I 1111111111111111 11111 111111111111111 IIIII IIIII 1111111111111111 IIII IIII IIII
`US009561177B2
`
`c12) United States Patent
`Keegan et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,561,177 B2
`*Feb. 7, 2017
`
`(54) NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`(71) Applicants:Adapt Pharma Limited, Dublin (IE);
`Opiant Pharmaceuticals, Santa
`Monica, CA (US)
`
`(72)
`
`Inventors: Fintan Keegan, Dublin (IE); Robert
`Gerard Bell, Clearwater, FL (US);
`Roger Crystal, Santa Monica, CA
`(US); Michael Brenner Weiss, New
`York, NY (US)
`
`(73) Assignees: ADAPT PHARMA LIMITED, Dublin
`(IE); OPIANT
`PHARMACEUTICALS, 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.: 15/183,441
`
`(22) Filed:
`
`Jun. 15, 2016
`
`(65)
`
`Prior Publication Data
`
`US 2016/0303041 Al
`
`Oct. 20, 2016
`
`(63)
`
`(60)
`
`(51)
`
`(52)
`
`Related U.S. Application Data
`
`Continuation-in-part of application No. 14/950,707,
`filed on Nov. 24, 2015, now Pat. No. 9,468,747,
`which
`is
`a 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.
`
`Provisional application No. 61/953,379, filed on Mar.
`14, 2014, provisional application No. 62/274,536,
`filed on Jan. 4, 2016, provisional application No.
`62/219,955, filed on Sep. 17, 2015.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61M 31/00
`A61M 5100
`A61F 13/00
`A61K 31156
`A61K 9/00
`A61K 9/08
`A61K 311485
`A61K 47102
`A61K 47118
`A61M 15108
`A61M 11100
`U.S. Cl.
`CPC ............... A61K 9/0043 (2013.01); A61K 9/08
`(2013.01); A61K 311485 (2013.01); A61K
`47102 (2013.01); A61K 471183 (2013.01);
`A61K 471186 (2013.01); A61M 111001
`
`(2014.02); A61M 111006 (2014.02); A61M
`111007 (2014.02); 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
`5,866,154 A
`9,192,570 B2
`9,211,253 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
`2015/0174061 Al
`2015/0258019 Al
`2016/0008277 Al
`
`1/1980 Bernstein ...................... 424/260
`8/1984 Hussain ........................ 424/260
`2/1999 Bahal et al.
`.................. 424/423
`11/2015 Wyse et al.
`12/2015 Crystal et al.
`4/2003 Wermeling ................... 424/400
`6/2006 N amburi et al.
`............... 424/45
`1/2009 Stinchcomb et al.
`........ 424/449
`5/2010 Wermeling et al. .......... 514/282
`7/2010 Chapleo et al.
`. ............. 514/282
`12/2010 Wermeling ................... 514/282
`2/2011 Chapleo et al.
`.............. 514/282
`10/2012 Wermeling . .................. 514/282
`1/2013 Edwards et al. .............. 604/143
`6/2015 Wyse et al. .......... A61K 9/0043
`9/2015 Crystal et al. ....... A61K 9/0043
`1/2016 Crystal et al.
`
`FOREIGN PATENT DOCUMENTS
`
`CN
`EP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`1575795
`2/2005
`1681057
`7/2006
`11/1982
`WO 82/03768
`7 /1998
`WO 98/30211
`WO 00/62757
`10/2000
`12/2000
`WO 00/74652
`8/2001
`WO 01/58447
`WO 01/82931
`11/2001
`2/2002
`WO 02/11778
`10/2003
`WO 03/084520
`7/2004
`WO 2004/054511
`3/2005
`WO 2005/020906
`(Continued)
`
`........... A61K 31/485
`........... A61K 31/485
`............. A61K 31/40
`............... A61K 9/72
`............... A61K 9/00
`............... A61K 9/12
`............. A61K 31/44
`. ........... A61M 31/52
`A61L 9/04
`............ A61M 31/00
`
`OTHER PUBLICATIONS
`
`Djupesland; Drug Deliv. and Transl. Res. (2013) 3:42-62.*
`(Continued)
`
`Primary Examiner -
`Jeffrey T Palenik
`(74) Attorney, Agent, or Firm - Harness, Dickey &
`Pierce, P.L.C.
`
`(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
`
`Opiant Exhibit 2190
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`

`

`US 9,561,177 B2
`Page 2
`
`(56)
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`WO 2006/089973
`WO 2007 /083073
`2009/040595
`WO 2012/026963
`WO 2012/156317
`WO 2013/128447
`2014/016653
`WO 2015/095644
`WO 2015/136373
`2016/007729
`
`8/2006
`7/2007
`4/2009
`3/2012
`11/2012
`9/2013
`1/2014
`6/2015
`9/2015
`1/2016
`
`A61K 9/28
`A61M 15/08
`A61K 9/00
`A61M 15/00
`A61K 9/00
`A61M 15/08
`A61K 31/485
`A61K 47/12
`A61K 31/485
`A61K 9/00
`
`OTHER PUBLICATIONS
`
`Kundoor et al.; Pharm. Res. (2011) 28:189501904.*
`Makidon et al.; Journal of Aerosol Medicine and Pulmonary Drug
`Delivery; vol. 23, No. 2 (2010); pp. 77-89.*
`U.S. Patent Documents-None.*
`International Search Report (ISR), dated Sep. 2, 2015 in Interna(cid:173)
`tional Application No. PCT/IB2015/000941, 4 pgs.
`Krieter, P., et al. (2016) "Pharmacokinetic Properties and Human
`Use Characteristics of an FDA-Approved Intranasal Naloxone
`Product for the Treatment of Opioid Overdose." The Journal of
`Clinical Pharmacology, pp. 1-11.
`Aptar UnitDose and BiDose product information sheet, available at
`www.aptar.com/docs/pharmaprescription/uds-bds-datasheet.pdf,
`publication date unknown, last accessed Mar. 26, 2015.
`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., "Intranasal administration of naloxone by
`paramedics." Prehosp. Emerg. Care, 6(1):54-58 (published Jan.
`2002).
`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):265-271 (published Oct. 2005).
`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).
`Doe-Simkins, M. et al., "Saved by the nose: bystander-administered
`intranasal naloxone hydrochloride for opioid overdose." Am. J.
`Public Health, 99(5):788-791 (published May 2009).
`Dowling, J. et al., "Population pharmacokinetics of intravenous,
`intramuscular, and intranasal naloxone in human volunteers." Ther
`Drug Monit, 30( 4):490-496 (published Aug. 2008).
`
`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).
`Kelly, A.M. et al., "Intranasal naloxone for life threatening opioid
`toxicity." Emerg. Med. J., 19(4):375 (published Jul. 2002).
`Kelly, A.M. 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-
`2074 (Epub Nov. 9, 2009).
`Loimer, N. et al., "Nasal administration ofnaloxone for detection of
`opiate dependence." J. Psychiatr. Res., 26( 1 ):39-43 (published Jan.
`1992).
`Loimer, N. et 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).
`Merlin, M.A. 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, D.P. et al., "Opioid harm reduction strategies: focus on
`expanded access
`to
`intranasal naloxone." Pharmacotherapy
`30(7):627-31 (published 2010).
`Wermeling, D.P. et al., "A response to the opioid overdose epidemic:
`naloxone nasal spray." Drug Delivery Transl. Res., 3(1):63-74
`(published Feb. 1, 2013).
`International Search Report (ISR) and Written Opinion (WO), dated
`Aug. 25, 2014 in International Application No. PCT/EP2014/
`064032 (WO 2015/000941) 11 pgs.
`Notice of Allowance and Fees Due, dated Oct. 9, 2015 in U.S. Appl.
`No. 14/659,472, 9 pgs.
`Corrected Notice of Allowance and Fees Due, dated Nov. 9, 2015
`in U.S. Appl. No. 14/659,472, 9 pgs.
`TEVA Pharmaceuticals USA, Inc., "Notice of ANDA No. 209522
`naloxone hydrochloride nasal spray, 4 mg/spray, with paragraph IV
`certification concerning U.S. Pat. No. 9,211,253", dated Sep. 13,
`2016.
`
`* cited by examiner
`
`Opiant Exhibit 2190
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
`
`

`

`U.S. Patent
`
`Feb.7,2017
`
`Sheet 1 of 7
`
`US 9,561,177 B2
`
`«-»$»:«0.4 mg IM
`
`-lt-2 rng IN
`
`Time Post Administration (hr)
`
`FIG.1
`
`Opiant Exhibit 2190
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
`
`

`

`U.S. Patent
`
`Feb.7,2017
`
`Sheet 2 of 7
`
`US 9,561,177 B2
`
`~0.4mg!M
`
`~2mglN
`.,,,,,,.:,,·,,,.4 rng IN
`
`Cl
`C
`0
`X
`~ 0.1
`z
`
`I
`
`·····•,•:,.;..,.,,.,,.,.,,.,,.,.❖:;., •• ,.,,.,,., •• ,.,,.J
`0.0 ·r························,························'.·························1·······················
`······················r·······················,:,:,:,
`5.0
`4.0
`10.0
`12.0
`2.0
`0.0
`8.0
`Time Post Administration (hr}
`
`FIG.2
`
`Opiant Exhibit 2190
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 4
`
`

`

`U.S. Patent
`
`Feb.7,2017
`
`Sheet 3 of 7
`
`US 9,561,177 B2
`
`10
`
`:=I"
`E
`---0)
`5
`C
`0
`'.;::,
`('0 ,_
`+-'
`C a., u
`0 u
`E
`
`C
`
`(ll
`
`Cl)
`('0
`
`0:::
`Q.J
`C
`0
`X
`
`0 ro z
`
`_,,_ 2 x 40 mg/ml
`_.,._ 2 x 20 mg/ml
`-.-.. 1 x40 mg/ml
`-.- 1 x20 mg/ml
`··+-· 0.4 mg IM
`
`2
`
`4
`
`6
`Hours Postdose
`
`8
`
`10
`
`12
`
`FIG.3A
`
`8
`
`4
`
`2
`
`1 O·
`
`:=I"
`E ---0')
`-S
`C
`0
`
`0.1
`
`~ .... c
`~
`C
`0 u
`(ll
`E 0.01
`Cl) rn
`0:::
`Q.J
`C
`~ 0.001
`
`_,,_ 2 x 40 mg/ml
`_.,._ 2 x 20 mg/ml
`-.- 1 x40 mg/ml
`-.- 1 x 20 mg/ml
`0 ro z
`-+- 0.4 mg IM
`0.0001 +--~---.-~--r--~-..--~----.---~--,---~---,
`10
`12
`2
`4
`6
`0
`8
`Hours Postdose
`
`FIG.3B
`
`Opiant Exhibit 2190
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
`
`

`

`U.S. Patent
`
`Feb.7,2017
`
`Sheet 4 of 7
`
`US 9,561,177 B2
`
`10
`::J'
`
`E --0)
`C 8 -C
`
`0
`:.;::::;
`~ .....
`C 6
`(I)
`(.}
`C
`0
`0
`ro
`E 4
`(/) ro
`a..
`(I)
`C 2
`0 >< 0
`rn
`z
`
`_...._ 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
`
`FIG. 4A
`
`10
`::J'
`E
`.._
`0)
`-S
`C:
`0
`
`~ 1
`c
`
`Q)
`(.)
`C:
`0
`0
`(IJ
`E
`"' ~0.1
`a..
`Q)
`C:
`
`0 ><
`0 ro
`z
`0.01
`0.0
`
`--+- 2 x40 mg/ml
`....... 2 x 20 mg/ml
`-.- 1 x 40 mg/ml
`...... 1 x 20 mg/ml
`-+- 0.4 mg IM
`
`0.5
`
`1.0
`
`2.5
`2.0
`1.5
`Hours Postdose
`
`3.0
`
`3.5
`
`4.0
`
`FIG. 4B
`
`Opiant Exhibit 2190
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 6
`
`

`

`U.S. Patent
`
`Feb.7,2017
`
`Sheet 5 of 7
`
`US 9,561,177 B2
`
`--g 1.0 -O>
`C: -§ 0.8
`~ -C:
`
`;;::::;
`
`~ 0.6
`C:
`0
`(.)
`~ 0.4
`(/) ro
`a..
`~ 0.2
`0
`X
`0
`~ 0.0
`0
`
`-_J 4
`C --C
`:;:::; 3 e ... C
`
`E
`.._
`0)
`
`0
`
`Q)
`()
`C
`0 2
`(.)
`m
`E
`(/)
`ro
`a.. 1
`Q)
`C:
`0
`X
`0
`
`~o
`0
`
`0.4 mg IM
`
`....... Male
`-.- Female
`
`2
`
`4
`
`6
`Hour
`
`FIG. SA
`
`8
`
`10
`
`12
`
`One Spray 20 mg/ml
`
`-.-
`.....
`
`Female
`
`Male
`
`2
`
`4
`
`6
`Hour
`
`FIG. 58
`
`8
`
`10
`
`12
`
`Opiant Exhibit 2190
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 7
`
`

`

`U.S. Patent
`
`Feb.7,2017
`
`Sheet 6 of 7
`
`US 9,561,177 B2
`
`--....I 8
`E -C)
`C -C:
`
`0
`:..::; 6
`~ .....
`
`C:
`Q)
`(.)
`C
`
`0 4 u
`ro
`E
`(I) ro
`CL 2
`(I)
`C
`
`0 >< 0
`~o
`0
`
`--....I 8
`E -C)
`C: -C
`
`0
`:..::; 6
`ro I-
`+ '
`C:
`(I)
`(.)
`C
`
`0 4 u
`ro
`E
`(/) ro
`CL 2
`(I)
`C
`
`0 >< 0
`~o
`0
`
`Two Sprays 20 mg/ml
`
`--- Male
`
`-It:- Female
`
`2
`
`4
`
`6
`Hour
`
`FIG. 6A
`
`8
`
`10
`
`12
`
`One Spray 40 mg/ml
`
`--- Male
`_._ Female
`
`2
`
`4
`
`6
`Hour
`
`FIG. 6B
`
`8
`
`10
`
`12
`
`Opiant Exhibit 2190
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 8
`
`

`

`U.S. Patent
`
`Feb.7,2017
`
`Sheet 7 of 7
`
`US 9,561,177 B2
`
`-...J 8
`E -0)
`I... -C
`
`C
`.__,
`C
`
`0 :.P6
`rn
`
`0)
`(.)
`C:
`04
`()
`rn
`E
`Cl) rn
`0... 2
`0)
`C:
`
`0 >< 0
`~o
`0
`
`Two Sprays 40 mg/ml
`
`-+- Male
`__._
`Female
`
`2
`
`4
`
`6
`Hour
`
`FIG. 7
`
`8
`
`10
`
`12
`
`Opiant Exhibit 2190
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 9
`
`

`

`US 9,561,177 B2
`
`1
`NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`2
`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 in recent years has been
`driven mainlyby overdoses of prescription analgesics.
`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
`10 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.
`U.S. Pat. No. 4,464,378 to Hussain reports a method for
`eliciting an analgesic or narcotic antagonist response in a
`warm-blooded animal, which comprises administering intra(cid:173)
`nasally (IN) to said animal to elicit a narcotic antagonist
`response, a narcotic antagonist effective amount of nalox-
`20 one.
`WO 82/03768 to Hussain reports a composition that
`contains 1 mg of naloxone hydrochloride per 0.1 ml of
`solution adapted for nasal administration used in the treat(cid:173)
`ment of narcotic induced respiratory depression (overdose)
`25 at a dosage approximately the same as that employed for
`intravenous (IV), intramuscular (IM) or subcutaneous (SQ)
`administration.
`WO 00/62757 to Davies reports pharmaceutical compo(cid:173)
`sitions for IN or oral (PO) administration which comprise an
`30 opioid antagonist, such as naloxone for application by spray
`in the reversal of opioid depression for treatment of patients
`suffering from opioid over-dosage, wherein the spray appli(cid:173)
`cator is capable of delivering single or multiple doses and
`35 suitable dosage units are in the range of 0.2 to 5 mg.
`The use of nasal naloxone is not without controversy. For
`instance, Dowling et al. (Ther Drug Monit, Vol 30, No 4,
`August 2008) reported that naloxone administered intrana(cid:173)
`sally displays a relative bioavailability of 4% only and
`40 concluded that the IN absorption is rapid but does not
`maintain measurable concentrations for more than an hour.
`U.S. Pat. No. 9,192,570 to Wyse reports naloxone formu(cid:173)
`lations for intranasal administration. Wyse reports ( column
`27, lines 29-37) that benzalkonium chloride is not suitable in
`45 such formulations, because it facilitates unacceptable deg(cid:173)
`radation of the naloxone. Wyse recommends (lines 41-43)
`benzyl alcohol and paraben preservatives in place of ben(cid:173)
`zalkonium chloride.
`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(cid:173)
`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 an alternative medical
`intervention to the patient, and to stabilize the patient until
`professional medical care becomes available.
`
`SUMMARY
`
`This section provides a general s=ary of the disclo(cid:173)
`sure, and is not a comprehensive disclosure of its full scope
`or all of its features.
`This disclosure provides an improved single-use, pre(cid:173)
`primed device adapted for nasal delivery of a pharmaceuti(cid:173)
`cal solution to a patient comprising: at least about 4% (w/v)
`naloxone hydrochloride or a hydrate thereof, wherein the
`
`This application is a continuation-in-part application of
`Ser. No. 14/950,707, filed on Nov. 24, 2015, which is a
`continuation of Ser. No. 14/942,344, filed on Nov. 16, 2015,
`which is a continuation-in-part application of Ser. No.
`14/659,472, filed on Mar. 16, 2015, now U.S. Pat. No.
`9,211,253, which claims benefit of Ser. No. 61/953,379, filed
`on Mar. 14, 2014. This application also claims benefit of Ser.
`No. 62/219,955, filed on 17 Sep. 2015 and Ser. No. 62/274,
`536, filed on 4 Jan. 2016. The entire disclosures of the 15
`applications identified in this paragraph are incorporated
`herein by references.
`
`JOINT RESEARCH AGREEMENT
`
`The subject matter disclosed and claimed herein was
`developed by or on behalf of LightLake Therapeutics Inc.
`and Adapt Pharma Operations Ltd., as parties to a joint
`research agreement, and as a result of activities undertaken
`within the scope of the joint research agreement. The joint
`research agreement was in effect on or before the effective
`filing date of the present claims.
`
`FIELD
`
`This disclosure generally relates to pharmaceutical com(cid:173)
`positions comprising an opioid receptor antagonist, medical
`devices for delivery of the pharmaceutical compositions,
`and methods of using the compositions and the medical
`devices.
`
`BACKGROUND
`
`This section provides background information related to
`the present disclosure which is not necessarily prior art.
`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 µ- and II-opioid 50
`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. Oxycodone and other
`opioid painkillers, as well as heroin and methadone are all 55
`implicated in fatal overdose.
`In the United States, mortality rates closely correlate with
`opioid sales. In 2014, there were 47,055 drug overdose
`deaths in the United States, representing a 6.5% increase
`from 2013 as reported by Rudd et al. (2016) Morbidity & 60
`Mortality Weekly Report 64(50): 1378-82 (starting at page
`10) "Increases in Drug and Opioid Overdose Deaths(cid:173)
`United States, 2000-2014." Over 28,000 of those were
`overdoses of heroin or prescription opioids, which repre(cid:173)
`sents nearly a four-fold increase since 1999. Drugs classed 65
`as prescription opioids include both typical analgesics, such
`as OxyContin® ( oxycodone HCl controlled-release) and
`
`Opiant Exhibit 2190
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 10
`
`

`

`US 9,561,177 B2
`
`3
`improvement comprises that the device is adapted to spray
`a round plume with an ovality ratio less than about 2, for
`example less than about 1.5.
`In another embodiment, there is provided a mist compris(cid:173)
`ing droplets of an at least 4% (w/v) naloxone hydrochloride
`solution, wherein no more than about 10%, for example no
`more than about 5%, of the droplets have a diameter less
`than 10 µm.
`In yet another embodiment, there is provided an improved
`single-use, pre-primed device adapted for nasal delivery of 10
`a pharmaceutical solution to a patient comprising: at least
`about 4% (w/v) naloxone hydrochloride or a hydrate thereof;
`and between about 0.2% and about 1.2% (w/v) of an
`isotonicity agent, wherein the improvement comprises that
`the device is adapted to spray a round plume with an ovality 15
`ratio less than about 2.0.
`In yet another embodiment, there is provided an improved
`single-use, pre-primed device adapted for nasal delivery of
`a pharmaceutical solution to a patient comprising: at least
`about 4% (w/v) naloxone hydrochloride or a hydrate thereof;
`and between about 0.005% and about 0.015% (w/v) of a
`preservative, wherein the improvement comprises that the
`device is adapted to spray a round plume with an ovality
`ratio less than about 2.0.
`
`25
`
`4
`macological effect, as opposed to an "inactive ingredient"
`which would generally be recognized as providing no phar(cid:173)
`maceutical benefit.
`The term "actuation," as used herein, refers to operation
`5 of the device such that the pharmaceutical composition is
`delivered therefrom.
`The term "agonist," as used herein, refers to as used
`herein refers to a moiety that interacts with and activates a
`receptor, and thereby initiates a physiological or pharmaco(cid:173)
`logical response characteristic of that receptor. The term
`"antagonist," as used herein, refers to a moiety that com-
`petitively binds to a receptor at the same site as an agonist
`(for example, the endogenous ligand), but which does not
`activate the intracellular response initiated by the active
`form of the receptor and can thereby inhibit the intracellular
`responses by an agonist or partial agonist. An antagonist
`does not diminish the baseline intracellular response in the
`absence of an agonist or partial agonist. The term "inverse
`agonist" refers to a moiety that binds to the endogenous form
`20 of the receptor or to the constitutively activated form of the
`receptor and which inhibits
`the baseline intracellular
`response initiated by the active form of the receptor below
`the normal base level of activity which is observed in the
`absence of an agonist or partial agonist.
`The term "antimicrobial preservative," as used herein,
`refers to a pharmaceutically acceptable excipient with anti(cid:173)
`microbial properties which is added to a pharmaceutical
`composition to maintain microbiological stability.
`The term "AUC," as used herein, refers to the area under
`30 the drug plasma concentration-time curve. The term "AUC0 _
`,," as used herein, refers to the area under the drug plasma
`concentration-time curve from t=0 to the last measurable
`concentration. The term "AUC0 _=," as used herein, refers to
`the area under the drug plasma concentration-time curve
`35 extrapolated to oo. The term "AUC0 _,w," as used herein,
`refers to the AUC0 _, normalized to 0.4 mg IM naloxone. The
`term "AUCo-=w," as used herein, refers to the AUC0 _=
`normalized to 0.4 mg IM naloxone
`The term "bioavailability (F)," as used herein, refers to
`the fraction of a dose of drug that is absorbed from its site
`of administration and reaches, in an unchanged form, the
`systemic circulation. The term "absolute bioavailability" is
`used when the fraction of absorbed drug is related to its IV
`bioavailability. It may be calculated using the following
`formula:
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the mean (±SD) naloxone plasma concen(cid:173)
`tration following administration of 0.4 mg intramuscular
`(IM), 2 mg intranasal (IN), and 4 mg IN in 14 human
`subjects.
`FIG. 2 shows the mean (±SD) naloxone plasma concen(cid:173)
`tration with logarithmic transformation following adminis(cid:173)
`tration of 0.4 mg intramuscular (IM), 2 mg intranasal (IN),
`and 4 mg IN in 14 human subjects.
`FIG. 3 shows the mean naloxone plasma concentration
`following single intranasal administrations (FIG. 3A) and
`intramuscular injections (FIG. 3B) of naloxone to healthy
`subjects (N=28) over a twelve-hour period.
`FIG. 4 shows the mean naloxone plasma concentration 40
`following single intranasal administrations (FIG. 4A) and
`intramuscular injections (FIG. 4B) of naloxone to healthy
`subjects (N=28) over a four-hour period.
`FIG. 5 shows the mean naloxone plasma concentration
`following intramuscular injection of 0.4 mg naloxone (FIG. 45
`SA, top) and one spray of20 mg/mL (i.e., 2% w/v) naloxone
`(FIG. 5B, bottom) to healthy male (N=16) and female
`(N=12) subjects over a twelve-hour period.
`FIG. 6 shows the mean naloxone plasma concentration
`following two sprays of 20 mg/mL (i.e., 2% w/v, FIG. 6A, 50
`top) and one spray of 40 mg/mL (i.e., 4% w/v, FIG. 6B,
`bottom) to healthy male (N=16) and female (N=12) subjects
`over a twelve-hour period.
`FIG. 7 shows the mean naloxone plasma concentration
`following two sprays of 40 mg/mL (i.e., 4% w/v) to healthy 55
`male (N=16) and female (N=12) subjects over a twelve-hour
`period.
`
`F=-A_U_C_a_~_~_"_"~-'x_D_o_se_;n_,m_w_no_~_
`A ucintravenous
`Doseextravascular
`
`The term relative bioavailability (F rez) is used to compare
`two different extravascular routes of drug administration and
`it may be calculated using the following formula:
`
`A UCextravascular 1
`Fret = A UCextravascular2 X Doseextravascular 1
`
`Doseextravascular2
`
`DETAILED DESCRIPTION
`
`Definition
`For clarity and consistency, the following definitions will
`be used throughout this patent document.
`The term "active ingredient" or "pharmaceutically active
`compound" is defined in the context of a "pharmaceutical
`composition" and is intended to mean a component of a
`pharmaceutical composition that provides the primary phar-
`
`60
`
`The term "clearance (CL)," as used herein, refers to the
`rate at which a drug is eliminated divided by its plasma
`concentration, giving a volume of plasma from which drug
`is completely removed per unit of time. CL is equal to the
`elimination rate constant (!,) multiplied by the volume of
`65 distribution (V d), wherein "VJ' is the fluid volume that
`would be required to contain the amount of drug present in
`the body at the same concentration as in the plasma. The
`
`Opiant Exhibit 2190
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 11
`
`

`

`US 9,561,177 B2
`
`6
`an embodiment wherein the amount of naloxone hydrochlo(cid:173)
`ride is specified to be 4 mg is not mutually exclusive with an
`embodiment in which less than about 10% of said pharma(cid:173)
`ceutical composition leaves the nasal cavity via drainage
`into the nasopharynx or externally.
`The term "naloxone," as used herein, refers to a com(cid:173)
`pound of the following structure:
`
`5
`
`5
`term "apparent clearance (CL/F)," as used herein, refers to
`clearance that does not take into account the bioavailability
`of the drug. It is the ratio of the dose over the AUC.
`The term "Cmax," as used herein, refers to the maximum
`observed plasma concentration. The term "Cmaxw," as used
`herein, refers to Cmax normalized to 0.4 mg IM naloxone.
`The term "coefficient of variation (CV)," as used herein,
`refers to the ratio of the sample standard deviation to the
`sample mean. It is often expressed as a percentage.
`The term "confidence interval," as used herein, refers to 10
`a range of values which will include the true average value
`of a parameter a specified percentage of the time.
`The term "device," as used herein, refers to an apparatus
`capable of delivering a drug to patient in need thereof.
`The term "delivery time," as used herein, refers to the 15
`amount of time that elapses between a determination made
`by a healthcare professional, or an untrained individual that
`an individual is in need of nasal delivery of an opioid
`antagonist and completion of the delivery.
`The term "elimination rate constant (!,)," as used herein, 20
`refers to the fractional rate of drug removal from the body.
`This rate is constant in first-order kinetics and is independent
`of drug concentration in the body. Ais the slope of the plasma
`concentration-time line (on a logarithmic y scale). The term
`, " as used herein, refers to the terminal phase elimination 25
`"A2
`rate constant, wherein the "terminal phase" of the drug
`plasma concentration-time curve is a straight line when
`plotted on a semilogarithmic graph. The terminal phase is
`often called the "elimination phase" because the primary
`mechanism for decreasing drug concentration during the 30
`terminal phase is drug elimination from the body. The
`distinguishing characteristic of the terminal elimination
`phase is that the relative proportion of drug in the plasma
`and peripheral volumes of distribution remains constant.
`During this "terminal phase" drug returns from the rapid and 35
`slow distribution volumes to the plasma, and is permanently
`removed from the plasma by metabolism or renal excretion.
`The term "equivalent," as used herein refers to a weight
`of an opioid antagonist selected from naloxone and phar(cid:173)
`maceutically acceptable salts thereof that is equimolar to a 40
`specified weight of naloxone hydrochloride. For example, 8
`mg of anhydrous naloxone hydrochloride (molecular
`weight, 363.84) is equivalent to about 7.2 mg of naloxone
`freebase (molecular weight, 327.37), and to about 8.8 mg of
`naloxone hydrochloride dihydrate
`(molecular weight 45
`399.87).
`The term "filled," as used herein, refers to an association
`between a device and a pharmaceutical composition, for
`example, when a pharmaceutical composition described
`herein comprising a therapeutically effective amount of an 50
`opioid antagonist is present within a reservoir that forms a
`part of a device described herein.
`The term "hydrate," as used herein, refers to an opioid
`antagonist described herein or a salt thereof that further
`includes a stoichiometric or non-stoichiometric amount of 55
`water bound by non-covalent intermolecular forces.
`The term "in need of treatment" and the term "in need
`thereof' when referring to treatment are used interchange(cid:173)
`ably and refer to a judgment made by a caregiver ( e.g.
`physician, nurse, nurse practitioner) that a patient will 60
`benefit from treatment.
`As used herein, two embodiments are "mutually exclu(cid:173)
`sive" when one is defined to be something which is different
`than the other. For example, an embodiment wherein the
`amount of naloxone hydrochloride is specified to be 4 mg is
`mutually exclusive with an embodiment wherein the amount
`of naloxone hydrochloride is specified to be 2 mg. However,
`
`or a pharmaceutically acceptable salt, hydrate, or solvate
`thereof. The CAS registry number for naloxone is 465-65-6.
`Other names for naloxone include: 17-allyl-4,5a-epoxy-3,
`14-dihydroxymorphinan-6-one; ( - )-17 -ally l-4,5a-epoxy-3,
`4, 5a-epoxy-3, 14-dihy(cid:173)
`14-dihydroxymorphinan-6-one;
`droxy- l 7 -(2-propeny l)morphinan-6-one; and ( - )-12-allyl-7,
`7a,8,9-tetrahydro-3,7a-dihydroxy-4aH-8,9c(cid:173)
`iminoethanophenanthro[ 4,5-bcd] furan-5 ( 6H)-one.
`Naloxone hydrochloride may be anhydrous (CAS Reg. No.
`357-08-4) and also forms a dihydrate (CAS No. 51481-60-
`8). It has been sold under various brand names including
`Narcan®, Nalone®, Nalossone®, Naloxona®, Naloxo(cid:173)
`num®, Narcanti®, and Narcon®.
`The term "nostril," as used herein, is synonymous with
`"naris."
`The term "opioid antagonist" includes, in addition to
`naloxone and pharmaceutically acceptable salts thereof:
`naltrexone, methylnaltrexone, and nalmefene, and pharma(cid:173)
`ceutically acceptable salt