(12) United States Patent
`Crystal et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,468,747 B2
`*Oct. 18, 2016
`
`US009468747B2
`
`(54)
`
`(71)
`
`(72)
`
`(73)
`
`(*)
`
`(21)
`(22)
`(65)
`
`(63)
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`Applicant: Lightlake Therapeutics, Inc., New
`York, NY (US)
`Inventors: Roger Crystal, Santa Monica, CA
`(US); Michael Brenner Weiss, New
`York, NY (US)
`Assignee: Opiant Pharmaceuticals, Inc., Santa
`Monica, CA (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is Subject to a terminal dis
`claimer.
`
`Notice:
`
`Appl. No.: 14/950,707
`
`Filed:
`
`Nov. 24, 2015
`
`Prior Publication Data
`US 2016/O184294 A1
`Jun. 30, 2016
`
`Related U.S. Application Data
`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.
`Provisional application No. 61/953,379, filed on Mar.
`14, 2014.
`
`Int. C.
`A6M 3L/00
`A6M 5/00
`A6DF 3/00
`A6 IK3I/56
`A61 K 47/02
`U.S. C.
`CPC ............... A61M 31/00 (2013.01); A61 K 47/02
`(2013.01)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Field of Classification Search
`None
`See application file for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`1, 1980 Bernstein
`4,181,726 A
`8, 1984 Hussain
`4,464,378 A
`2f1999 Bahal et al.
`5,866,154 A
`9,192.570 B2 * 1 1/2015 Wyse ................... A61K 9.0043
`2003/OO77300 A1
`4/2003 Wermeling
`2006, O120967 A1
`6, 2006 Namburi et al.
`2009.00171 O2 A1
`1/2009 Stinchcomb et al.
`2010/0113495 A1
`5/2010 Wermeling et al.
`2010, 0168147 A1
`7/2010 Chapleo et al.
`2010/0331354 A1 12/2010 Wermeling
`2011 0046172 A1
`2/2011 Chapleo et al.
`2012/0270895 A1 10/2012 Wermeling
`2013, OO23825 A1
`1/2013 Edwards et al.
`
`2015,0174061 A1
`2015,0258O19 A1
`2016,0008277 A1
`
`6/2015 Wyse et al.
`9/2015 Crystal et al.
`1/2016 Crystal et al.
`
`FOREIGN PATENT DOCUMENTS
`
`2, 2005
`1575795
`CN
`8, 2008
`1681.057 B1
`EP
`WO 82O3768 A1 11, 1982
`WO
`WO983O211 A1
`7, 1998
`WO
`WO OO62757 A1 10/2000
`WO
`WOOO74652 A1 12/2000
`WO
`WO O158447 A1
`8, 2001
`WO
`WO 0182931 A1
`11 2001
`WO
`WO O211778 A1
`2, 2002
`WO
`WO O3O84520 A2 10/2003
`WO
`WO WO 2004054511 A2
`T 2004
`WO WO 2005O2O906 A2
`3, 2005
`WO WO 2006089973 A2
`8, 2006
`WO WO 2007083073 A1
`7/2007
`WO WO 2009040595 A1
`2, 2009
`WO WO 2012O26963 A2
`3, 2012
`WO WO 2012 156317 A2 11/2012
`WO WO 2013 128447 A1
`9, 2013
`WO WO 2014O16653 A1
`1, 2014
`WO WO 2015095.644 A1
`6, 2015
`WO WO 2015.136373 A1
`9, 2015
`WO WO 2016.007729 A1
`1, 2016
`
`OTHER PUBLICATIONS
`
`U.S. Appl. No. 14/942,344, filed Nov. 16, 2015, Crystal et al.
`Walley, A Yet al. "Opioid overdose rates and implementation of
`overdose education and nasal naloxone distribution in Massachu
`setts: interrupted time series analysis.” BMJ 346:f174. (Published
`Jan. 31, 2013).
`Walley A. Yet 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
`overdose?” Prehosp Emerg Care 16:2, 289-92 (Epub Dec. 22.
`2011).
`Merlin M A et al., “Intranasal naloxone delivery is an alternative to
`intravenous naloxone for opioid overdoses.” Am J Emerg Med28:3.
`296-303 (Epub Jan. 28, 2010).
`Kerr D et al., “Randomized controlled trial comparing the effec
`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
`intravenous naloxone for prehospital narcotic overdose.” Prehosp
`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
`
`ABSTRACT
`(57)
`Drug products adapted for nasal delivery, comprising 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
`
`Nalox1251
`Nalox-1 Pharmaceuticals, LLC
`Page 1 of 37
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`

`

`US 9,468,747 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`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-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 30:4490-96 (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 A M et al., “Randomised trial of intranasal versus intramus
`cular naloxone in prehospital treatment for Suspected opioid over
`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 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 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 D Pet al., “A response to the opioid overdose epidemic:
`naloxone nasal spray.” Drug Delivery Transl. Res. 3:1, 63-74
`(published Feb. 1, 2013).
`Wermeling DP et al., “Opioid harm reduction strategies: focus on
`expanded access to intranasal naloxone.' Pharmacotherapy 30:7.
`627-31, 2010.
`Aptar UnitDose and BilDose 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
`pg.S.
`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
`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
`
`Nalox1251
`Nalox-1 Pharmaceuticals, LLC
`Page 2 of 37
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`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 1 of 7
`
`US 9,468,747 B2
`
`
`
`A
`
`i.
`
`{
`
`.
`
`2.
`3
`..{
`fine Past Administration thr
`
`s
`
`38
`
`Nalox1251
`Nalox-1 Pharmaceuticals, LLC
`Page 3 of 37
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`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 2 of 7
`
`US 9,468,747 B2
`
`FG, 2.
`
`x2 ng N
`84 ng 38
`
`
`
`
`
`3.
`
`38
`
`---
`{
`:
`8.0
`8.
`ints post Administration hr.
`
`{
`
`32.8
`
`Nalox1251
`Nalox-1 Pharmaceuticals, LLC
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`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 3 of 7
`
`US 9,468,747 B2
`
`O
`
`8
`
`6
`
`
`
`F.G. 3
`
`3A
`
`-v- 2 x 40 mg/mL
`-- 2 x 20 mg/mL
`-a- 1 x 40 mg/ml.
`-0- 1 x 20 mg/mL
`-- 0.4 mg IM
`
`Hours Postdose
`
`103-
`
`12
`
`3B
`
`0.01
`
`OOO1
`
`-v- 2 x 40 mg/mL
`-- 2 x 20 mg/ml.
`-A - 1 x 40 mg/mL
`-0- 1 x 20 mg/ml.
`-- 0.4 mg IM
`
`OOOO1
`O
`
`2
`
`4.
`
`6
`Hours Postdose
`
`8
`
`10
`
`12
`
`Nalox1251
`Nalox-1 Pharmaceuticals, LLC
`Page 5 of 37
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`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 4 of 7
`
`US 9,468,747 B2
`
`FIG. 4
`
`4A
`
`-v- 2 x 40 mg/mL
`-- 2 x 20 mg/mL
`-k- 1 x 40 mg/mL
`-o- 1 x 20 mg/mL
`-- 0.4 mg M
`
`
`
`2.5
`2O
`15
`HOurS Postdose
`
`3.0
`
`3.5
`
`4.0
`
`r------------,
`
`0.5
`
`1.0
`
`1 O
`
`8
`
`
`
`
`
`6-
`
`OO
`
`1 O
`
`Y
`
`-v- 2 x 40 mg/ml.
`-- 2 X 20 mg/mL
`-A- 1 x 40 mg/ml.
`-o- 1 x 20 mg/mL
`-- 0.4 mg M
`
`O 1
`OO
`
`O5
`
`1 O
`
`2.5
`2O
`15
`Hours Postdose
`
`3.0
`
`3.5
`
`4.0
`
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`Nalox-1 Pharmaceuticals, LLC
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`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet S of 7
`
`US 9,468,747 B2
`
`F.G. 5
`0.4 mg M
`
`
`
`3. E 10
`O)
`S
`5 0.8
`t
`E
`3 0.6
`O
`O
`0.4
`
`c
`
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`X
`9
`s' 0.0
`
`4
`2
`5 3
`E
`9
`32
`i
`n 1
`CD
`9
`C
`SO
`O
`
`Hour
`
`One Spray 20 mg/mL
`
`5B
`
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`-O- Male
`
`2
`
`4
`
`6
`HOur
`
`8
`
`10
`
`12
`
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`Nalox-1 Pharmaceuticals, LLC
`Page 7 of 37
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`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 6 of 7
`
`US 9,468,747 B2
`
`F.G. 6
`Two Sprays 20 mg/ml.
`
`Hour
`
`One Spray 40 mg/ml.
`
`
`
`8
`
`6
`
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`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 7 Of 7
`
`US 9,468,747 B2
`
`FIG. 7
`
`Two Sprays 40 mg/ml.
`
`
`
`8
`
`6
`
`4.
`
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`

`1.
`NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`US 9,468,747 B2
`
`5
`
`10
`
`15
`
`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
`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
`scription opioid mortality trends in New York City, 1990
`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
`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
`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 par
`ticular opioid overdose, in national drug policies, where
`appropriate, and to share best practices and information on
`the prevention and treatment of drug overdose, in particular
`opioid overdose, including the use of opioid receptor
`antagonists Such as naloxone.”
`U.S. Pat. No. 4,464,378 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 of naloxone. WO
`82/03768 discloses a composition that contains 1 mg of
`naloxone hydrochloride per 0.1 ml of solution adapted for
`nasal administration used in the treatment of narcotic
`induced respiratory depression (overdose) at a dosage
`approximately the same as that employed for intravenous
`(IV), intramuscular (IM) or subcutaneous (SQ) administra
`tion. 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
`fering from opioid over-dosage, wherein the spray applica
`tor is capable of delivering single or multiple doses and
`Suitable dosage units are in the range of 0.2 to 5 mg.
`The use of nasal naloxone is not without controversy. For
`instance, Loimer et al. (International Journal of Addictions,
`29(6), 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 concluded that the IN absorption is rapid but does not
`maintain measurable concentrations for more than an hour.
`One early study of 196 consecutive patients with sus
`pected opioid overdose conducted in an urban out-of-hos
`pital setting, had shown the mean interval from emergency
`medical services (EMS) arrival to a respiratory rate of >10
`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).
`
`This application is a continuation of U.S. application Ser.
`No. 14/942,344, filed Nov. 16, 2015, which is a continua
`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
`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
`position comprising an opioid receptor antagonist, pharma
`ceutical compositions comprising an opioid receptor antago
`nist, and methods of use thereof.
`Opioid receptors are G protein-coupled receptors (GP
`CRs) that are activated both by endogenous opioid peptides
`and by clinically important alkaloid analgesic drugs such as
`morphine. There are three principal types of opioid recep
`tors: the 6-opioid receptor, the K-opioid receptor, and the
`u-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 u-opioid receptors and in the medulla via K- and Ö-opioid
`receptors. While there are a number of neurotransmitters
`mediating the control of respiration, glutamate and Y-amin
`obutyric acid (GABA) are the major excitatory and inhibi
`tory neurotransmitters, respectively. This explains the poten
`tial for interaction of opioids with 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
`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
`tion modifies receptor function, changes (usually in the
`opposite direction) also result from use of antagonists, for
`example, SuperSensitivity to opioids following a period of
`administration of antagonists such as naltrexone.
`In the United States, mortality rates closely correlate with
`opioid sales. In 2008, approximately 36,450 people died
`from drug overdoses. At least 14,800 of these deaths
`involved prescription opioid analgesics. Moreover, accord
`ing to the Substance Abuse and Mental Health Services
`Administration, the 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
`oids in this study include both typical analgesics, such as
`OxyContin R (oxycodone HC1 controlled-release) and
`methadone (used in the treatment of dependence on other
`opioids such as heroin and also prescribed for pain), but the
`increase in the rate of drug overdose over the 16 years of the
`
`25
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`30
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`25
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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
`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
`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
`tion, time of IV 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
`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, 1942 individuals were trained and
`30
`prescribed naloxone through the DOPE Project, of whom
`24% returned to receive analoxone 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 (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, 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
`fornia EMS Agency in order to compare the prehospital time
`intervals from patient contact and medication administration
`to clinical response for IN versus intravenous IV naloxone
`in patients with Suspected narcotic overdose. The protocol
`for the treatment of opioid overdose with intranasal nalox
`one was as follows: “Intranasal (IN)—Administer 2 mg
`intranasally (1 mg per nostril) using mucosal atomizer
`55
`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)—
`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
`and less than 1 year old. Patients with suspected narcotic
`overdose treated in the prehospital setting over 17 months,
`
`50
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`40
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`45
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`65
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`4
`between March 2003 and July 2004 were included. Para
`medics documented dose, route of administration, and posi
`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.
`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
`IV groups, respectively (p=0.3). The mean time between
`naloxone administration and clinical response was longer for
`the INgroup (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
`vs. 20.7 min, p=0.9). More patients in the INgroup received
`two doses of naloxone (34% vs. 18%, p=0.05), and three
`patients in the INgroup received a subsequent dose of IV 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
`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
`successful overdose reversals (Doe-Simkins et al. Overdose
`prevention education with distribution of intranasal nalox
`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
`(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 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
`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
`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
`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.
`
`Nalox1251
`Nalox-1 Pharmaceuticals, LLC
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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
`setts: interrupted time series analysis. BMJ 2013: 346:
`f174).
`10
`Naloxone prescription programs are also offered by com
`munity-based organizations in Los Angeles and Philadel
`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
`received naloxone prescriptions and those who had never
`received naloxone prescriptions. In both L.A. and Philadel
`phia, IDUs reported Successfully administering naloxone to
`reverse recently witnessed overdoses. Reversals often
`occurred in public places by both housed and homeless
`IDUs. Despite these successes, IDUs 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 discomfort with the idea of carry
`ing naloxone on them as their reason for not gaining a
`prescription.
`A randomized trial comparing 2 mg naloxone delivered
`intranasally with a mucosal atomizer to 2 mg intramuscular
`naloxone was reported by Kelly et 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 difference between the IM and IN groups for
`needing rescue naloxone (13% IIM 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
`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
`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
`mg and 16 mg, was administered as 400 uL IN (200 uL 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
`nostril and it is sprayed 2 times into the nostril. The subject
`should gently breath inward through the nostril, the device
`
`45
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`25
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`30
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`35
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`40
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`50
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`55
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`60
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`65
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`US 9,468,747 B2
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`5
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`is removed, and the steps are repeated for the other nostril.
`The mean T 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:
`3(1): 63-74) 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
`formulations of naloxone are approved for intravenous (IV),
`intramuscular (IM) and Subcutaneous (SC) administration,
`with IV being the recommended route. Wermeling also
`predicts that a 2 mg nasal Solution dose of naloxone will
`likely have a C of 3-5 ng/mL and at 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 personnel (for intravenous injection) or a
`trained carer (for intramuscular injection). Secondly,
`depending on 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 intravenously. 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 (Wilburn, Needlestick and sharps injury preven
`tion, 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 typi
`cal therapeutic dose of naloxone is administered to an opioid
`overdose patient there is often the need to re-administer
`naloxone, in Some cases even several times, and it is
`important 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
`consumers are able to use safely. A nasal spray device that
`was pre-filled with a naloxone 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, medi
`cal device called the Mucosal Atomization Device.
`Thus, there remains a need for durable, easy-to-use,
`needleless devices with storage-stable formulations, that can
`enable untrained individuals to quickly deliver a therapeu
`tically effective dose of a rapid-acting opioid antagonist to
`an opioid overdose patient. The therapeutically 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 patient, and to stabilize the patient until professional
`medical care becomes available. The devices described
`herein meet this and other needs.
`Provided are devices adapted for nasal delivery of a
`pharmaceutical composition to a patient, comprising a thera
`peutically effective amount of an o