`
`US009629965B2
`
`c12) United States Patent
`Crystal et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,629,965 B2
`* Apr. 25, 2017
`
`(54) NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`(71) Applicant: Opiant Pharmaceuticals, Inc., Santa
`Monica, CA (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.
`
`4,987,136 A
`5,866,154 A
`9,192,570 B2
`9,211,253 B2
`9,468,747 B2
`9,480,644 B2
`2003/0077300 Al
`2006/0120967 Al
`2009/0017102 Al
`2010/0113495 Al
`2010/0168147 Al
`2010/0331354 Al
`2011/0046172 Al
`2012/0270895 Al
`2013/0023825 Al
`2016/0008277 Al
`2016/0303041 Al
`
`1/1991 Kreek et al.
`2/ 1999 Bahal et al.
`11/2015 Wyse et al.
`12/2015 Crystal et al.
`10/2016 Crystal et al.
`11/2016 Crystal et al.
`4/2003 Wermeling
`6/2006 Namburi et al.
`1/2009 Stinchcomb et al.
`5/2010 Wermeling et al.
`7/2010 Chapleo et al.
`12/2010 Wermeling
`2/2011 Chapleo et al.
`10/2012 Wermeling
`1/2013 Edwards et al.
`1/2016 Crystal et al.
`10/2016 Keegan et al.
`
`FOREIGN PATENT DOCUMENTS
`
`(21) Appl. No.: 15/335,145
`
`(22) Filed:
`
`Oct. 26, 2016
`
`(65)
`
`Prior Publication Data
`
`US 2017/0043107 Al
`
`Feb. 16, 2017
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 14/942,344, filed on
`Nov. 16, 2015, now Pat. No. 9,480,644, 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)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2017.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61M 31/00
`A61M 5100
`A61F 13/00
`A61K 31156
`A61M 11100
`A61K 9/00
`A61K 311485
`A61K 47102
`A61K 47118
`A61K 9/08
`A61M 15108
`(52) U.S. Cl.
`CPC ......... A61M 111006 (2014.02); A61K 9/0043
`(2013.01); A61K 9/08 (2013.01); A61K 311485
`(2013.01); A61K 47102 (2013.01); A61K 47118
`(2013.01); A61K 471183 (2013.01); A61K
`471186 (2013.01); A61M 15108 (2013.01);
`A61M 31/00 (2013.01)
`( 58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,181,726 A
`4,464,378 A
`
`l/ 1980 Bernstein
`8/ 1984 Hussain
`
`CN
`EP
`WO
`WO
`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 2015136373 A3
`WO 2016007729 Al
`WO 2016007729 A3
`
`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
`9/2015
`1/2016
`1/2016
`
`OTHER PUBLICATIONS
`
`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.
`(Continued)
`
`Primary Examiner -
`Jeffrey T Palenik
`(74) Attorney, Agent, or Firm - Dennis A. Bennett;
`Cynthia Hathaway
`
`(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.
`
`30 Claims, 7 Drawing Sheets
`
`Adapt & Opiant Exhibit 2038
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 1
`
`
`
`US 9,629,965 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Ashton H et al., "Best evidence topic report. Intranasal naloxone in
`suspected opioid overdose," Emerg Med J 23:3, 221-23 (published
`Mar. 2006).
`Bailey A M et al., "Naloxone for opioid overdose prevention:
`pharmacists' role in community-based practice settings," Ann.
`Pharmacother 48:5, 601-06 (published May 2014).
`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).
`Barton E D et al., "Intranasal administration of naloxone by
`paramedics," Prehosp Emerg Care 6: 1, 54-58 (published Jan. 2002).
`Crystal r. et al., Nasal drug products and methods of their use,
`Lightlake Therapeutics, Inc., U.S. Pat. No. 9,211,253, Notice of
`Allowance,Oct. 9, 2015.
`Crystal r. et al., Nasal drug products and methods of their use,
`Lightlake Therapeutics, Inc., U.S. Pat. No. 9,211,253, Notice of
`Allowance,Nov. 9, 2015.
`Crystal r. et al., Nasal drug products and methods of their use,
`Lightlake Therapeutics, Inc., U.S. Pat. No. 9,468,747, Notice of
`Allowance, Apr. 12, 2016.
`Crystal r. et al., Nasal drug products and methods of their use,
`Lightlake Therapeutics, Inc., U.S. Pat. No. 9,468,747, Notice of
`Allowance, Jul. 26, 2016.
`Crystal r. et al., Nasal drug products and methods of their use,
`Lightlake Therapeutics, Inc., U.S. Pat. No. 9,480,644, Examiner
`initiated interview summary, Mar. 31, 2016.
`Crystal r. et al., Nasal drug products and methods of their use,
`Lightlake Therapeutics, Inc., U.S. Pat. No. 9,480,644, Notice of
`Allowance, Mar. 31, 2016.
`Crystal r. et al., Nasal drug products and methods of their use,
`Lightlake Therapeutics, Inc., U.S. Pat. No. 9,480,644, Notice of
`Allowance, Jul. 7, 2016.
`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).
`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).
`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).
`Kelly AM et al., "Intranasal naloxone for life threatening opioid
`toxicity," Emerg Med J 19:4, 375 (published Jul. 2002).
`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).
`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).
`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.
`Loimer Net al., "Nasal administration of naloxone for detection of
`opiate dependence," J Psychiatr Res 26: 1, 39-43 (published Jan.
`1992).
`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).
`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).
`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).
`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).
`
`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).
`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).
`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.
`Teva Pharmaceuticals USA, Inc., "Notice of ANDA No. 209522
`naloxone hydrochloride nasal spray, 4mg/spray, with paragraph IV
`certification concerning U.S. Pat. No. 9,211,253", dated Sep. 13,
`2016.
`Adapt Pharma Operations Limited, et al. v. Teva Pharmaceuticals
`USA, Inc., et al., U.S. District Court for the District of New Jersey.
`Civ. Action No. 2:16-cv-07721 (Nov. 26, 2016); Exhibit A U.S. Pat.
`9,211,253.
`Adapt Pharma Operations Limited, et al. v. TEVA Pharmaceuticals
`USA, Inc., et al., U.S. District Court for the District of New Jersey.
`Civ. Action No. 2: 17-cv-00864 (Feb. 8, 2017); U.S. Pat. 9,468,747.
`Beletsky, L. et al., "Physicians_Knowledge of and Willingness to
`Prescribe Naloxone to Reverse Accidental Opiate Overdose: Chal(cid:173)
`lenges and Opportunities." Journal of Urban Health: Bulletin of the
`New York Academy of Medicine, 84( 1 ): 126-136 (published 2006).
`Corrected Notice Allowance, U.S. Appl. No. 14/659,472, Nov.
`2015, 9 pgs.
`Corrected Notice of Allowance and Fees Due, dated Nov. 9, 2015
`in U.S. Appl. No. 14/659,472, 9 pgs.
`Crystal R. et al., Nasal drug products and methods of their use,
`Lightlake Therapeutics, Inc., U.S. Appl. No. 14/659,472, Notice of
`Allowance, Nov. 9, 2015.
`Crystal R. et al., Nasal drug products and methods of their use,
`Lightlake Therapeutics, Inc., U.S. Appl. No. 14/942,344, Notice of
`Allowance, Mar. 31, 2016.
`Crystal R. et al., Nasal drug products and methods of their use,
`Lightlake Therapeutics, Inc., U.S. Appl. No. 14/950,707, Notice of
`Allowance, Apr. 12, 2016.
`Djupesland; Drug Deliv. and Transl. Res. (2013) 3:42-62.
`International Search Report (ISR), dated Sep. 2, 2015 in Interna(cid:173)
`tional Application No. PCT/IB2015/000941, 4 pgs.
`International Search Report and Written Opinion for Application
`No. IB/2015/000941; Sep. 2, 2015; 11 pages.
`International Search Report and Written Opinion for WO/2015/
`136373; Sep. 2, 2015; 10 pages.
`International Search Report and Written Opinion for WO/2016/
`007729; Dec. 4, 2015; 16 pages.
`Krieter Pet 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. Oct. 2016;56
`(10)1243-1253.
`Kundoor et al.;Effect of formulation- and administration-related
`variables on deposition pattern of nasal spray pumps evaluated
`using a nasal, Pharm. Res. (2011) 28:1895-1904.
`Makidon PE, et al., Characterization of stability and nasal delivery
`systems for immunization with nanoemulsion-based vaccines, J
`Aerosol Med Pulm Drug Deliv. Apr. 2010;23(2):77-89.
`Notice of Allowance, U.S. Appl. No. 14/659,472, Oct. 9, 2015, 9
`pgs.
`TEVA Pharmaceuticals USA, Inc., Notice of ANDA No. 209522
`naloxone hydrochloride nasal spray, 4mg/spray, with paragraph IV
`certification concerning U.S. Pat. No. 9,468,747, dated Dec. 29,
`2016.
`U.S. Appl. No. 15/268,066, filed Sep. 16, 2016, Nasal drug products
`and methods of their use, Keegan F. et al.
`U.S. Appl. No. 15/415,221, filed Jan. 25, 2017, Nasal drug products
`and methods of their use, Keegan F. et al.
`U.S. Appl. No. 15/428,705, filed Feb. 9, 2017 Nasal drug products
`and methods of their use, Keegan F. et al.
`
`Adapt & Opiant Exhibit 2038
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 2
`
`
`
`U.S. Patent
`
`Apr. 25, 2017
`
`Sheet 1 of 7
`
`US 9,629,965 B2
`
`FIG.1
`
`Adapt & Opiant Exhibit 2038
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 3
`
`
`
`U.S. Patent
`
`Apr. 25, 2017
`
`Sheet 2 of 7
`
`US 9,629,965 B2
`
`FIG.2
`
`~0Amgltv1
`
`~2mg!N
`
`0.0
`
`0,0
`
`2.0
`
`4.0
`
`6.0
`8.0
`Time Post Administr;3tion (hr)
`
`10,0
`
`12,0
`
`Adapt & Opiant Exhibit 2038
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 4
`
`
`
`U.S. Patent
`
`Apr. 25, 2017
`
`Sheet 3 of 7
`
`US 9,629,965 B2
`
`FIG.3
`
`3A
`
`_...., 2 x40 mg/ml
`--- 2 x 20 mg/ml
`_..., 1 x 40 mg/ml
`-+- 1 x 20 mg/ml
`-+- 0.4mglM
`
`10
`:::J'
`E
`---0)
`..s 8
`-C 6
`
`C
`0
`:,;::;
`~
`
`~
`C
`0
`(.)
`co
`E 4
`(/) co
`a..
`C 2
`0
`X
`0 m z
`
`(I)
`
`2
`
`4
`
`6
`Hours Postdose
`
`8
`
`10
`
`12
`
`38
`
`10
`
`1
`
`:::?
`E
`---0,
`C
`
`-C
`
`0.1
`
`0
`~
`C:
`~
`C
`0
`(.)
`ro
`E 0.01
`a::
`
`!/)
`(ti
`
`(I)
`C
`~ 0.001
`0
`ro
`z
`0.0001
`
`_,._ 2 x40 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 2038
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 5
`
`
`
`U.S. Patent
`
`Apr. 25, 2017
`
`Sheet 4 of 7
`
`US 9,629,965 B2
`
`FIG.4
`
`10
`
`.'.J"'
`
`E --0)
`C: 8 -C:
`
`0
`:.;::;
`ro ,_
`.....
`C: 6
`(1)
`(.)
`C:
`0
`(.)
`co
`E 4
`(/) ro
`a..
`C: 2
`0
`X
`0
`ro
`z
`
`(1)
`
`4A
`
`_._ 2 x40 mg/ml
`-a- 2 x 20 mg/ml
`_.._ 1 x40 mg/ml
`-+-- 1 x 20 mg/ml
`-+- 0.4 mg IM
`
`~
`
`0
`0.0
`
`0.5
`
`1.0
`
`2.5
`2.0
`1.5
`Hours Postdose
`
`3.0
`
`3.5
`
`4.0
`
`10
`
`....J
`
`----
`E --0)
`C: -C:
`
`0
`:.;::;
`~ 1
`.....
`C:
`Q) u
`C:
`0
`0
`ro
`E
`!f!0.1
`a..
`(1)
`C:
`0
`X
`
`(/)
`
`0 m
`z
`0.01
`0.0
`
`-~- 2 x 40 mg/ml
`-a- 2 x 20 mg/ml
`-.- 1 x40 mg/ml
`-+-- 1 x 20 mg/ml
`-+- 0.4 mg IM
`
`0.5
`
`1.0
`
`1.5
`2.5
`2.0
`Hours Postdose
`
`3.0
`
`3.5
`
`4.0
`
`Adapt & Opiant Exhibit 2038
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 6
`
`
`
`U.S. Patent
`
`Apr. 25, 2017
`
`Sheet 5 of 7
`
`US 9,629,965 B2
`
`--
`-g 1.0 -Cl
`
`......,
`C:
`§ 0.8
`:;::; cu s...
`+-'
`C:
`~ 0.6
`C:
`0 u
`E o.4
`(J) cu
`a..
`~ 0.2
`0
`X
`0
`~ 0.0
`0
`
`-....I 4
`
`E
`-...
`0)
`C
`..._,
`C
`0
`:;::; 3
`co
`....
`.....
`C
`Q) u
`C
`0 2
`0
`co
`E
`co
`a.. 1
`
`(/)
`
`Q)
`C
`0
`X
`0
`
`~o
`0
`
`FIG.5
`
`0.4 mg IM
`
`SA
`
`--- 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 2038
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 7
`
`
`
`U.S. Patent
`
`Apr. 25, 2017
`
`Sheet 6 of 7
`
`US 9,629,965 B2
`
`....I 8
`
`-
`E -0)
`C: -C:
`
`26
`ro ,_
`.....,
`C:
`(I)
`(.)
`C:
`0 4
`0
`ro
`E
`ti) ro
`a.. 2
`(I)
`C:
`
`0 ><
`0
`~o
`0
`
`-...J 8
`-0)
`
`E
`
`C
`"-"
`C
`0 :.:i6
`ro ....
`.....
`C
`(l)
`0
`C
`0 4
`0
`ro
`E
`(/) ro
`0.. 2
`CD
`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 2038
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 8
`
`
`
`U.S. Patent
`
`Apr. 25, 2017
`
`Sheet 7 of 7
`
`US 9,629,965 B2
`
`FIG.7
`
`Two Sprays 40 mg/ml
`
`--- Male
`...... Female
`
`2
`
`4
`
`6
`Hour
`
`8
`
`10
`
`12
`
`..--..
`...J 8
`
`E --0)
`C: -C: 26
`
`co
`....
`.....
`C:
`Q)
`(.)
`C:
`04
`()
`co
`E
`Cl) co
`Cl.. 2
`(])
`c::
`0
`X
`0
`
`~o
`0
`
`Adapt & Opiant Exhibit 2038
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 9
`
`
`
`US 9,629,965 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, now U.S. Pat. No.
`9,480,644, which is a continuation-in-part of U.S. applica(cid:173)
`tion Ser. No. 14/659,472, filed Mar. 16, 2015, now U.S. Pat.
`No. 9,211,253, which claims the benefit of U.S. Provisional
`Application No. 61/953,379, filed Mar. 14, 2014, the dis(cid:173)
`closures of which are hereby incorporated by reference as if
`written herein in their entirety.
`Provided are drug products adapted for nasal delivery
`comprising a pre-primed device and a pharmaceutical com(cid:173)
`position comprising an opioid receptor antagonist, pharma(cid:173)
`ceutical compositions comprising an opioid receptor antago- 15
`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- 20
`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 25
`via µ-opioid receptors and in the medulla via µ- 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 paten- 30
`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, 35
`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 50
`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 65
`methadone (used in the treatment of dependence on other
`opioids such as heroin and also prescribed for pain), but the
`
`2
`increase in the rate of drug overdose over the 16 years of the
`study was driven entirely by overdoses of typical analgesics.
`Over the same time period, methadone overdoses remained
`stable, and overdoses from heroin declined. Whites were
`5 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-
`IO 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(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
`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(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
`naloxone hydrochloride per 0.1 ml of solution adapted for
`nasal administration used in the treatment of narcotic
`40 induced respiratory depression (overdose) at a dosage
`approximately the same as that employed for intravenous
`(IV), intramuscular (IM) or subcutaneous (SQ) administra(cid:173)
`tion. WO 00/62757 teaches pharmaceutical compositions for
`IN or oral (PO) administration which comprise an opioid
`45 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(cid:173)
`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,
`55 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-
`60 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
`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
`
`Adapt & Opiant Exhibit 2038
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 10
`
`
`
`US 9,629,965 B2
`
`3
`subcutaneous naloxone for out-of-hospital management
`a/presumed opioid overdose. Acad Emerg Med. 1998 April;
`5(4):293-9).
`The Denver Health Paramedic system subsequently
`investigated the efficacy and safety of atomized intranasal 5
`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 10
`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). 15
`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 30
`(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 50
`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
`to clinical response for IN versus intravenous IV naloxone
`in patients with suspected narcotic overdose. The protocol 55
`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
`device (MAD™) if suspected narcotic intoxication and
`respiratory depression (rate 8 or less). This dose may be 60
`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)(cid:173)
`Administer 1 mg if unable to administer intranasally (see
`special considerations). May repeat once in 5 minutes. 65
`Intravenous (IV)-Administer 1 mg slow IV push if no
`response to intranasal or IM administration after 10 minutes.
`
`4
`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,
`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.
`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
`20 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
`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
`25 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
`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
`35 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-
`40 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
`45 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
`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(cid:173)
`ments per 100,000 population (adjusted rate ratio 0.73, 95%
`confidence interval 0.57 to 0.91) and community-year strata
`
`Adapt & Opiant Exhibit 2038
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 11
`
`
`
`US 9,629,965 B2
`
`5
`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.
`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 L. A. and Philadelphia. Pro(cid:173)
`grams in both cities target IDUs. Studies which recruited
`150 IDUs across both sites for in-depth qualitative inter(cid:173)
`views 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- 20
`phia, IDUs reported successfully administering naloxone to
`reverse recently witnessed overdoses. Reversals often
`occurred in public places by bo