I 1111111111111111 11111 1111111111 111111111111111 1111111111111111 IIII IIII IIII
`US009468747B2
`
`c12) United States Patent
`Crystal et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,468,747 B2
`*Oct. 18, 2016
`
`(54) NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`2015/0174061 Al
`2015/0258019 Al
`2016/0008277 Al
`
`6/2015 Wyse et al.
`9/2015 Crystal et al.
`1/2016 Crystal et al.
`
`(71) Applicant: Lightlake Therapeutics, Inc., New
`York, NY (US)
`
`(72)
`
`Inventors: Roger Crystal, Santa Monica, CA
`(US); Michael Brenner Weiss, New
`York, NY (US)
`
`(73) Assignee: Opiant Pharmaceuticals, Inc., Santa
`Monica, CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 14/950,707
`
`(22) Filed:
`
`Nov. 24, 2015
`
`(65)
`
`Prior Publication Data
`
`US 2016/0184294 Al
`
`Jun. 30, 2016
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 14/942,344, filed on
`Nov. 16, 2015, which is a continuation-in-part of
`application No. 14/659,472, filed on Mar. 16, 2015,
`now Pat. No. 9,211,253.
`
`(60) Provisional application No. 61/953,379, filed on Mar.
`14, 2014.
`
`(51)
`
`Int. Cl.
`A61M 31/00
`A61M 5100
`A61F 13/00
`A61K 31156
`A61K 47/02
`(52) U.S. Cl.
`CPC ............... A61M 31/00 (2013.01); A61K 47/02
`(2013.01)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`( 58) Field of Classification Search
`None
`See application file for complete search history.
`
`FOREIGN PATENT DOCUMENTS
`
`CN
`EP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`1575795
`1681057 Bl
`WO 8203768 Al
`WO 9830211 Al
`WO 0062757 Al
`WO 0074652 Al
`WO 0158447 Al
`WO 0182931 Al
`WO 0211778 Al
`WO 03084520 A2
`WO 2004054511 A2
`WO 2005020906 A2
`WO 2006089973 A2
`WO 2007083073 Al
`WO 2009040595 Al
`WO 2012026963 A2
`WO 2012156317 A2
`WO 2013128447 Al
`WO 2014016653 Al
`WO 2015095644 Al
`WO 2015136373 Al
`WO 2016007729 Al
`
`2/2005
`8/2008
`11/1982
`7 /1998
`10/2000
`12/2000
`8/2001
`11/2001
`2/2002
`10/2003
`7/2004
`3/2005
`8/2006
`7/2007
`2/2009
`3/2012
`11/2012
`9/2013
`1/2014
`6/2015
`9/2015
`1/2016
`
`OTHER PUBLICATIONS
`
`U.S. Appl. No. 14/942,344, filed Nov. 16, 2015, Crystal et al.
`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 wno take methadone," J Subst Abuse Treat
`44:2, 241-47 (Epub Sep. 12, 2012).
`Weber J M et al., "Can nebulized naloxone be used safely and
`effectively by emergency medical services for suspected opioid
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`2011).
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`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 effec(cid:173)
`tiveness 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
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`Emerg Care 13:4, 512-15 (Published Oct. 2009).
`(Continued)
`
`Primary Examiner -
`Jeffrey T Palenik
`(74) Attorney, Agent, or Firm - Dennis A. Bennett;
`Cynthia Hathaway
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,181,726 A
`4,464,378 A
`5,866,154 A
`9,192,570 B2 *
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`
`A61K 9/0043
`
`(57)
`
`ABSTRACT
`
`Drug products adapted for nasal delivery, compnsmg a
`pre-primed device filled with a pharmaceutical composition
`comprising an opioid receptor antagonist, are provided.
`Methods of treating opioid overdose or its symptoms with
`the inventive drug products are also provided.
`
`45 Claims, 7 Drawing Sheets
`
`Adapt & Opiant Exhibit 2035
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 1
`
`

`

`US 9,468,747 B2
`Page 2
`
`(56)
`
`References Cited
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`OTHER PUBLICATIONS
`Doe-Simkins M et 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 flurnazenil and naloxone to reverse
`over-sedation in a child undergoing dental restorations," Paediatr
`Anaesth 19:8 795-99 (published Aug. 2009).
`Dowling J et al., "Population pharmacokinetics of intravenous,
`intramuscular, 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).
`Barton E D et al., "Efficacy of intranasal naloxone as a needleless
`alternative for treatment of opioid overdose in the prehospital
`setting," J Emerg Med 29:3, 265-71 (published Oct. 2005).
`Kelly AM et al., "Randomised trial of intranasal versus intramus(cid:173)
`cular naloxone in prehospital treatment for suspected opioid over(cid:173)
`dose," Med J Aust 182:1 24-27 (published Jan. 3, 2005).
`Kelly A M et al., "Intranasal naloxone for lite threatening opioid
`toxicity," Emerg Med J 19:4, 375 (published Jul. 2002).
`Barton E D et al., "Intranasal administration of naloxone by
`paramedics," 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 A M et al., "Naloxone for opioid overdose prevention:
`pharmacists' 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
`(published Feb. 1, 2013).
`Wermeling D P et al., "Opioid harm reduction strategies: focus on
`expanded access to intranasal naloxone," Pharrnacotherapy 30:7,
`627-31, 2010.
`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 pgs.
`Notice of Allowance, U.S. Appl. No. 14/659,472, Oct. 9, 2015, 9
`pgs.
`Corrected Notice Allowance, U.S. Appl. No. 14/659,472, Nov.
`2015, 9 pgs.
`U.S. Appl. No. 15/183,441, filed Jun. 14, 2016, Keegan F. et al.
`Krieter P. et al., Pharmacokinetic Properties and Human Use Char(cid:173)
`acteristics of an FDA Approved Intranasal Naloxone Product for the
`Treatment of Opioid Overdose, J Clin Pharmacol, 2016, pp. 1-11.
`International Search Report and Written Opinion for WO2016/
`007729, Dec. 4, 2015, 16 pages.
`
`* cited by examiner
`
`Adapt & Opiant Exhibit 2035
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 2
`
`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 1 of 7
`
`US 9,468,747 B2
`
`FIG.1
`
`~0.4mg!M
`
`~2mglN
`
`-:-:---.. ::.:,--,-,4 mg IN
`
`:: ]
`
`:gs,o --
`1
`?a
`i
`E 4,0 "\
`:
`.._,,
`Ill
`:
`i:::
`:
`o 3.0 ··(
`:<
`:
`0
`:
`m
`. .J
`:.f
`z 2,0
`, ,,,:,._
`
`:::~--.·.·.·.·-~ -··~.
`
`0~
`
`QS
`
`2~
`1D
`15
`Time Post Administration (hr)
`
`2.5
`
`3~
`
`Adapt & Opiant Exhibit 2035
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 3
`
`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 2 of 7
`
`US 9,468,747 B2
`
`FIG.2
`
`-•=0.4rnglM
`
`~2rng!N
`
`·=···.,.:.,, ==:-4 mg IN
`
`-_,J
`E -
`
`E 1.0
`tio
`
`0.0
`
`0,0
`
`2,0
`
`6,0
`4,0
`8,0
`Time Post Administration (hr)
`
`10,0
`
`12,0
`
`Adapt & Opiant Exhibit 2035
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 4
`
`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 3 of 7
`
`US 9,468,747 B2
`
`FIG.3
`
`3A
`
`_,,_ 2 x40 mg/ml
`-ii- 2 x 20 mg/ml
`_,._ 1 x 40 mg/ml
`...... 1 x 20 mg/ml
`-+- 0.4 mg IM
`
`10
`
`8
`
`6
`
`4
`
`2
`
`-...J
`E -0)
`C --C
`0
`·.;::::;
`.....
`.....
`(0
`C
`(l)
`(.)
`C
`0
`(.)
`(0
`E
`(/)
`(0
`Cl.
`(l)
`C
`0
`X
`0
`
`n:, z
`
`0
`0
`
`2
`
`4
`
`6
`Hours Postdose
`
`8
`
`10
`
`12
`
`10
`
`1
`
`3B
`
`C:
`0
`:.;:::;
`n:,
`
`..... c
`~
`C:
`0
`0
`m
`E 0.01
`
`0.1
`
`_,,_ 2 x40 mg/ml
`(/)
`(0
`-- 2 x 20 mg/ml
`Cl..
`(l)
`-.- 1 x40 mg/ml
`C
`~ 0.001
`...... 1 x20 mg/ml
`0
`co z
`-+ 0.4 mg IM
`0 .0001 + - - -~ - - - , -~ - - - - - , - -~ - - - r - - -~ - . , - - -~~ -~ - - - .
`10
`12
`2
`4
`0
`6
`8
`Hours Postdose
`
`Adapt & Opiant Exhibit 2035
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 5
`
`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 4 of 7
`
`US 9,468,747 B2
`
`FIG.4
`
`4A
`
`....,,_
`
`2 x 40 mg/ml
`-- 2 x 20 mg/ml
`-..... 1 x 40 mg/ml
`---- 1 x 20 mg/ml
`--+- 0.4 mg IM
`
`10
`
`----'
`-0)
`--C
`
`E
`C 8
`0
`:;::;
`....
`ro
`.....
`C 6
`~
`C
`0 u
`ro
`E 4
`(/) co
`0...
`(I)
`C 2
`0
`X
`0
`"ffi z
`
`0
`0.0
`
`0.5
`
`1.0
`
`2.5
`2.0
`1.5
`Hou rs Postdose
`
`3.0
`
`3.5
`
`4.0
`
`..-
`--'
`
`10
`E ---0)
`C -C
`
`(/)
`
`0
`:;:::;
`....
`co 1
`.....
`C
`~
`C
`0 u
`ro
`E
`roo .1
`0...
`(I)
`C
`~
`0
`ro
`z
`0.01
`0.0
`
`48
`
`_._ 2x40mg/ml
`-- 2 x 20 mg/ml
`-..... 1 x 40 mg/ml
`--e- 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 2035
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 6
`
`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 5 of 7
`
`US 9,468,747 B2
`
`-
`-g 1.0 -0)
`C -§ 0.8
`
`:.::; rn
`'-,._.
`C
`~ 0.6
`C
`0
`0
`~ 0.4
`(/) rn
`a...
`~ 0.2
`0
`X
`0
`rn z 0.0
`0
`
`.-.
`_J 4
`E
`C
`
`-0)
`
`-----C
`0
`:;:::; 3
`ro
`.......
`I...
`C
`Q)
`(.)
`C
`0 2
`()
`ro
`E
`en
`ro
`a... 1
`
`Q)
`C
`0
`X
`0
`
`~o
`0
`
`FIG.5
`
`0.4 mg IM
`
`5A
`
`.... Male
`
`.\- Female
`
`2
`
`4
`
`6
`Hour
`
`8
`
`10
`
`12
`
`One Spray 20 mg/ml
`
`58
`
`Female
`
`Male
`
`.\-
`
`---
`
`2
`
`4
`
`6
`Hour
`
`8
`
`10
`
`12
`
`Adapt & Opiant Exhibit 2035
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 7
`
`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 6 of 7
`
`US 9,468,747 B2
`
`....I 8
`
`-
`E -0)
`C -C
`I... -C
`
`0 .:;6
`co
`
`Q)
`(..)
`C
`
`0 4 u
`co
`E
`(/) co
`0.. 2
`Q)
`C
`0
`X
`0
`
`~o
`0
`
`,_
`....I 8
`E
`
`C
`...__,,
`C
`0
`:;::; 6
`ro
`
`-0)
`I... -C
`
`Q)
`(..)
`C
`0 4
`0
`ro
`E
`(/) ro
`a. 2
`Q)
`C
`0
`X
`0
`
`~o
`0
`
`FIG.6
`
`Two Sprays 20 mg/ml
`
`6A
`
`--- Male
`...... Female
`
`2
`
`4
`
`6
`Hour
`
`8
`
`10
`
`12
`
`One Spray 40 mg/ml
`
`68
`
`--- Male
`...... Female
`
`2
`
`4
`
`6
`Hour
`
`8
`
`10
`
`12
`
`Adapt & Opiant Exhibit 2035
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 8
`
`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 7 of 7
`
`US 9,468,747 B2
`
`---_J 8
`E -0)
`C --C
`
`0
`:;::; 6
`ro s...
`.....,
`C
`(I) u
`C
`0 4
`(.)
`ro
`E
`(J)
`ro
`0.. 2
`(I)
`C
`
`0 >< 0
`ro 0
`z
`0
`
`FIG. 7
`
`Two Sprays 40 mg/ml
`
`--- Male
`
`-Ir Female
`
`2
`
`4
`
`6
`Hour
`
`8
`
`10
`
`12
`
`Adapt & Opiant Exhibit 2035
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00693
`Page 9
`
`

`

`US 9,468,747 B2
`
`1
`NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`This application is a continuation of U.S. application Ser.
`No. 14/942,344, filed Nov. 16, 2015, which is a continua(cid:173)
`tion-in-part of U.S. application Ser. No. 14/659,472, filed
`Mar. 16, 2015, which claims the benefit of U.S. Provisional
`Application No. 61/953,379, filed Mar. 14, 2014, the dis(cid:173)
`closure of which is hereby incorporated by reference as if
`written herein in its entirety.
`Provided are drug products adapted for nasal delivery
`comprising a pre-primed device and a pharmaceutical com(cid:173)
`position comprising an opioid receptor antagonist, pharma(cid:173)
`ceutical compositions comprising an opioid receptor antago(cid:173)
`nist, and methods of use thereof.
`Opioid receptors are G protein-coupled receptors (GP(cid:173)
`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(cid:173)
`tors: the II-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 K- and II-opioid
`receptors. While there are a number of neurotransmitters
`mediating the control of respiration, glutamate and y-amin(cid:173)
`obutyric acid (GABA) are the major excitatory and inhibi(cid:173)
`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 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 formation of these metabolites due to
`genetic factors and the use of other drugs could explain
`differential sensitivity to overdose. Metabolites of metha(cid:173)
`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 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 experienced opioid users. While agonist administra(cid:173)
`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(cid:173)
`ing to the Substance Abuse and Mental Health Services
`Administration, the number/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-fold, from 0.39 per
`100,000 persons to 2.7. Drugs classed as prescription opi(cid:173)
`oids in this study include both typical analgesics, such as
`OxyContin®
`(oxycodone HCl controlled-release) and
`methadone (used in the treatment of dependence on other 65
`opioids such as heroin and also prescribed for pain), but the
`increase in the rate of drug overdose over the 16 years of the
`
`2
`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
`5 analgesics, and deaths mostly occurred in neighborhoods
`with lower rates of poverty, suggesting differential access to
`doctors who can write painkiller prescriptions may be a
`driving force behind the racial disparity. (Cerda et al. "Pre(cid:173)
`scription opioid mortality trends in New York City, 1990-
`10 2006: Examining the emergence of an epidemic," Drug and
`Alcohol Dependence Volume 132, Issues 1-2, 1 Sep. 2013,
`53-62.)
`Naloxone is an opioid receptor antagonist that is approved
`for use by injection for the reversal of opioid overdose and
`15 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 those who
`20 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 par(cid:173)
`ticular opioid overdose, in national drug policies, where
`25 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. 4,464,378 describes a method for eliciting
`30 an analgesic or narcotic antagonist response in a warm(cid:173)
`blooded animal, which comprises administering intranasally
`(IN) to said animal to elicit a narcotic antagonist response,
`a narcotic antagonist effective amount of naloxone. WO
`82/03768 discloses a composition that contains 1 mg of
`35 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-
`40 tion. WO 00/62757 teaches pharmaceutical compositions for
`IN or oral (PO) administration which comprise an opioid
`antagonist, such as naloxone for application by spray in the
`reversal of opioid depression for treatment of patients suf(cid:173)
`fering from opioid over-dosage, wherein the spray applica-
`45 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), 819-827, 1994) reported that the nasal administration
`50 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 concluded that the IN absorption is rapid but does not
`55 maintain measurable concentrations for more than an hour.
`One early study of 196 consecutive patients with sus(cid:173)
`pected opioid overdose conducted in an urban out-of-hos(cid:173)
`pital setting, had shown the mean interval from emergency
`medical services (EMS) arrival to a respiratory rate of 2:10
`60 breaths/min was 9.3±4.2 min with administration of nalox-
`one 0.4 mg IV, versus 9.6±4.58 min with administration of
`naloxone 0.8 mg SQ. The authors concluded that the slower
`rate of absorption via the SQ route was offset by the delay
`in establishing an IV line. (Wanger et al., Intravenous vs
`subcutaneous naloxone for out-of-hospital management of
`presumed opioid overdose. Acad Emerg Med. 1998 April;
`5(4):293-9).
`
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`US 9,468,747 B2
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`3
`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 of intranasal naloxone as a needle(cid:173)
`less alternative for treatment of opioid overdose in the
`prehospital 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(cid:173)
`tion were included in the study. IN naloxone (2 mg) was
`administered immediately upon patient contact and before
`IV insertion and administration of IV naloxone (2 mg).
`Patients were then treated by EMS protocol. The main
`outcome measures were: time of IN naloxone administra(cid:173)
`tion, time ofIV naloxone administration, time of appropriate
`patient response as reported by paramedics. 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 respec(cid:173)
`tively.
`The Drug Overdose Prevention and Education (DOPE)
`Project was the first naloxone prescription program (NPP)
`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
`prescribed 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
`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 (IDU s) 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, et al., Overdose prevention and naloxone
`prescription for opioid users in San Francisco. J Urban
`Health. 2010 December; 87(6):931-41).
`Another reported study reviewed EMS and hospital
`records before and after implementation of a protocol for
`administration of intranasal naloxone by the Central Cali(cid:173)
`fornia EMS Agency in order to compare the prehospital time
`intervals from patient contact and medication administration 50
`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(cid:173)
`one was as follows: "Intranasal (IN)-Administer 2 mg
`intranasally (1 mg per nostril) using mucosa! atomizer 55
`device (MAD™) 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)- 60
`Administer 1 mg if unable to administer intranasally (see
`special considerations). May repeat once in 5 minutes.
`Intravenous (IV)-Administer 1 mg slow IV push if no
`response to intranasal or IM administration after 10 minutes.
`Pediatric dose-0.1 mg/kg intranasally, if less than 10 kg 65
`and less than 1 year old". Patients with suspected narcotic
`overdose treated in the prehospital setting over 17 months,
`
`4
`between March 2003 and July 2004 were included. Para(cid:173)
`medics documented dose, route of administration, and posi(cid:173)
`tive response times using an electronic record. Clinical
`response was defined as an increase in respiratory rate
`(breaths/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 to clinical
`response. Secondary variables included numbers of doses
`administered and rescue doses given by an alternate route.
`10 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 noted in 33 (66%) and 58 (56%) of the IN and
`15 IV groups, respectively (p=0.3). The mean time between
`naloxone administration and clinical response was longer for
`the IN group (12.9 vs. 8.1 min, p=0.02). However, the mean
`times from patient contact to clinical response were not
`significantly different between the IN and IV groups (20.3
`20 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 IN group received a subsequent dose of IV or
`IM naloxone. (Robertson et al., Intranasal naloxone is a
`viable alternative to intravenous naloxone for prehospital
`25 narcotic overdose. Prehosp Emerg Care. 2009 October(cid:173)
`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-
`30 one education and distribution of the spray to potential
`bystanders. Participants were instructed by trained staff to
`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
`35 successful overdose reversals (Doe-Simkins et al. Overdose
`prevention education with distribution of intranasal nalox(cid:173)
`one is a feasible public health intervention to address opioid
`overdose. Am J Public Health. 2009; 99:788-791).
`Overdose education and nasal naloxone distribution
`40 (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 the impact ofOEND programs on rates of opioid
`45 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
`Massachusetts 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 rescue kits and trained them how to prevent,
`recognize, and respond to an overdose by engaging emer(cid:173)
`gency medical services, providing rescue breathing, and
`delivering naloxone. Among these communities, OEND
`programs trained 2,912 potential bystanders who reported
`327 rescues. Both community-year strata with 1-100 enroll(cid:173)
`ments per 100,000 population (adjusted rate ratio 0.73, 95%
`confidence interval 0.57 to 0.91) and community-year strata
`with greater than 100 enrollments per 100,000 population
`(0.54, 0.39 to 0.76) had significantly reduced adjusted rate
`ratios compared with communities with no implementation.
`
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`US 9,468,747 B2
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`5
`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 naloxone distribution in Massachu(cid:173)
`setts: 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 Philadel(cid:173)
`phia. Programs in both cities target IDUs. Studies which
`recruited 150 IDUs across both sites for in-depth qualitative
`interviews compared two groups of IDUs, those who had 15
`received naloxone prescriptions and those who had never
`received naloxone prescriptions. In both L.A. and Philadel(cid:173)
`phia, IDUs reported successfully administering naloxone to
`reverse recently witnessed overdoses. Reversals often
`occurred in public places by both housed and homeless 20
`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 IDU s did not feel comfortable carrying naloxone
`in the event of being stopped by police. Similarly, some 25
`untrained IDUs reported discomfort with the idea of carry(cid:173)
`ing 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 30
`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 35
`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 difference between the IM and IN groups for 40
`needing rescue naloxone (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) 45
`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
`(72.3%) for 2 mg IN naloxone versus 69/89 (77.5%) for 2 50
`mg IM naloxone. The mean response times were 8.0 minutes
`and 7 .9 minutes for IN and IV naloxone respectively.
`Supplementary naloxone was administered to fewer patients
`who received IM naloxone (4.5%) than IN (18.1%).
`WO2012156317 describes a study in which naloxone, 8 55
`mg and 16 mg, was administered as 400 µL IN (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 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. The device is inserted into the open 65
`nostril and it is sprayed 2 times into the nostril. The subject
`should gently breath inward through the nostril, the device
`
`6
`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 8 and 16 mg doses respectively.
`Wermeling (Drug Deliv Transl Res. 2013 February 1;
`5 3(1): 63-74) teaches that the initial adult dose ofnaloxone 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
`formulations of naloxone are approved for intravenous (IV),
`intramuscular (IM) and subcutaneous (SC) administration,
`10 with IV being the recommended route. Wermeling also
`predicts that a 2 mg nasal solution dose of naloxone will
`likely have a Cmax of 3-5 ng/mL and a tmax of approximately
`20 minutes.
`Since the onset of action of naloxone used in opioid
`overdose 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 purposes. The administration of naloxone via injection
`into the blood stream or into the muscle requires first of all
`trained medical