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`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`
`
`October 25, 2018
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`
`
`THE RECORDS OF THIS OFFICE OF:
`
`
`
`U.S. PATENT: 9,561,177
`ISSUE DATE: February 07, 2017
`
`
`
`
`
`
`
`
`
`
`By Authority ofthe
`Under Secretary of Commerce for Intellectual Property
`
`and Director of the United States Patent and Trademark Office
`
`P. R. GRANT
`
`Certifying Officer
`
`
`
`Nalox1001
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 1 0f 43
`
`

`

`USOO9561177BQ
`
`021 United States Patent
`(10) Patent N0.:
`US 9,561,177 132
`Keegan et a1.
`(45) Date of Patent:
`*Feb. 7, 2017
`
`
`(54) NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`(2014.02); A0111: 11m0(2014.02);A61M
`111/00? (2014.02); A6111! 115208 (2013.01);
`
`;
`
`,
`,
`,
`11.51.1131
`None
`(58) Field of Classification Search
`_
`_
`See applicalion file for complete search history.
`
`(2013.01)
`
`(11)
`
`('12)
`
`(IE)
`
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`Ad
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`Opium Pharmaceuticals, Santa
`M
`. CA US
`onion
`(
`)
`Inventors: Fintan Keegan, Dublin (114:): Robert
`Gerard Bell, Clearwuter, FL (US);
`Roger Crystal. Santa Monica, CA
`(US); Michael Brenner Welss, New
`York, NY (US)
`
`‘
`
`y
`.
`) Notice.
`
`(
`
`(l3) 05513an: ADAPT PHARMA LIMITED» Duh‘ifl
`(IE); OPIANT
`PHARMACEUTICALS, Santa
`Monica. CA (Us)
`.‘
`.
`‘
`.
`.
`Subject to any dlSLlallTlEr. the term oflhu.
`PM?“t is eflended or adjusted under 35
`U S‘C- 154(b) by U darS-
`-
`1
`.
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`32:11:01 ’3 “he“ to a lemma] d'S
`I
`
`_
`(2” Appl' No" 156133341
`:.
`.
`(22) 1"“
`Jun.15,2016
`(65)
`Prior Publlcatlon Data
`US 201610303041 A1
`Oct. 20. 2016
`
`Related 0s. Application Data
`(63) Continuation-impart of application No. 141950.107,
`filed on Nov. 24, 2015, now Pat. No. 9,468,147,
`which
`is
`a
`continuation of application No.
`141942,:544, filed 0]] NOV. 16, 2015, now P211. No.
`9.480644, which is
`a
`continuation-in-pan of
`application No. 1416595172, filed on Mar. 16, 2015,
`now pm‘ No, 9311253.
`
`(56)
`
`CN
`EP
`3
`wo
`$8
`we
`we
`Wu
`“:0
`\M’)
`
`References Cited
`[15‘ PA'I‘ENT DOCUMENTS
`.. 4241260
`4,131,726 A
`111930 Bernstein
`4.464.378 A
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`4241250
`
`211999 Rahal ct a].
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`11.52015 Wye: et 31.
`9.192.510 BE
`9.211.253 82
`1212015 Crystal a a1.
`200330077300 A1
`412003 Wenneling ........
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`5141282
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`2.12011 Chaplet: el at.
`51412112
`201210270595 11]
`10.-"2012 Wamling
`514E282
`201330023825 AI
`lr'2013 Edwalds el :1].
`604-"143
`201510174001 Al
`012015 Wyse et a].
`1511: 910043
`201530258019 AI
`912015 Crystal etal.
`A61K‘)-"0043
`2010-0000211 A1
`112016 Crystal at 31.
`FOREIGN PATENT LitDCUMIjNTS
`
`_
`1575795
`.. A61K 311485
`2.2005
`1681057
`112006
`A61K 313485
`
`
`fig 3333:5113
`. {$111333
`11-3133;
`
`010 00-0255?
`I: AélK 9.100
`1012000
`$3 gwg‘éfig
`159330
`A5115 9:13
`
`W0 01182931
`1130511111002:
`”gm;
`“1002;111:753
`2;sz
`A611.91'04
`
`“10031004520
`.. A0110 31100
`1012003
`“:0 20041054311
`112004
`“O 2005-0209013
`3.12005
`(Continued)
`
`
`
`O'l'l-IER PUBLlCAIlONS
`_
`_
`1
`.
`lbupesland; Drug Dellv. and Trans]. Res. (20b) 3:42-62.
`(Continued)
`
`*
`
`Primary Examiner — Jeffrey T Palcnik
`(7'4) Attorney, Agem‘, or Firm - Harness. Dickey 35
`Pierce P.l..C.
`‘
`'
`
`(5?)
`
`ABSTRACT
`
`Dmg products adapted for nasal delivery, comprising a
`pro-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 chug products are also provided.
`
`30 Claims, '1" Drawing Shcels
`
`i
`
`l
`l
`I
`1
`'
`
`.
`_
`!
`
`I
`i
`
`,
`
`(60)
`
`(5')
`
`Provisional application No. 611953079, filed on Mar.
`14. 2014, provisional application No.
`(121214536,
`filed on Jan. 4, 2016, provisional application No.
`521219-351 filed 011 Sep. 17' 2015
`1.
`.
`[n C[
`A611M31/00
`Adl‘M 5/00
`A61”? 13600
`A613 31/56
`A6111" 11/00
`AISLE 9/193
`AMK 31/435
`A61K47/02
`216114738
`AGIM 15/08
`A6”! 11/00
`(52) 0.5. CI.
`(.‘PC
`
`(2006.01)
`(2006.01)
`(2006-01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(200601)
`(2005.01)
`
`A61K 9213043 (2013.01); A61K 9/03
`(2013.01); AME 31/485 (2013.01); AMT
`472192 (2013.01); A61K 47/183 (2013.01);
`A61K 47/136 (2013.01); A61.” 11/001
`
`Copy provided by USPTO from the PIRS Image Database on 10-23—2013
`
`NaloxlOOl
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 2 of 43
`
`

`

`US 9,561,177 B2
`Page 2
`
`(56}
`
`References Cited
`
`FOREIGN PATENT lmUMEN'l'S
`
`W0 W0 20065059973
`8i'2t106
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`132007
`WO
`2009340595
`4.32009
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`3-"2012
`W0
`WO 2012056317
`ll-"20l2
`“50 W0 2013-12844?
`9320”
`W0
`2014r’016653
`132014
`“(0 W0 20153095644
`6-“20I5
`W0 W0 20153136373
`92015
`WU
`20]6-’DDT?29
`1.20m
`
`.o’tolK 9&8
`. AfiiM 15:08
`AfilK 9’00
`
`. A6134 lSI'OO
`.. NSIK 9.500
`
`. ASIM 15:03
`AélK 313485
`
`.. AGIK 4?.” 2
`AGIK 313485
`
`....... AolK W00
`
`OTHER PUBLICATIONS
`
`Kundoor ct ah, Pharm. Res. (201 I) ZflzlSQSUIEKH.‘
`Makidoo et at; Journal of Aerosol Medicine and Pulmonary Drug
`Dalivery; vol. 23. No. 2 (2010); pp. T7-89.‘
`US. Patent Documents None.‘
`International Search Report {13R}, dated Sep. 2, 2015 in Interna-
`tional Application No. PCl'IlBEiIllS-“méll. 4 pgs.
`Krieter. R, at a]. (2016) “Pharn'laraokineiic Properties and Human
`[Ise 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.c0m-"docsiphannaprcscriptioniuds-brLs-datasheetpdfi
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`Ashton. H.. et al.. “Best evidence topic report. Lntranasal ualortone
`in suspected Opioid overdose“, Emerg. Med.
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`Barton. ED. et at. "lntranasal administration of naloxone by
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`limerg. Care. 6(1);54-58 [published Jan.
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`alternative for treatment of opioid overdose in the prehospita]
`setting.“ J. Emerg. Med, 29(3):265v2‘l‘l (published Oct. 2005).
`Beletsky, L. el 11., “Physicians Knowledge of and Willingness to
`Prescribe Naloxone to Reverse Accidental Opiate Overdose: Chal-
`lenges and Opportunities." Journal of Urban Health: Bulletin of Lhe
`New York Academy of Medicine. 8401126436 (published 200(1).
`Doe-Sunkin 5. Ni. et ai.. “Saved by the nose: bystander-administered
`iJltianasal naloxone hydrochloride for opioid overdose.” Am. J.
`Public Health. 99(5):?88-791 (published May 2009].
`Bowling. J. et 3.1.. “Population pliannacokinetics of intravenous.
`intramuscular, and intranasal naloxone in human volunteers." Ther
`Drug Monit. 30(4):49IJ-496 (published Aug. SOUR).
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`Heard. C. et 31.. "inuanasal fiumazenil and naloxone to reverse
`Over-sedation in a child undergoing dental restorations." Pact‘liafl‘.
`Anaesth, 19(3):?9539 (published Aug. 2009).
`Kelly. A M at at. "lntrmsal naloxone for life threatening opioid
`toxicity." Emerg. Med. J.. 19(4):3?5 (published Jul. 2002).
`Kelly. AM. et al.. "Randomised trial of intranasal versus intramus—
`cular naloxone in prehospital treatment for suspected opioid over-
`dose." Med. J. Aug. 182“}:24-27 (published Jan. 3. 2005}.
`Kerr. D. ei at, "Randomimd controlled trial comparing the efl'ec-
`tiveness and safety of intranasal and intramuscular naloxone for Ihe
`treatment of suspected heroin overdose." Addiction l04(12):206?-
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`Loirner. N. et al.. “Nasal administration oinaloxone for detection of
`opiate dependence." J. Psychiatr. Res. firth-3943 (published Jan.
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`Loimer, N. et al.. "Nasal administration of naloxone is as eflective
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`Treat. 44(2)::24147 (Epub Sep. 12. 2012).
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`overdose education and nasal naloxoni: distribution in Massachu-
`selts: intenupted tint series analysis." HMJ 346:fl74. (Published
`Jan. 31. 2013).
`Waber. J. M. et at. "Can nebulized naloxone be used safely and
`effectively by emergency medical services for suspected opioid
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`nalcxune.
`rum'rriaunuordpy
`expanded access
`to intranasal
`30(T):627-3I (published 2010).
`Wen'neling, DP. e1 .11., "A response to the opioid overdose epidemic:
`naloxone nasal spray." Drug Delivery Transl. Res. 3(1]:63—74
`(published Feb.
`I. 20w).
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`Aug. 25, 2014 in International Application No. PCT-£1320”:
`064032 (Wt) sols-000941) [1 pgs.
`Notice ofAJIowanco and Fees Due, danxl Oct. 9. 2015 in L15. Appl.
`No. ӣ659.43. 9 pgs-
`Corrected Notice oI‘Allowance and Fees Due. dated Nov. 9. 2015
`in US. Appl. No. [rt-”659.472. 9 pgs.
`TE'v'fii Pharmaceuticals USA. inn. ”Notice of ANEA No. 209522
`naloxone hydrochloride nasal spray. 4 mg-"spmy, with paragraph W
`certification concerning US. Pat. No. 9.211.253". dated Sep. 13.
`2016.
`
`* cited by examiner
`
`
`
`Copy provided by USPTO From the PlRS image Database On 10-23-2015
`
`NaloxlOOl
`
`Nalox-l Pharmaceuticals, LLC
`
`Page 3 01°43
`
`

`

`_._._.___...--—---—-—--—--————.—._-___.._
`
`
`US Patent
`
`Feb. 7, 2017
`
`Sheet 1 of 7
`
`US 9,561,177 B2
`
`7‘0 -
`
`6.0
`
`a 5.0 n
`
`W04 mg IM
`
`W2 mg IN
`
`Wfiafifi mg EN
`
`2-: 4‘0
`I?
`g 30
`53
`2 2‘0
`
`
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`
`00
`
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`g E
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`
`E
`
`Copy provided by USPTO film] the PIRS Image Database on l0-23-20l3
`
`Nalox'lOO'l
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`Page 4 of 43
`
`

`

`U.S. Patent
`
`Feb. 7, 2017
`
`Sheet 2 of?
`
`US 9,561,177 B2
`
`3: 5%:
`
`
`
`.
`"'o -
`%%d*.m ;
`0.6 euflfl,ewweflewwewfi
`0.0
`2.0
`4.0
`6.0
`8.0
`10.0
`3.2.0
`
`Time Post adminmratian (hr)
`
`E
`
`FIG. 2
`
`
`
`Copy provided by USPTO from [he PIRS Image Database on 10-23-2018
`
`Nalox'lOOl
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`Page 5 of 43
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`

`

`
`
`US. Patent
`
`Feb. 7, 2017
`
`Sheet 3 of 7
`
`US 9,561,177 132
`
`I
`
`.5 D
`
`
`
`NabxonePlasmaConcentration(nglmL)
`
`
`
`
`
`.1
`
`m
`
`‘3’“
`
`fl
`
`\
`
`"H“:-'1’
`
`
`
`
`4- 2 x 40 mgfrnL
`+ 2 x 20 mgme
`+ 1 x 40 mgImL
`+ 1 x 20 mglmL
`+ 0.4 mg EM
`
`Hours Postdose
`
`FIG. 3A
`
`)
`
`10-
`
`
`
`
`+ 2 x40 mgme
`+ 2 x 20 mglmL
`““
`
`
`
`NaloxonePlasmaConcentration(:19me
`
`
`
`
`
`0.1 '
`
`0.01
`
`
`
`
`
`.._.._._..—_—...._...___.—nm.._=—.-—.~_.
`
`\,
`
`+ 1 x 40 mm.
`
`+ 1 x 20 mgi'ml.
`4- 0.4 mg IM
`
`
`
`
`D
`
`2
`
`4
`
`6
`Hours Posidose
`
`8
`
`10
`
`12
`
`FIG. 38
`
`Copy provided by [JSPTO from the P] RS Image Database on 10-23-2018
`
`Naloxl 001
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`Page 6 of 43
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`

`

`US. Patent
`
`Feb. 7, 2017
`
`Sheet 4 of 7
`
`US 9,561,177 32
`
`10-!
`
`81
`
`6~
`
`+ 2 x40 mglmL
`
`+ 2 x 20 ngmL
`+ 1x 40 mgimL
`+ 1 x20 mgrmL
`+ 0.4 mg IM
`
`
`
`
`0.0
`
`0.5
`
`1.0
`
`2.5
`2.0
`1.5
`Hours Postdose
`
`3.0
`
`3.5
`
`4.0
`
`FIG. 4A
`
`';
`i
`
`103
`i-
`
`“x
`
`
`
`NalaxonePlasmaConcentration(ngme)
`
`
`
`
`
`in“
`;
`
`r:
`
`
`
`
`:9: HI \ \
`o X H
`E:
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`
`1
`
`+ 2 x 40 mgfrnL
`~— 2 x 20 mgme
`+ 1 x40 mgimL
`+ 1 x 20 mgfrnL
`+ 0.4 mg {M
`
`0011"”— r——-.—.v—.._.__W m_,_‘
`0.
`0.5
`1.0
`1.5
`2.0
`2.5
`3.0
`Hours Postdose
`
`_,_|_'_fi_r___‘
`3.5
`4.0
`
`FIG. 43
`
`Copy provided by USPTO from the PIRS Image Database on 10-23—2018
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`Naloxl 001
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`Page 7 of 43
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`

`

`US. Patent
`
`Feb. 7,2017
`
`Sheet 5 of?
`
`US 9,561,177 B2
`
`0.4 mg EM
`
`+ Male
`+ Femate
`
`{$1.0
`“6:
`
`5 5
`
`0.8
`
`%1:.C.‘
`8 0.6
`I:
`o
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`
`0.2
`
`0.0
`
`E 4
`‘2"
`
`O
`
`2
`
`4
`
`6
`Hour
`FIG. 5A
`
`8
`
`10
`
`12
`
`One Spray 20 mgme
`
`.
`.§
`ll!
`:[
`-F
`9
`l
`
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`
`o E
`
`» g
`
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`
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`
`2
`
`1
`
`1— Female
`4- Male
`
`a:
`E
`0-
`{I}
`f:
`
`2
`
`4
`
`6
`Hour
`
`FIG. SB
`
`8
`
`10
`
`12
`
`o
`
`0
`
`S2 2
`
`Copy provided by USP’I'O from [he PIRS Image Database on 10-23-2018
`
`NaloxlOOl
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`Page 8 of 43
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`

`

`“——""I
`
`US. Patent
`
`Feb. 7, 2017
`
`Sheet 6 of 7
`
`US 9,561,177 B2
`
`Two Sprays 20 mgImL
`
`
`
`
`NatoxonePiasmaConcentration(nglmL)
`
`
`
`NaloxonePtasmaConcentration(ngme)
`
`I
`
`O:
`
`Hour
`
`FIG. 6A
`
`One Spray 40 mgimL
`
`Copy provided by USP'I'O from the PIRS Image Database on 10—23—2013
`
`NaloxlOOl
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`Page 9 of 43
`
`

`

`US. Patent
`
`Feb. 7, 2017
`
`Sheet 7 of 7
`
`US 9,561,177 32
`
`no
`
`Two Sprays 40 mglmL
`
`0')
`
`
`
`
`
`
`
`NaloxonePlasmaConcentration(nglmL)m4:
`
` ._-.\J':H_fi——'WF‘—"flfl'-
`
`
`
`
`
`Copy provided by USPTU from the PIRS Image Database on 10-23-2018
`
`NaloxlOOl
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`Page 10 0f 43
`
`

`

`US 9,561,]?? BZ
`
`l
`NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`CROSS-[{El-l-ZRIZNCE TO RELAI‘EI)
`APPLICATIONS
`
`This application is a continuation—impart application of
`Ser. No. 143950301 filed on Nov. 24, 2015. which is a
`continuation of Ser. No. 14842344, filed on Nov. 16, 2015.
`which is a continuation-in-part application of Ser. No.
`14f659,4i'2. filed on Mar. 16, 2015, now US. Pat. No.
`9,211,253, which claims benefit of Ser. No. 61l953,3?9, filed
`on Mar. 14, 20] 4. This application also claims benefit ol'Ser.
`No. 62r‘2]9,955._ filed on I? Sep. 2015 and Ser. No. 62r’2'r’4,
`536, filed on 4 Jan. 20l6. The entire disclosures of the
`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 LightLaltc Therapeutics Inc.
`and Adapt l’harma 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.
`I’IEI D
`
`This disclosure generally relates to pharmaceutical com-
`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 an.
`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 tin-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 u- and b-opioid
`receptors. While there are a number of neurotransmitters
`mediating the control of respiration, glutamate and "Ir-amin-
`obntyric acid (GABA) are the major cxcitatory and inhibi-
`tory neurotransmitters. respectively. Oxycodone and other
`opioid painkillers, as well as herein and methadone are all
`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 20l3 as reported by Rudd et a]. (20W) Morbidity at:
`Mortality Weekfv Report 54(50):]3i‘R—82 [starting at page
`10} “Increases in Drug and Opioid Overdose Deaths—
`United States, 2000—2014." Over 23,000 of those were
`overdoses of herein or prescription opioids, which repre-
`sents nearly a four—fold increase since 1999. Drugs classed
`as prescription opioids include both typical analgesics, such
`as OxyC‘ontin® (oxycodone HCl controlled-release) and
`
`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.
`Nalo xone is an opioid receptor antagonist that is approved
`for use by injection for the reversal of opioid overdose and
`for adinnct 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.
`US. Pat. No. 4,464,378 to Hussein reports a method for
`eliciting an analgesic or narcotic antagonist response in a
`warm-bIooded animal, which comprises administering intra-
`nasally (IN) to said animal to elicit a narcotic antagonist
`response, a narcotic antagonist clToctive amount of mint-
`one.
`
`W0 82l03’r‘68 to Hussein reports a composition that
`contains 1 mg of naloxone hydrochloride per 0.1 ml of
`solution adapted for nasal administration used in the treat-
`ment of narcotic induced respiratory depression (overdose)
`at a dosage approxir'nately the same as that employed for
`intravenous (IV). intramuscular (IM) or subcutaneous (SQ)
`administration.
`W0 WSZTST to Davies reports pharmaceutical compo-
`sitions 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
`suffering fi'om opioid over-dosage, wherein the spray appli-
`cator 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, Dowling et al. (Ther Drug Monit, Vol 30, No 4,
`August 2008) reported that naloxone administered intrans-
`sally 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.
`US. Pat. No. 9,192,570 to Wyse reports naloxonc formu-
`lations for intranasal administration. Wyse reports (column
`2?. lines 29-3?) that benzalkonium chloride is not suitable in
`such formulations, because it facilitates unacceptable deg—
`radation of the rialoxone. Wysc recommends (lines 41-43)
`benzyl alcohol and paraben preservatives in place of hen-
`zaikonium 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—
`tically effective dose of a rapid—acting opioid antagonist to
`an opioid overdose patient. The therapeutically efiecdve
`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- bcrcorncs available.
`
`SUMMARY
`
`This section provides a general summary of the disclo-
`sure, and is not a comprehensive disclosure of its full scope
`or all of its features.
`This disclosure provides an improved single-use. pre—
`primcd device adapted for nasal delivery of a pharmaceuti-
`cal solution to a patient comprising: at least about 4% (wlv)
`naloxone hydrochloride or a hydrate thereof, wherein the
`
`[0
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`Copy provided by USPTO from the PIRS image Database on ltl-23-20 l E
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`....._._._._.-_-_--._-ML_.._..-
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`Naloxl 001
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`Nalox-l Pharmaceuticals, LLC
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`US 9,561,177 B2
`
`3
`improvement comprises that the device is adapted to spray
`a round plume with an ovalin ratio less than about 2. for
`example less than about 1.5.
`In anoLher embodiment, there is provided a mist compris—
`ing droplets of an at least 4% (wlv) naloxone hydroeltloride
`solution, wherein no more than about 10%, for example no
`more than about 5%, of the droplets have a diameter less
`than 10 pm.
`In yet another embodiment, there is provided an improved
`single—use, poo—primed device adapted for nasal delivery of
`a pharmaceutical solution to a patient comprising: at least
`about 4% (wlv) naloxone hydrochloride or a hydrate thereof;
`and between about 0.2% and about 1.2% (wily) of an
`isotoniciry agent, wherein the improvement comprises that
`the device is adapted to spray a round plume with an ovality
`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% (wtv) naloitone hydrochloride or a hydrate thereof:
`and between about 0.005% and about 0.0l5% (wlv) 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.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the mean (:SD) naioxone plasma concen—
`tration following administration of 0.4 mg intramuscular
`(1M), 2 mg inuanasal (IN). and 4 mg IN in 14 human
`subjects.
`FIG. 2 shows the mean (:SD) naloxone plasma concen-
`tration with logarithmic transformation following adminis-
`tration of 0.4 mg intramuscular (TM). 2 mg intranasal (I N).
`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. SB) of naloxone to healthy
`subjects (N=28] over a twelve—hour period.
`FIG. 4 shows the mean naloxone plasma concentration
`following single intranasal administrations (FIG. 4A) and
`intramuscular injections (FIG. 43} of naloxone to healthy
`subjects (N=28) over a four-hour period.
`FIG. 5 shows the mean naloxonc plasma conccnu'auicn
`following intramuscular injection of 0.4 mg naloxone (FIG.
`5A, top) and one spray of 20 mgt'mL 0.3.. 2% wfv) naloxone
`(FIG. SB. bottom) to healthy male (N=lt§) and female
`(N=12) subjects over a twelve-hour period.
`FIG. 6 shows the mean nalcxonc plasma concentration
`following two sprays of 20 mgme (i.e.._ 2% wtv, FIG. 6A,
`top) and one spray of 40 inglml. (i.e., 4% wt'v, FIG. 63,
`bottom) to healthy male (N=l a) and female (N= 1 2) subjects
`over a twelve-hour period.
`FlG. 7 shows the mean naloxone plasma concentration
`following two sprays of40 mgme Ge, 4% wfv) to healthy
`male {N=l 6) and female (N 12) subjects overa twelve—hour
`period.
`
`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-
`
`10
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`IS
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`20
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`4a
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`50
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`4
`macological effect, as Opposed to an “inactive ingredient"
`which would generally be recognized as providing no phar-
`mawutical benefit.
`The term “actuation.“ as used herein. refers to operation
`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—
`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 panial agonist. The term “inverse
`agonist” refers to a moiety that binds to the endogenous fonn
`of the receptor or to the constitutively activated form ofthe
`receptor and which inhibits
`the baseline intracellular
`response initiated by the active form ofthe 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 phannaceutically acceptable excipient with anti-
`microbial pmperlies which is added to a pharmaceutical
`composition to maintain microbiological stability.
`The term “AUC,” as used herein, refers to the area under
`the drug plasma concentration—time curve. The term “AUG”,
`1." as used herein. refers to the area under the drug plasma
`concentration-time curve from t=0 to the last measurable
`concentration. The term “AUCO.,,,,“ as used herein, refers to
`the area under the drug plasma concentration-time curve
`extrapolated to w. The term “AllCu_,_.D," as used herein,
`refers to the AUC0_, normalized to 0.4 mg IM naioxone. The
`term “AUCQWD,” as used herein, refers to the AUCUJ,
`normalized to 0.4 mg 1M naloxone
`The term “Iticlav'ailabiiit}.r (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 N
`bioavailability.
`It may be calculated using the following
`formula:
`
`A ”Cent-mum! 3068th
`X
`A UCmmm. Dmnmmm
`
`The term relative hioavailability (FM) is used to compare
`two different exlravascular routes ot'drng administration and
`it may be calculated using the following fom‘tula:
`
`rel
`
`_ AUCnrmmmm-I Dnsea-muhrl
`Auctummxfluz Downirmmuori
`
`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 dmg
`is completely removed per unit of time. CL is equal to the
`elimination rate constant (3.) multiplied by the volume of
`distribution (Vd), wherein “V,,;" is the fluid volume that
`would be required to contain the amount of dnig present in
`the body at the same concentration as in the plasma. The
`
`Copy provided by [ISP'TO from the PIRS Image Database on 10-23-2018
`
`"lav—um.
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`Nalox1001
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`Nalox-l Phamiaceuticals, LLC
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`Page 12 of 43
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`US 9,56l,l?7 BZ
`
`g
`term “apparent clearance (CLIP)? as used herein, refers to
`clearance that does not take into account the bioavailability
`of the dmg. It is the ratio of the dose over the AUC.
`The term "Chm" as used herein, refers to the maximum
`observed plasma concentration. The term ‘17,...“er as used
`herein, refers to Cm, normalized to 0.4 mg 1M naloxone.
`The term “coeficient 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
`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
`amount of time that elapses betwmn a detennination 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 (1),“ as used herein,
`refers to the fractional rate of drug removal from the body.
`This rate is constant in first-order kinetics and is independent
`ofdrug concentration in the body. its the slope ot'the plasma
`concentration—time line (on a logarithmic y scale). The term
`“3?," as used herein, refers to the terminal phase elimination
`rate consan 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
`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
`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-
`maceutically acceptable salts thereof that is equimolar to a
`specified weight of naloxonc hydrochloride. For example, 8
`mg of anhydrous nalnxonc hydrochloride (molecular
`weight, 363.84) is equivalent to about 7.2 mg of naloxone
`lreebase (molecular weight, 327.37), and to about 8 .8 mg of
`naloxone hydrochloride dihydrate
`(molecular weight
`3993?).
`The term “filled." as used heroin1 refers to an association
`between a device and a pharmaceutical composition, for
`example. whcn a pharmaceutical composition described
`herein comprising a therapeutically efi'ective amount of an
`opioid antagonist is present within a reservoir that forms a
`part of a device descnbed 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-stoichiornetric amount of
`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-
`ably and refer to a judgment made by a caregiver (cg.
`physician, nurse, nurse practitioner) that a patient will
`benefit from treatment.
`As used herein, twu embodiments are "mutually exclu-
`sive“ when one is defined to be something which is dill'erent
`than the other. For example, an embodiment wherein the
`amount ofnaloxone hydrochloride is specified to be 4 mg is
`mutually exclusive with an embodiment wherein the amount
`ofnaloxone hydrochloride is specified to be 2 mg. However,
`
`6
`an embodiment wherein the amount of naloxone hydrochlo-
`ride is specified to be 4 mg is not mutually exclusive with an
`embodiment in which less than about 10% of said pharma-
`ceutical composition leaves the nasal cavity via drainage
`into the nasopbarynx or externally.
`The term “naloxoue.” as used herein, refers to a com-
`pound of the following structure:
`
`10
`
`15
`
`20
`
`25
`
`in
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`35
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`45
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`St]
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`55
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`60
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`65
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`
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`or a phannaocuticully acceptable salt, hydrate, or solvate
`thereof. The CAS rcgistty number for naloxone is 465—65—6.
`Other names for naloxonc include:
`l?-allyl-4,5a—cpoxy—3,
`I 4—dil‘tydroxymorphinan-6-onc;
`(— J— l T-allyl—4,Sa epoxy—3,
`ld—dihydroxymorphina n-o -one;
`4,5a-epoxy—3,l 4—dihy—
`droxy-1T-(Z-propenyl)morphinan-6-one; and (-)-12-allyl-'t.
`73,8,9—tetrahydro-3,?a-dihydroxy~4aH-S,9c—
`iminoethanuphenanthro[4,5-bcd]fi1run-S(6l l)-one.
`Naloxonc hydrochloride may be anhydrous (CA3 Reg. No.
`35108-4) and also forms a dihydrate (CAS No. 51481-60-
`8}. ll has been sold under various brand names including
`Narcan®, Nalone'EJ. Nalossonefit. Naloxona®._ Naloxo-
`nuleS'F. Narcanti®_. and Narcon®.
`The term “nostril," as used herein, is synonymous with
`“naris.”
`in addition to
`The term “opioid antagonist" includes,
`naloxone and phannacetttically acceptable salts thereof:
`naltrexone. methylnaltrcxone, and nalmefene, and pharma—
`ceutically acceptable salts thereof. In some embodiments.
`the opioid antagonist is naloxone hydrochloride. In some
`embodiments, the opioid antagonist is naloxone hydrochlo~
`ride dihydrate. In some embodiments, the opioid antagonist
`is naltrexone hydrochloride.
`In some embodiments,
`the
`Opioid antagonist
`is methylnattrexone bromide.
`In some
`embodiments, the opioid antagonist is nalmefene hydrochlo-
`ride.
`ln some embodiments.
`the nasally administering is
`accomplished using a device described heroin.
`The term "opioid overdose,“ as used herein, refers to an
`acute medical condition induced by excessive use of one or
`more opioids. Symptoms of opioid overdose include includ—
`ing respiratory depression, central nervous system depres-
`sion (which may include sedation, altered level conscious-
`ness, miotic
`(constricted) pupils).
`and cardiovascular
`depression (which may include hypoxemia and hypoten—
`sion). Visible signs of opioid overdose or suspected opioid
`overdose include: unresponsiveness andfor
`loss of con-
`seiousness (won’t respond to stimuli such as shouting,
`shaking, or rubbing knuckles on sternum): slow. erratic, or
`stopped breathing; slow, erratic, or stopped pulse; deep
`snoring or chokingt'gurgling sounds; blue or purple finger-
`nails or tips; pale andt’or clammy face; slack or limp muscle
`tone; contracted pupils; and vomiting. Because opioid over-
`dose may be difficult to diagnose andlor