minutes.
`Since the onset of action of naloxone used in opioid over-
`5 dose cases should be as fast as possible, naloxone is thus far
`mainly administered intravenously or intramuscularly by
`emergency health care personnel. Due to a high first pass
`metabolism, oral dosage forms comprising naloxone display
`a low bioavailability and thus seem to be not suitable for such
`10 purposes. The administration of naloxone via injection into
`the blood stream or into the muscle requires first of all trained
`medical personnel (for intravenous injection) or a trained
`carer (for intramuscular injection). Secondly, depending on
`15 the constitution of the addict and the period of intravenous
`drug abuse, it can be particularly difficult to find access into a
`vein of the addict's body for administering naloxone intrave(cid:173)
`nously. Clearly, there is a risk of exposure to blood borne
`pathogens for the medical personnel or the trained carer since
`20 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 (Wilburn,
`25 Needlestick and sharps injury prevention, Online J Issues
`Nurs 2004, Sep. 30; 9(3):5).
`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
`30 overdose patient there