(12) United States Patent
`Wyse et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,192,570 B2
`Nov. 24, 2015
`
`US0091925.70B2
`
`(54) INTRANASALNALOXONE COMPOSITIONS
`AND METHODS OF MAKING AND USING
`SAME
`
`(71) Applicant: AntiGp, Inc., Lexington, KY (US)
`
`(72) Inventors: Joseph Wyse, Nicholasville, KY (US);
`Michael Paul DeHart, Winterville, NC
`US
`s
`s
`(
`)
`(73) Assignee: AntiGp, Inc., Lexington, KY (US)
`(*) Notice:
`Subject to any disclaimer, the term of this
`past its, G adjusted under 35
`.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 14/576,357
`
`(22) Filed:
`
`Dec. 19, 2014
`
`(65)
`
`O
`O
`Prior Publication Data
`US 2015/O174061 A1
`June 25, 2015
`s
`
`Related U.S. Application Data
`(60) Provisional application No. 61/918,802, filed on Dec.
`20, 2013.
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`(2006.01)
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`FOREIGN PATENT DOCUMENTS
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`A6 IK3I/70
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`O 88O352 B1
`2, 1998
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`1399
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`W 8.359
`(2013.01); A61 K47/10 (2013.01); A61 K47/12 W
`8.8
`WOOOf 74652
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`WO
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`USPC ............................................................ 514/23
`WO WO 2008/139170
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`Primary Examiner — Rei-Tsang Shiao
`(74) Attorney, Agent, or Firm — Frost Brown Todd LLC
`(57)
`ABSTRACT
`ioid
`Disclosed herei
`1sclosed nerein are compositions containing an opio
`antagonist Such as naloxone and one or more pharmaceuti
`cally acceptable excipients. The compositions may be used
`for intranasal delivery of Naloxone for the treatment of, for
`example, opioid overdose in an individual in need thereof.
`Also disclosed are methods of making compositions contain
`ing Naloxone, and devices for nasal delivery of naloxone
`compositions.
`
`15 Claims, 5 Drawing Sheets
`
`Neurelis - EX.2030
`Aquestive Therapeutics, Inc. v. Neurelis, Inc. - IPR2019-00451
`
`

`

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`* cited by examiner
`
`Neurelis - EX.2030
`Aquestive Therapeutics, Inc. v. Neurelis, Inc. - IPR2019-00451
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`

`U.S. Patent
`
`Nov. 24, 2015
`
`Sheet 1 of 5
`
`US 9,192.570 B2
`
`FIG
`
`Analyte-Naloxone
`
`
`
`E
`S.
`.E.
`s
`
`3
`?
`c
`e
`
`-O- A
`A- B
`-- C
`-o- D
`-8- E
`-- F
`
`Neurelis - EX.2030
`Aquestive Therapeutics, Inc. v. Neurelis, Inc. - IPR2019-00451
`
`

`

`U.S. Patent
`
`Nov. 24, 2015
`
`Sheet 2 of 5
`
`US 9,192.570 B2
`
`FG 2
`
`
`
`-
`
`E.
`s e
`S.
`
`s
`
`n
`s
`
`-
`- E
`--
`-3-3
`-- E
`-- F
`
`Neurelis - EX.2030
`Aquestive Therapeutics, Inc. v. Neurelis, Inc. - IPR2019-00451
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`

`

`U.S. Patent
`
`Nov. 24, 2015
`
`Sheet 3 of 5
`
`US 9,192.570 B2
`
`FIG 3
`
`8:888s: Ross:
`
`FG 4A
`
`-0- Treatment A (n-33)
`~O- Treatment B (n=35)
`-A- reatment C (n=34)
`
`88: 88
`
`5
`
`4.
`
`
`
`3
`
`2
`
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`Aquestive Therapeutics, Inc. v. Neurelis, Inc. - IPR2019-00451
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`

`U.S. Patent
`
`Nov. 24, 2015
`
`Sheet 4 of 5
`
`US 9,192.570 B2
`
`O
`
`
`
`-0- Treatment A (n-33)
`-O- Treatment B (n-35)
`~A- Treatment C (n-34)
`
`Neurelis - EX.2030
`Aquestive Therapeutics, Inc. v. Neurelis, Inc. - IPR2019-00451
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`

`U.S. Patent
`
`Nov. 24, 2015
`
`Sheet 5 of 5
`
`US 9,192.570 B2
`
`FIG 5
`
`
`
`-O- Treatment A (n=33)
`-O- Treatment 8 (n=35)
`-A- Treatment C (n=34)
`
`5 -
`
`4 -
`
`2 -
`
`1 -
`
`8
`
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`
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`S.
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`9
`c
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`
`s
`s
`
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`O
`O
`20
`30
`AO
`50
`80
`FC
`80
`90 100
`1
`20
`
`Time (min)
`
`Neurelis - EX.2030
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`

`1.
`INTRANASALNALOXONE COMPOSITIONS
`AND METHODS OF MAKING AND USING
`SAME
`
`TECHNICAL FIELD
`
`The instant invention relates to compositions comprising
`an opioid antagonist, and methods and devices for using
`SaC.
`
`BACKGROUND
`
`Naloxone was approved by FDA in 1971 and first marketed
`as Narcan R injection for the complete or partial reversal of
`opioid intoxication. It has subsequently become a multi
`Source prescription generic drug and is currently manufac
`tured by International Medication Systems, Limited (IMS)
`and Hospira, Inc. The injection is available in two strengths,
`0.4 mg/mL and 1.0 mg/mL. Naloxone injection is approved
`worldwide and is on the WHO Model list of Essential Medi
`cines as a specific antidote.
`Presently, naloxone is a standard inventory item for emer
`gency services personnel to carry in ambulances and medi
`cation kits for reversal of suspected opioid overdose in the
`pre-hospital setting. Hospital emergency departments also
`use this medication routinely for this purpose. The initial
`parenteral dose of naloxone for adults with known or Sus
`pected narcotic overdose is 0.4 to 2 mg, which may be
`repeated as needed to a total dose of 10 mg. The currently
`available formulations of naloxone are approved for intrave
`nous (IV), intramuscular (IM) and subcutaneous (SC) admin
`istration. Naloxone is also indicated as a reversal agent when
`the effects of therapeutic use of opioids are no longer medi
`cally necessary, Such as in reversal of opioid effects in general
`anesthesia.
`In 2008, poisoning Surpassed motor vehicle accidents as
`the leading cause of “injury deaths” in the United States
`(Warner 2011). Nearly 90% of poisoning deaths are caused
`by drugs. During the past 3 decades, the number of drug
`poisoning deaths increased six-fold from about 6,100 in 1980
`to 36,500 in 2008. Of the 36,500 drug poisoning deaths in
`2008, 14,800 involved prescription opioid analgesics.
`Approximately 3,000 deaths also involved heroin overdose
`(Warner 2011).
`In emergency situations, it is known that the onset of action
`of the IV injection will be faster, so is preferred. Narcan R is
`a commercially available intravenous formulation of nalox
`one HCl that is administered to unresponsive opioid users
`who have overdosed. The shortcomings of this formulation
`and route of administration are 1) it takes time to establish IV
`access and this is exacerbated in individuals who have poor
`veins from frequent injections with dirty needles; 2) that those
`who are administering the drug are putting themselves at risk
`from needle-stick injury from an awakening an agitated
`patient; and 3) the immediate high blood levels are associated
`with inducing more frequent and severe opioid withdrawal
`effects. Further, IV administration requires delivery by a
`trained professional, limiting the use of the drug to a small
`percentage of the population who can receive EMS care.
`Naloxone can be given by IM or SC injection, and has a more
`gradual onset of action because the drug must be absorbed
`from the muscle or skin. Although naloxone can also be given
`by IM or SC administration, the utility of delivering naloxone
`by lay persons using a needle is not common medical prac
`tice. There are currently no over-the-counter medications
`used by lay persons that require needle-based delivery. Thus,
`an unmet medical need is a needle-free delivery system
`
`2
`capable of delivering naloxone in a properly designed product
`sufficient to achieve therapeutically effective blood levels of
`naloxone, and that can be used by a lay person accurately
`under intense emotional and environmental pressure to treat a
`person Suspected of Suffering an opioid overdose—most
`commonly an immediate family member or close acquain
`tance.
`An additional problem with the current standard of care
`using naloxone to treat drug overdose is that the delivery of
`naloxone to patients in a state of drug overdose can result in a
`variety of responses in the drug overdosed patient. Depending
`on the route administered, naloxone can rapidly reverse the
`effects of the opioid, and in many instances, can induce
`instant and severe pain, nausea, vomiting, the occasional Sei
`Zure, agitation, and/or combativeness. This can be dangerous
`both to the patient and to the emergency responder. Once
`awakened, the patient may be in a state of distress and uncer
`tainty. Medical staff and/or the patient handling an
`unsheathed needle may risk puncture as a result of a disori
`ented or agitated patient. Thus, administration of a naloxone
`formulation, which would lessen a Sudden reversal as
`observed using IV administration, is desired.
`Finally, the current standard of care for a patient with a
`Suspected opioid intoxication is to Support ventilation and
`administernaloxone either IV, IM, or subcutaneously (SC). A
`demonstration of unmet medical need is the off-label admin
`istration of naloxone injection intranasally. The injection for
`mulation, which is not formulated for intranasal use, has to be
`given intranasally via a separate mucosal atomizer device
`using ad hoc methods (Barton 2005, Kelly 2005, Kerr 2008,
`Merlin 2010, Robertson 2009, Sporer 2007). For example, the
`San Francisco EMS uses this drug administration technique
`as a standard-of-care to prevent needle-stick injuries to
`EMTs. While naloxone injection formulations currently
`administered intranasally by EMS personnel in the field as an
`opioid antidote using the FDA-approved parenteral product
`and a Mucosal Atomization Device (“MAD' device, avail
`able from Teleflex and/or LMA), there are numerous draw
`backs that detract from the efficacy of the method. These
`include formulations not suited for intranasal delivery, a lack
`of a complete device containing naloxone and designed for
`intranasal delivery, and a lack of compositions specifically
`designed for manufacture with intranasal devices that do not
`utilize terminal autoclave sterilization, which can also be
`stored and conveniently and safely used and transported, a
`multi-step process to assemble the required elements subject
`to confusion and error, and which can be stored for long
`periods of time without causing product damage (i.e., frac
`turing of a glass container) or naloxone degradation resulting
`in the formation of 7,8-didehydronaloxone, a substance con
`sidered by the FDA to be undesirable/potentially genotoxic.
`Further, currently formulations are not designed for nasal
`delivery However, Dowling, et al., “Population Pharmacoki
`netics of Intravenous, Intramuscular, and Intranasal Nalox
`one in Human Volunteers. Therapeutic Drug Monitoring,
`30(4): 490-496 (2008) (hereafter “Dowling') describes the
`absorption and pharmacokinetics of a dilute naloxone injec
`tion type solution administered intranasally. The bioavailabil
`ity was only 4%, suggesting that intranasal naloxone absorp
`tion is poor and leading a person skilled in the art away from
`the present invention. In fact, the au