[go: up one dir, main page]

WO2017049181A1 - Produits médicamenteux d'administration par voie nasale et leurs méthodes d'utilisation - Google Patents

Produits médicamenteux d'administration par voie nasale et leurs méthodes d'utilisation Download PDF

Info

Publication number
WO2017049181A1
WO2017049181A1 PCT/US2016/052280 US2016052280W WO2017049181A1 WO 2017049181 A1 WO2017049181 A1 WO 2017049181A1 US 2016052280 W US2016052280 W US 2016052280W WO 2017049181 A1 WO2017049181 A1 WO 2017049181A1
Authority
WO
WIPO (PCT)
Prior art keywords
naloxone
patient
naloxone hydrochloride
less
opioid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2016/052280
Other languages
English (en)
Inventor
Fintan Keegan
Robert Gerard Bell
Roger CRYSTAL
Michael Brenner Weiss
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Emergent Biosolutions Ireland Ltd
Opiant Pharmaceuticals Inc
Original Assignee
Adapt Pharma Ltd
Opiant Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Adapt Pharma Ltd, Opiant Pharmaceuticals Inc filed Critical Adapt Pharma Ltd
Priority to EP16847459.1A priority Critical patent/EP3349756A4/fr
Priority to MX2018003349A priority patent/MX2018003349A/es
Priority to CA2950687A priority patent/CA2950687C/fr
Publication of WO2017049181A1 publication Critical patent/WO2017049181A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose

Definitions

  • This disclosure generally relates to pharmaceutical compositions comprising an opioid receptor antagonist, medical devices for delivery of the pharmaceutical compositions, and methods of using the compositions and the medical devices.
  • 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 administration of the drug. The proper use of naloxone is important. Firstly, if an inadequate dose is administered, the patient may either not recover from the opioid overdose, or may recover only to lapse back into overdose as effect of naloxone wears off. The half-life of naloxone is shorter than certain opioids.
  • This disclosure provides 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, wherein the improvement comprises that the device is adapted to spray a round plume with an ovality ratio less than about 1 .2.
  • a mist comprising droplets of an at least 4% (w/v) naloxone hydrochloride solution, wherein no more than about 5% of the droplets have a diameter less than 10 ⁇ .
  • 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 0.2% 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 ratio less than about 2.0.
  • 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.
  • This disclosure provides methods and devices for treating overdoses from fentanyl or a fentanyl derivative, by delivering a spray from a pre-primed device into a nostril of an overdose patient, wherein the device is adapted for nasal delivery and the spray delivers a pharmaceutical solution comprising at least about 4 mg naloxone.
  • This disclosure also provides methods and devices to prevent the use of naloxone to titrate opioid receptor occupancy, by delivering a spray from a pre-primed device into a nostril of an overdose patient, wherein the device is adapted for nasal delivery and the spray delivers a pharmaceutical solution comprising at least about 2 mg— for example, at least about 4 mg— naloxone.
  • This disclosure also provides methods and devices to reverse an opioid overdose completely, by delivering a spray from a pre-primed device into a nostril of an overdose patient, wherein the device is adapted for nasal delivery and the spray delivers a pharmaceutical solution comprising at least about 2 mg— for example, at least about 4 mg— naloxone.
  • Figure 1 shows the mean ( ⁇ SD) naloxone plasma concentration following administration of 0.4 mg intramuscular (IM), 2 mg intranasal (IN), and 4 mg IN in 14 human subjects.
  • Figure 2 shows the mean ( ⁇ SD) naloxone plasma concentration with logarithmic transformation following administration of 0.4 mg intramuscular (IM), 2 mg intranasal (IN), and 4 mg IN in 14 human subjects.
  • 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 pharmacological effect, as opposed to an "inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit.
  • actuation refers to operation of the device such that the pharmaceutical composition is delivered therefrom.
  • agonist refers to as used herein refers to a moiety that interacts with and activates a receptor, and thereby initiates a physiological or pharmacological response characteristic of that receptor.
  • antagonist refers to a moiety that competitively 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.
  • inverse agonist refers to a moiety that binds to the endogenous form 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.
  • antimicrobial preservative refers to a pharmaceutically acceptable excipient with antimicrobial properties which is added to a pharmaceutical composition to maintain microbiological stability.
  • AUC refers to the area under the drug plasma concentration-time curve.
  • AUCo- ⁇ refers to the area under the drug plasma concentration-time curve extrapolated to ⁇ .
  • AUCo-t/D refers to the AUC 0 -t normalized to 0.4 mg IM naloxone.
  • AUC 0 - ⁇ /D refers to the AUC 0 - ⁇ normalized to 0.4 mg IM naloxone
  • bioavailability (F) 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.
  • absolute bioavailability is used when the fraction of absorbed drug is related to its IV bioavailability. It may be calculated using the following formula:
  • in need of treatment and the term “in need thereof” when referring to treatment are used interchangeably and refer to a judgment made by a caregiver ⁇ e.g. physician, nurse, nurse practitioner) that a patient will benefit from treatment.
  • two embodiments are "mutually exclusive" when one is defined to be something which is different than the other.
  • 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.
  • an embodiment wherein the amount of naloxone hydrochloride is specified to be 4 mg is not mutually exclusive with an embodiment in which less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
  • titrate as used herein with reference to opioid receptors conveys a process by which naloxone is administered step-wise in small doses until opioid drug has been displaced from just enough receptors to reverse an overdose while the user retains a large enough percentage of receptors occupied by opioids to sustain an analgesic effect.
  • titrate does not refer to the titration of naloxone by medical professionals who appropriately administer additional doses of naloxone if the initial dose(s) do(es) not achieve a sufficient reversal of an opioid overdose.
  • 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®, Naloxonum®, Narcanti®, and Narcon®.
  • A is aryl or heteroaryl optionally substituted with halo, C1-C3 alkyl, or C1-C3 alkoxy,
  • Y is Ci-C 4 alkyl, C2-C3 alkenyl, C1-C3 alkoxy, C1-C3 alkoxyalkyl, cycloalkyl, or heteroaryl,
  • opioid overdose refers to an acute medical condition induced by excessive use of one or more opioids. Symptoms of opioid overdose include including respiratory depression, central nervous system depression (which may include sedation, altered level consciousness, miotic (constricted) pupils), and cardiovascular depression (which may include hypoxemia and hypotension).
  • Visible signs of opioid overdose or suspected opioid overdose include: unresponsiveness and/or loss of consciousness (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 choking/gurgling sounds; blue or purple fingernails or lips; pale and/or clammy face; slack or limp muscle tone; contracted pupils; and vomiting.
  • opioid overdose may be difficult to diagnose and/or quantify, particularly by a lay person, as used herein, treatment of opioid overdose is meant to include treatment of suspected opioid overdose in opioid-intoxicated patients.
  • the opioid agonist is selected from Acurox® Oxycodone DETERx®, Oxycontin®, Egalet hydrocodone, Egalet morphine, Egalet oxycodone, Exalgo®, Opana®, Opana® ER, Vicodin®, Percocet® and Remoxy®.
  • patient refers to any subject (preferably human) afflicted with a condition likely to benefit from a treatment with a therapeutically effective amount of an opioid antagonist.
  • permeation enhancer and “penetration enhancer,” as disclosed herein, are intended to be equivalent, both referring to an agent which aids in absorption of a compound, such as through the nasal mucosa.
  • composition refers to a composition comprising at least one active ingredient; including but not limited to, salts, solvates and hydrates of the opioid antagonists described herein, whereby the composition is amenable to use for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • pre-primed refers to a device, such as a nasal spray which is capable of delivering a pharmaceutical composition to a patient in need thereof with the first actuation of the spray pump, i.e., without the need to prime the pump prior to dosing, such as by actuating the pump one or more times until a spray appears.
  • receptor binding or occupancy refers to a characterization of the kinetics between a radioactive drug and receptors or other binding sites throughout the body, and characterization of the radioactive drug binding affinity to these receptors.
  • recovery position means a position of the human body in which a patient lies on his/her side, with a leg or knee out in front (e.g., to prevent rolling onto his/her stomach) and at least one hand supporting the head (e.g., to elevate the face to facilitate breathing and prevent inhalation of vomit).
  • solvate refers to an opioid antagonist described herein or a salt, thereof, that further includes a stoichiometric or non- stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
  • pharmaceutically acceptable refers to a component of a pharmaceutical composition that it compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.
  • substantially free of antimicrobial preservatives is understood by one of ordinary skill in the art to describe a pharmaceutical composition that may comprise less than 1 % w/w antimicrobial preservatives.
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, or individual that is being sought by a researcher, healthcare provider or individual.
  • the term "untrained individual” refers to an individual administering to patient an opioid antagonist using a device described herein, wherein the individual is not a healthcare professional and has received little or no training in the use of the device, such as through an overdose education and nasal naloxone distribution (OEND) program.
  • server refers to a machine that comprise at least one computer-readable medium.
  • computer-readable medium does not encompass transitory electrical or electromagnetic signals propagating through a medium (such as on a carrier wave); the term computer-readable medium is therefore considered tangible and non-transitory.
  • Non-limiting examples of a non-transitory computer-readable medium are nonvolatile memory devices (such as a flash memory device, an erasable programmable read-only memory device, or a mask read-only memory device), volatile memory devices (such as a static random access memory device or a dynamic random access memory device), magnetic storage media (such as an analog or digital magnetic tape or a hard disk drive), and optical storage media (such as a CD, a DVD, or a Blu-ray Disc).
  • nonvolatile memory devices such as a flash memory device, an erasable programmable read-only memory device, or a mask read-only memory device
  • volatile memory devices such as a static random access memory device or a dynamic random access memory device
  • magnetic storage media such as an analog or digital magnetic tape or a hard disk drive
  • optical storage media such as a CD, a DVD, or a Blu-ray Disc
  • the therapeutically effective amount is equivalent to about 2 mg to about 24 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2 mg to about 12 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3 mg to about 18 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg to about 10 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 5 mg to about 1 1 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 6 mg to about 10 mg of naloxone hydrochloride.
  • the therapeutically effective amount is equivalent to about 4 mg to about 8 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 7 mg to about 9 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3.4 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 5 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 6 mg of naloxone hydrochloride.
  • EMS emergency medical services
  • Some emergency medical services (EMS) programs have developed a system using existing technologies of an approved drug and an existing medical device to administer naloxone intranasally, albeit in a non-FDA approved manner. This has been accomplished by using the injectable formulation (1 img/mL) and administering 1 imL per nostril via a marketed nasal atomizer/nebulizer device.
  • the system combines an FDA-approved naloxone injection product (with a Luer fitted tip, no needles) with a marketed, medical device called the Mucosal Atomization Device (MADTM Nasal, Wolfe Tory Medical, Inc.).
  • MADTM Nasal, Wolfe Tory Medical, Inc. the Mucosal Atomization Device
  • the human nasal cavity has a volume of -200-250 ⁇ _.
  • the 1 imL delivery volume per nostril is larger than that generally utilized for intranasal drug administration. Therefore, there is loss of drug from the nasal cavity, due either to drainage into the nasopharynx or externally from the nasal cavity.
  • the devices described herein are improved ready-to-use products specifically optimized, concentrated, and formulated for nasal delivery.
  • the single- and bi-dose devices mentioned above consist of a reservoir, a piston, and a swirl chamber (see, e.g., the UDS UnitDose and BDS BiDose devices from Aptar, formerly Pfeiffer).
  • the spray is formed when the liquid is forced out through the swirl chamber.
  • These devices are held between the second and the third fingers with the thumb on the actuator.
  • a pressure point mechanism incorporated in some devices secures reproducibility of the actuation force and emitted plume characteristics.
  • a volume of 125 ⁇ _ is filled in the device (Pfeiffer/Aptar single-dose device) used for the intranasal migraine medications Imitrex (sumatriptan) and Zomig (zolmitriptan) and about half of that for a bi-dose design.
  • Sterile drug products may be produced using aseptic processing or terminal sterilization. Terminal sterilization usually involves filling and sealing product containers under high-quality environmental conditions.
  • the individual parts of the final product are generally subjected to various sterilization processes. For example, glass containers are subjected to dry heat; rubber closures are subjected to moist heat; and liquid dosage forms are subjected to filtration. Each of these manufacturing processes requires validation and control.
  • said patient is in a lying, supine, or recovery position. In some embodiments, said patient is in a lying position. In some embodiments, said patient is in a supine position. In some embodiments, said patient is in a recovery position.
  • said therapeutically effective amount of an opioid antagonist is delivered by an untrained individual. Also disclosed herein are methods of improving accuracy of dose delivery by an untrained individual, the method comprising administering a dose of opioid antagonist from a device as described herein.
  • said therapeutically effective amount is equivalent to about 4 mg to about 10 mg of naloxone hydrochloride. In some embodiments, said therapeutically effective amount is equivalent to an amount chosen from about 2 mg naloxone hydrochloride, about 4 mg naloxone hydrochloride, and about 8 mg naloxone hydrochloride. In some embodiments, said therapeutically effective amount is equivalent to about 2 mg of naloxone hydrochloride. In some embodiments, said therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride. In some embodiments, said therapeutically effective amount is equivalent to about 8 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3.4 mg of naloxone hydrochloride.
  • about 100 ⁇ _ of said pharmaceutical composition in said reservoir is delivered to said patient in one actuation.
  • said pharmaceutical composition further comprises one or more excipients selected from water and NaCI.
  • Spray characterization ⁇ e.g., plume geometry, spray pattern, pump delivery, droplet size distribution, DSD
  • DSD droplet size distribution
  • D10, D50, D90, span [(D90-D10)/D50] percentage of droplets less than 10 mm.
  • the formulation will have a narrow DSD.
  • n is an integer selected from the group consisting of 8, 10, 12, 14, 16, and 18.
  • n can be an integer selected from the group consisting of 10, 12, and 14.
  • a formulation as disclosed herein comprising benzalkonium chloride in an amount effective to function as a permeation/penetration enhancer and/or a cationic surfactant will yield a formulation that is at least 35% bioavailable, at least 40% bioavailable, at least 45% bioavailable, at least 50% bioavailable, or at least 55% bioavailable.
  • a drug product comprising a combination of a therapeutically effective amount of an opioid agonist and a therapeutically effective amount of naloxone hydrochloride or a hydrate thereof, wherein said naloxone hydrochloride or hydrate thereof is contained in a single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, and wherein the single-use, pre-primed device comprises a reservoir containing a pharmaceutical composition which is an aqueous solution of about 100 ⁇ _ comprising:
  • the single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient comprises about 2 mg, about 4 mg, or about 8 mg of the naloxone hydrochloride or a hydrate thereof.
  • the aqueous solution comprises:
  • a stabilizing agent between about 0.1 mg and about 0.5 mg of a stabilizing agent; and an amount of acid sufficient to achieve a pH of 3.5-5.5.
  • the stabilizing agent is disodium edetate
  • the aqueous solution comprises:
  • a drug product comprising a combination of a therapeutically effective amount of an opioid agonist and a therapeutically effective amount of naloxone hydrochloride or a hydrate thereof, wherein said naloxone hydrochloride or hydrate thereof is contained in a pre-primed, bi-dose device adapted for nasal delivery of a pharmaceutical composition to a patient, wherein a first volume of said pharmaceutical composition is present in a first reservoir, and a second volume of said pharmaceutical composition is present in a second reservoir, and wherein said therapeutically effective amount of said opioid antagonist is delivered essentially by a first actuation of said drug delivery device from said first reservoir into a nostril of said patient and a second actuation of said drug delivery device from said second reservoir into a nostril of said patient; each reservoir comprising a pharmaceutical composition which is an aqueous solution of about 100 ⁇ _ comprising:
  • benzalkonium chloride in an amount effective to function as a permeation/penetration enhancer and/or a cationic surfactant;
  • each reservoir of the pre-primed, bi-dose device adapted for nasal delivery of a pharmaceutical composition to a patient comprises between about 2 mg and about 12 mg of the naloxone hydrochloride or a hydrate thereof.
  • each reservoir of the pre-primed, bi-dose device adapted for nasal delivery of a pharmaceutical composition to a patient comprises about 2 mg, about 4 mg, or about 8 mg of the naloxone hydrochloride or a hydrate thereof.
  • the aqueous solution comprises:
  • a stabilizing agent between about 0.1 mg and about 0.5 mg of a stabilizing agent; and an amount of acid sufficient to achieve a pH of 3.5-5.5.
  • the isotonicity agent is NaCI
  • the stabilizing agent is disodium edetate
  • the acid is hydrochloric acid.
  • the aqueous solution comprises:
  • the aqueous solution comprises:
  • naloxone hydrochloride dihydrate between about 0.001 mg and about 0.1 mg ⁇ i.e., about 0.01 % w/v to about 1 % w/v) benzalkonium chloride;
  • each reservoir comprises about 2.2 mg of the naloxone hydrochloride dihydrate.
  • each reservoir comprises about 4.4 mg of the naloxone hydrochloride dihydrate.
  • Also provided herein is a method of lowering opioid overdose risk in an individual at risk for opioid overdose comprising providing to the individual at risk for opioid overdose a combination of a therapeutically effective amount of an opioid agonist and a therapeutically effective amount of naloxone hydrochloride or a hydrate thereof, wherein said naloxone hydrochloride or hydrate thereof is contained in a single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, and wherein the single-use, pre-primed device comprises a reservoir containing a pharmaceutical composition which is an aqueous solution of about 100 ⁇ _ comprising:
  • naloxone hydrochloride or a hydrate thereof
  • benzalkonium chloride in an amount effective to function as a permeation/penetration enhancer and/or a cationic surfactant
  • the single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient comprises between about 2 mg and about 12 mg of the naloxone hydrochloride or a hydrate thereof.
  • the single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient comprises about 2 mg, about 4 mg, or about 8 mg of the naloxone hydrochloride or a hydrate thereof.
  • the aqueous solution comprises: between about 2 mg and about 12 mg of the naloxone hydrochloride or a hydrate thereof;
  • a stabilizing agent between about 0.1 mg and about 0.5 mg of a stabilizing agent; and an amount of acid sufficient to achieve a pH of 3.5-5.5.
  • the isotonicity agent is NaCI
  • the stabilizing agent is disodium edetate
  • the acid is hydrochloric acid.
  • the aqueous solution comprises:
  • the aqueous solution comprises:
  • Also provided herein is a method of lowering opioid overdose risk in an individual at risk for opioid overdose comprising providing to the individual at risk for opioid overdose a combination of a therapeutically effective amount of an opioid agonist and a therapeutically effective amount of naloxone hydrochloride or a hydrate thereof, wherein said naloxone hydrochloride or hydrate thereof is contained in a pre-primed, bi- dose device adapted for nasal delivery of a pharmaceutical composition to a patient, wherein a first volume of said pharmaceutical composition is present in a first reservoir, and a second volume of said pharmaceutical composition is present in a second reservoir, and wherein said therapeutically effective amount of said opioid antagonist is delivered essentially by a first actuation of said drug delivery device from said first reservoir into a nostril of said patient and a second actuation of said drug delivery device from said second reservoir into a nostril of said patient; each reservoir comprising a pharmaceutical composition which is an aqueous solution of about 100 ⁇ _ comprising:
  • naloxone hydrochloride or a hydrate thereof
  • benzalkonium chloride in an amount effective to function as a permeation/penetration enhancer and/or a cationic surfactant
  • the single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient comprises between about 2 mg and about 12 mg of the naloxone hydrochloride or a hydrate thereof.
  • each reservoir of the single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient comprises about 2 mg, about 4 mg, or about 8 mg of the naloxone hydrochloride or a hydrate thereof.
  • each reservoir comprises about 2 mg of the naloxone hydrochloride or a hydrate thereof.
  • each reservoir comprises about 4 mg of the naloxone hydrochloride or a hydrate thereof.
  • the aqueous solution comprises:
  • an isotonicity agent between about 0.2 mg and about 1 .2 mg of an isotonicity agent; between about 0.1 mg and about 0.5 mg of a stabilizing agent; and an amount of acid sufficient to achieve a pH of 3.5-5.5.
  • the isotonicity agent is NaCI
  • the stabilizing agent is disodium edetate
  • the acid is hydrochloric acid.
  • each reservoir comprises:
  • each reservoir comprises:
  • said pharmaceutical composition further comprises one or more excipients selected from water, NaCI, benzalkonium chloride, sodium edetate, disodium edetate, and hydrochloric acid.
  • said pharmaceutical composition further comprises water, NaCI, benzalkonium chloride, disodium edetate, and hydrochloric acid.
  • said pharmaceutical composition further comprises:
  • said pharmaceutical composition comprises: between about 0.2 mg and about 1 .2 mg of an isotonicity agent;
  • the compound which is a preservative, cationic surfactant, and/or permeation enhancer is benzalkonium chloride
  • the stabilizing agent is disodium edetate
  • said pharmaceutical composition comprises:
  • said pharmaceutical composition comprises:
  • said device is filled with said pharmaceutical composition using sterile filling.
  • said pharmaceutical composition is storage-stable for about twelve months at about 25 °C and about 60% relative humidity.
  • said device is a single-dose device, wherein said pharmaceutical composition is present in one reservoir, and wherein said therapeutically effective amount of said opioid antagonist is delivered essentially by one actuation of said device into one nostril of said patient.
  • about 100 ⁇ _ of said pharmaceutical composition is delivered by said actuation.
  • said device is actuatable with one hand.
  • the delivery time is less than about 25 seconds. In some embodiments, the delivery time is less than about 20 seconds.
  • the 90% confidence interval for dose delivered per actuation is ⁇ about 2%. In some embodiments, the 95% confidence interval for dose delivered per actuation is ⁇ about 2.5%.
  • the nasal cavity via drainage into the nasopharynx or externally upon nasal delivery of said pharmaceutical composition to said patient, less than about 20% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, upon nasal delivery of said pharmaceutical composition to said patient, less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, upon nasal delivery of said pharmaceutical composition to said patient, less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
  • the plasma concentration versus time curve of said opioid antagonist in said patient has a t ma x of less than 30 minutes. In some embodiments, the plasma concentration versus time curve of said opioid antagonist in said patient has a t max of less than 25 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a t max of less than 20 minutes. In some embodiments, the plasma concentration versus time curve of said opioid antagonist in said patient has a t ma x of about 20 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a t max of less than 19 minutes.
  • the plasma concentration versus time curve of the opioid antagonist in the patient has a t ma x of about 18.5 minutes.
  • delivery of said therapeutically effective amount to said patient provides occupancy at t ma x of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 90%.
  • delivery of said therapeutically effective amount to said patient provides occupancy at t ma x of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 95%.
  • delivery of said therapeutically effective amount to said patient provides occupancy at t max of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 99%.
  • said patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
  • said device is a bi-dose device, wherein a first volume of said pharmaceutical composition is present in a first reservoir and a second volume of said pharmaceutical composition is present in a second reservoir, and wherein said therapeutically effective amount is delivered essentially by a first actuation of said device into a first nostril of said patient and a second actuation of said device into a second nostril of said patient.
  • said first volume and said second volume combined is equal to not more than about 380 ⁇ _.
  • about 100 ⁇ _ of said first volume of said pharmaceutical composition is delivered by said first actuation.
  • about 100 ⁇ _ of said second volume of said pharmaceutical composition is delivered by said second actuation.
  • said device is actuatable with one hand.
  • the delivery time is less than about 25 seconds. In some embodiments, the delivery time is less than about 20 seconds.
  • the 90% confidence interval for dose delivered per actuation is ⁇ about 2%. In some embodiments, the 95% confidence interval for dose delivered per actuation is ⁇ about 2.5%.
  • the plasma concentration versus time curve of said opioid antagonist in said patient has a t ma x of less than 30 minutes. In some embodiments, the plasma concentration versus time curve of said opioid antagonist in said patient has a t max of less than 25 minutes. In some embodiments, the plasma concentration versus time curve of said opioid antagonist in said patient has a t max of about 20 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a t ma x of less than 19 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a t max of about 18.5 minutes.
  • delivery of said therapeutically effective amount to said patient provides occupancy at t ma x of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 90%. In some embodiments, delivery of said therapeutically effective amount to said patient, provides occupancy at t ma x of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 95%. In some embodiments, delivery of said therapeutically effective amount to said patient, provides occupancy at t max of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 99%.
  • said patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
  • a single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, having a single reservoir comprising about 100 ⁇ _ of a pharmaceutical composition which is an aqueous solution comprising:
  • a stabilizing agent between about 0.1 mg and about 0.5 mg of a stabilizing agent; and an amount of acid sufficient to achieve a pH of 3.5-5.5.
  • the device comprises about 4 mg naloxone hydrochloride or a hydrate thereof. In some embodiments, the device comprises about 2 mg naloxone hydrochloride or a hydrate thereof. In some embodiments, the device comprises about 4.4 mg naloxone hydrochloride dihydrate. In some embodiments, the device comprises about 2.2 mg naloxone hydrochloride dihydrate.
  • the isotonicity agent is NaCI
  • the compound which is a preservative cationic surfactant and/or permeation enhancer is benzalkonium chloride;
  • the stabilizing agent is disodium edetate;
  • the acid is hydrochloric acid.
  • the device comprises:
  • the device comprises:
  • the device comprises about 4.4 mg naloxone hydrochloride dihydrate. In some embodiments, the device comprises about 2.2 mg naloxone hydrochloride dihydrate.
  • the plasma concentration versus time curve of said naloxone hydrochloride in said patient has a t ma x of between about 20 and about 30 minutes.
  • said device is actuatable with one hand.
  • the delivery time is less than about 25 seconds. In some embodiments, the delivery time is less than about 20 seconds.
  • the 90% confidence interval for dose delivered per actuation is ⁇ about 2%. In some embodiments, the 95% confidence interval for dose delivered per actuation is ⁇ about 2.5%.
  • the nasal cavity via drainage into the nasopharynx or externally upon nasal delivery of said pharmaceutical composition to said patient, less than about 20% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, upon nasal delivery of said pharmaceutical composition to said patient, less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, upon nasal delivery of said pharmaceutical composition to said patient, less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
  • the plasma concentration versus time curve of said opioid antagonist in said patient has a t ma x of less than 30 minutes. In some embodiments, the plasma concentration versus time curve of said opioid antagonist in said patient has a t max of less than 25 minutes. In some embodiments, the plasma concentration versus time curve of said opioid antagonist in said patient has a t max of about 20 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a t ma x of less than 19 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a t max of about 18.5 minutes.
  • delivery of said therapeutically effective amount to said patient provides occupancy at t ma x of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 90%. In some embodiments, delivery of said therapeutically effective amount to said patient, provides occupancy at t ma x of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 95%. In some embodiments, delivery of said therapeutically effective amount to said patient, provides occupancy at t max of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 99%.
  • said patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
  • said device is filled with said pharmaceutical composition using sterile filling.
  • said pharmaceutical composition is storage-stable for about twelve, about fifteen, or even about eighteen months at about 25 °C and about 60% relative humidity.
  • said opioid antagonist is the only pharmaceutically active compound in said pharmaceutical composition.
  • an opioid overdose symptom selected from: respiratory depression, postoperative opioid respiratory depression, altered level consciousness, miotic pupils, cardiovascular depression, hypoxemia, acute lung injury, aspiration pneumonia, sedation, and hypotension.
  • said respiratory depression is caused by the illicit use of opioids or by an accidental misuse of opioids during medical opioid therapy.
  • narcotic depression including respiratory depression, induced by opioids selected from: natural and synthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocine and butorphanol.
  • opioids selected from: natural and synthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocine and butorphanol.
  • said patient is an opioid overdose patient or a suspected opioid overdose patient.
  • said patient is in a lying, supine, or recovery position. In some embodiments, said patient is in a lying position. In some embodiments, said patient is in a supine position. In some embodiments, said patient is in a recovery position. [00189] In some embodiments, said therapeutically effective amount of an opioid antagonist is delivered by an untrained individual.
  • kits comprising a device described herein and written instructions for using the device.
  • kits comprising a device described herein and an opioid agonist.
  • the kit further comprises written instructions.
  • the opioid agonist is selected from codeine, morphine, methadone, fentanyl, oxycodone HCI, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, and certain narcotic-antagonist analgesics, such as, nalbuphine, pentazocine and butorphanol.
  • the opioid agonist is selected from tapentadol and tramadol.
  • Tamper-proof and tamper-resistant formulating technologies have been developed for safer delivery of opioid antagonists, but such formulations are still abused resulting in opioid overdose.
  • One such technology (Abuse Deterrent Prolonged Release Erosion Matrix (ADPREM); Egalet) utilizes a water-degradable polymer matrix technology that erodes from the surface at a constant rate. The matrix consists of one or more plasticizing polymers that cannot be crushed or melted.
  • Another such technology (Abuse Resistant Technology (ART); Elite Laboratories) utilizes a proprietary coating technology consisting of various polymers that can sequester an opioid antagonist (naltrexone) in fragile micropellets that are indistinguishable from the pellets containing the opioid.
  • the formulation is designed to release sequestered antagonist only if the dosage is crushed or otherwise damaged for extraction.
  • Oral dosage forms are prepared by coating powders, crystals, granules, or pellets with various polymers to impart different characteristics.
  • the formulations can release the active drug in both immediate and sustained release form. Chronodelivery formulations using this technology can effectively delay drug absorption for up to five hours.
  • Aversion (Acura Pharmaceuticals) utilizes certain proprietary combinations of functional excipients (e.g., gelling agents) and active ingredients intended to discourage the most common methods of prescription drug misuse and abuse.
  • Ingredients may include nasal irritants (e.g., capsaicin) and aversive agents (e.g., niacin).
  • the opioid agonist is in a tamper-proof formulation. In some embodiments, the opioid agonist is in a tamper-resistant formulation. In some embodiments, the opioid agonist is selected from Acurox® Oxycodone DETERx®, Oxycontin®, Egalet hydrocodone, Egalet morphine, Egalet oxycodone, Exalgo®, Opana®, Opana® ER, Vicodin®, Percocet® and Remoxy®.
  • the method of preventing the use of naloxone to titrate opioid receptor occupancy comprises: actuating a pre-primed, single use device to deliver a spray into a nostril of a patient, wherein the device contains a pharmaceutical solution comprising at least 2% (w/v) naloxone hydrochloride or a hydrate thereof, and wherein the device is configured to deliver no less than about 2 mg of naloxone per actuation.
  • the pharmaceutical solution comprises about 2% (w/v) to about 4% (w/v) naloxone HCI or a hydrate thereof.
  • Titration can be prevented by administering naloxone from a single-use, fixed dose metered spray device.
  • a pre-primed single use device delivers a spray into a nostril of a patient who is overdosing or who is suspected of being in process of overdosing.
  • the device contains a pharmaceutical solution as described herein, for example a solution comprising at least about 2% (w/v) up to about 4% (w/v) naloxone ⁇ e.g., naloxone HCI or a hydrate thereof).
  • the device Being a metered dose spray device, the device is configured to deliver a specific dose, for example at least about 2 mg, at least about 4 mg, or even at least about 8 mg in a single spray.
  • the volume of the spray can be anywhere from about 25 ⁇ _ to about 250 ⁇ _, for example about 50 ⁇ _, about 100 ⁇ _, about 150 ⁇ _, about 200 ⁇ _, and about 225 ⁇ _.
  • a 100 ⁇ _ spray of a 4% (w/v) naloxone HCI solution would deliver a 4 mg dose
  • a 200 ⁇ _ spray of the same solution would deliver an 8 mg dose.
  • compositions Because no less than 2 mg can be delivered from such a device, it is not possible to administer small ⁇ i.e., less than 0.5 mg) increments of naloxone to achieve a precise degree of opioid receptor occupancy, where the patient comes back from overdose but remains in a near-overdose state.
  • compositions comprising one or more opioid antagonist.
  • the pharmaceutical compositions comprise an opioid antagonist and a pharmaceutically acceptable carrier.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.
  • Some embodiments of the present invention include a method of producing a pharmaceutical composition comprising admixing at least one opioid antagonist and a pharmaceutically acceptable carrier. Pharmaceutical compositions are applied directly to the nasal cavity using the devices described herein. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • Liquid preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. Additional ingredients in liquid preparations may include: antimicrobial preservatives, such as benzalkonium chloride(which may also act as a cationic surfactant and/or a permeation enhancer),, methylparaben, sodium benzoate, benzoic acid, phenyl ethyl alcohol, and the like, and mixtures thereof; surfactants such as Polysorbate 80 NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate,
  • opioid antagonists described herein can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington: The Science and Practice of Pharmacy, 21 st ed., Lippincott Williams & Wilkins, Philadelphia, PA (2005).
  • the opioid antagonists described herein may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like, such as those pharmaceutically acceptable salts listed by Berge et al., Journal of Pharmaceutical Sciences, 66:1 -19 (1977).
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the opioid antagonists described herein may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • compositions for intranasal administration comprising, in an aqueous solution of not more than about 140 ⁇ _:
  • said opioid antagonist is the only pharmaceutically active compound in said pharmaceutical composition.
  • said opioid antagonist is naloxone hydrochloride, or a hydrate thereof.
  • said opioid antagonist is naloxone hydrochloride dihydrate.
  • the pharmaceutical formulation comprises an amount equivalent to about 4 mg to about 10 mg of naloxone hydrochloride. In some embodiments, the pharmaceutical formulation comprises an amount equivalent to an amount chosen from about 2 mg naloxone hydrochloride, about 4 mg of naloxone hydrochloride, and about 8 mg naloxone hydrochloride. In some embodiments, the pharmaceutical formulation comprises an amount equivalent to about 2 mg of naloxone hydrochloride. In some embodiments, the pharmaceutical formulation comprises an amount equivalent to about 4 mg of naloxone hydrochloride. In some embodiments, the pharmaceutical formulation comprises an amount equivalent to about 8 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3.4 mg of naloxone hydrochloride.
  • the pharmaceutical formulation comprises about 2.2 mg to about 13.2 mg of naloxone hydrochloride dihydrate. In some embodiments, the pharmaceutical formulation comprises about 4.4 mg to about 1 1 mg of naloxone hydrochloride dihydrate. In some embodiments, the pharmaceutical formulation comprises an amount chosen from about 2.2 mg naloxone hydrochloride dihydrate, about 4.4 mg of naloxone hydrochloride dihydrate, and about 8.8 mg naloxone hydrochloride dihydrate. In some embodiments, the pharmaceutical formulation comprises about 2.2 mg of naloxone hydrochloride dihydrate. In some embodiments, the pharmaceutical formulation comprises about 4.4 mg of naloxone hydrochloride dihydrate. In some embodiments, the pharmaceutical formulation comprises about 8.8 mg of naloxone hydrochloride dihydrate.
  • the device comprises about 4.4 mg naloxone hydrochloride dihydrate. In some embodiments, the device comprises about 2.2 mg naloxone hydrochloride dihydrate.
  • the pharmaceutical composition is in an aqueous solution of about 100 ⁇ _.
  • less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
  • the plasma concentration versus time curve of said naloxone hydrochloride in said patient has a t ma x of between about 20 and about 30 minutes.
  • said device is actuatable with one hand.
  • the delivery time is less than about 25 seconds. In some embodiments, the delivery time is less than about 20 seconds.
  • the 90% confidence interval for dose delivered per actuation is ⁇ about 2%. In some embodiments, the 95% confidence interval for dose delivered per actuation is ⁇ about 2.5%.
  • the plasma concentration versus time curve of said opioid antagonist in a patient has a t max of less than 30 minutes. In some embodiments, the plasma concentration versus time curve of said opioid antagonist in said patient has a tmax of less than 25 minutes. In some embodiments, the plasma concentration versus time curve of said opioid antagonist in said patient has a t ma x of about 20 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a t max of less than 19 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a t ma x of about 18.5 minutes.
  • delivery of said pharmaceutical formulation to a patient provides occupancy at t ma x of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 90%. In some embodiments, delivery of said pharmaceutical formulation to said patient, provides occupancy at t ma x of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 95%. In some embodiments, delivery of said pharmaceutical formulation to said patient, provides occupancy at t max of said opioid antagonist at the opioid receptors in the respiratory control center of said patient of greater than about 99%.
  • said patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. In some embodiments, said patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
  • compositions for intranasal administration comprising, in an aqueous solution of not more than about 140 ⁇ _:
  • the isotonicity agent is NaCI
  • the compound which is a preservative, cationic surfactant, and/or permeation enhancer is benzalkonium chloride;
  • the stabilizing agent is disodium edetate;
  • the acid is hydrochloric acid.
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises about 4 mg naloxone hydrochloride or a hydrate thereof. In some embodiments, the pharmaceutical formulation comprises about 2 mg naloxone hydrochloride or a hydrate thereof. In some embodiments, the pharmaceutical formulation comprises about 4.4 mg naloxone hydrochloride dihydrate. In some embodiments, the pharmaceutical formulation comprises about 2.2 mg naloxone hydrochloride dihydrate.
  • compositions for intranasal administration comprising, in an aqueous solution of about 100 ⁇ _:
  • a stabilizing agent between about 0.1 mg and about 0.5 mg of a stabilizing agent; and an amount of acid sufficient to achieve a pH of 3.5-5.5.
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises:
  • compositions for intranasal administration comprising, in an aqueous solution of about 100 ⁇ ⁇ _:
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises about 4.4 mg naloxone hydrochloride dihydrate. In some embodiments, the pharmaceutical formulation comprises about 2.2 mg naloxone hydrochloride dihydrate.
  • devices adapted for nasal delivery of a pharmaceutical composition to a patient comprising a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein the device is pre-primed, and wherein the therapeutically effective amount, is equivalent to about 2 mg to about 12 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4.4 mg of naloxone hydrochloride.
  • the pharmaceutical composition comprises a solution of naloxone hydrochloride dihydrate. In some embodiments, the pharmaceutical composition further comprises one or more excipients selected from water and NaCI. In some embodiments, the pharmaceutical composition is substantially free of antimicrobial preservatives. In some embodiments, the device is substantially free of benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenyl ethyl alcohol. In some embodiments, the device is filled with the pharmaceutical composition in a sterile environment. In some embodiments, the pharmaceutical composition is storage-stable for about twelve months at about 25 °C. In some embodiments, the pharmaceutical composition comprises less than 0.1 % w/w antimicrobial preservatives.
  • the pharmaceutical composition comprises 0.01 % w/w or less antimicrobial preservatives. In some embodiments, the pharmaceutical composition comprises 0.01 % w/w - 0.001 % w/w antimicrobial preservatives. In some embodiments, the pharmaceutical composition comprises less than 0.001 % w/w antimicrobial preservatives.
  • devices for "combination-therapy" comprising pharmaceutical compositions comprising at least one opioid antagonist described herein, together with at least one known pharmaceutical agent and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a short-acting opioid antagonist and a long-acting opioid antagonist.
  • the pharmaceutical composition comprises naloxone and naltrexone.
  • the pharmaceutical composition comprises naloxone and methylnaltrexone.
  • the pharmaceutical composition comprises naloxone and nalmefene.
  • any embodiment above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • Naloxone prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine. Naloxone causes abrupt reversal of narcotic depression which may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures and cardiac arrest, however, there is no clinical experience with naloxone hydrochloride overdosage in humans.
  • a method of preventing complications from severe opioid withdrawal comprising administering a dose of naloxone according to the devices and/or formulations disclosed herein, and then monitoring the patient for a symptom selected from the group consisting of vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures and cardiac arrest.
  • the intravenous LD50 is 150 ⁇ 5 mg/kg and 109 ⁇ 4 mg/kg respectively.
  • the LD50 (95% CL) is 260 (228-296) mg/kg.
  • Subcutaneous injection of 100 mg/kg/day in rats for 3 weeks produced only transient salivation and partial ptosis following injection: no toxic effects were seen at 10 mg/kg/day for 3 weeks.
  • Naloxone hydrochloride injection is indicated for the complete or partial reversal of narcotic depression, including respiratory depression, induced by opioids selected from: natural and synthetic narcotics, propoxyphene, methadone, and certain narcotic-antagonist analgesics: nalbuphine, pentazocine and butorphanol.
  • opioids selected from: natural and synthetic narcotics, propoxyphene, methadone, and certain narcotic-antagonist analgesics: nalbuphine, pentazocine and butorphanol.
  • Naloxone hydrochloride is also indicated for the diagnosis of suspected acute opioid overdosage. For the treatment of known or suspected narcotic overdose in adults an initial dose of 0.4 mg to 2 mg of naloxone hydrochloride intravenously is indicated. If the desired degree of counteraction and improvement in respiratory functions is not obtained, administration may be repeated at 2 to 3 minute intervals.
  • naloxone hydrochloride If no response is observed after 10 mg of naloxone hydrochloride have been administered, the diagnosis of narcotic-induced or partial narcotic-induced toxicity should be questioned.
  • the usual initial dose in children is 0.01 mg/kg body weight given IV. If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg body weight may be administered.
  • naloxone hydrochloride injection in neonates a product containing 0.02 img/mL ⁇ i.e., 0.002% w/v) should be used.
  • naloxone hydrochloride is an effective agent for the reversal of the cardiovascular and respiratory depression associated with narcotic and possibly some non-narcotic overdoses.
  • kits for treating opioid overdose or a symptom thereof comprising nasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein said therapeutically effective amount is equivalent to about 2 mg to about 12 mg of naloxone hydrochloride or a hydrate thereof.
  • the therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof is delivered in not more than about 140 ⁇ _ of an aqueous carrier solution.
  • kits for treating opioid overdose or a symptom thereof comprising nasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein said therapeutically effective amount is equivalent to about 2 mg to about 12 mg of naloxone hydrochloride or a hydrate thereof in not more than about 140 ⁇ _ of an aqueous carrier solution.
  • kits for treating opioid overdose, or a symptom thereof comprising nasally administering with a spray device to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein the spray device is capable of spraying droplets having a median droplet size between about 30 and about 100 ⁇ .
  • the spray device is capable of spraying a formulation having a median distribution volume (Dv(50)) Dv(50) of 30-70 ⁇ and a Dv(90) ⁇ 100 ⁇ .
  • the spray device is capable of spraying in a manner that the percent of droplets less than 10 ⁇ is less than 10%. In certain embodiments, the percent of droplets less than 10 ⁇ is less than 5%. In certain embodiments, the percent of droplets less than 10 ⁇ is less than 2%. In certain embodiments, the percent of droplets less than 10 ⁇ is less than 1 %.
  • the spray device is capable of spraying a uniform circular plume spray pattern with an ovality ratio close to 1 .
  • Ovality ratio is calculated as the quotient of the maximum diameter (Dmax) and the minimum diameter (Dmin) of a spray pattern taken orthogonal to the direction of spray flow (e.g., from the "top").
  • the ovality ratio is less than 2.0.
  • the ovality ratio is less than 1 .5.
  • the ovality ratio is less than 1 .3.
  • the ovality ratio is less than 1 .2.
  • the ovality ratio is less than 1 .1 .
  • the ovality ratio is about 1 .0.
  • kits for treating opioid overdose or a symptom thereof comprising nasally administering to a patient in need thereof a single dose of a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein said therapeutically effective amount is equivalent to about 2 mg to about 12 mg of naloxone hydrochloride or a hydrate thereof in not more than about 140 ⁇ _ of an aqueous carrier solution.
  • said opioid antagonist is the only pharmaceutically active compound in said pharmaceutical composition.
  • said opioid antagonist is naloxone hydrochloride. In some embodiments, said opioid antagonist is naloxone hydrochloride dihydrate.
  • said pharmaceutical composition comprises a solution of naloxone hydrochloride, or a hydrate thereof.
  • said patient is an opioid overdose patient or a suspected opioid overdose patient.
  • said patient is in a lying, supine, or recovery position. In some embodiments, said patient is in a lying position. In some embodiments, said patient is in a supine position. In some embodiments, said patient is in a recovery position.
  • said therapeutically effective amount of an opioid antagonist is delivered by an untrained individual.
  • said therapeutically effective amount is equivalent to about 4 mg to about 10 mg of naloxone hydrochloride. In some embodiments, said therapeutically effective amount is equivalent to an amount chosen from about 2 mg naloxone hydrochloride, about 4 mg of naloxone hydrochloride, and about 8 mg naloxone hydrochloride. In some embodiments, said therapeutically effective amount is equivalent to about 2 mg of naloxone hydrochloride. In some embodiments, said therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride. In some embodiments, said therapeutically effective amount is equivalent to about 8 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3.4 mg of naloxone hydrochloride.
  • said therapeutically effective amount is about 2.2 mg to about 13.2 mg of naloxone hydrochloride dihydrate. In some embodiments, said therapeutically effective amount is about 4.4 mg to about 1 1 mg of naloxone hydrochloride dihydrate. In some embodiments, said therapeutically effective amount is an amount chosen from about 2.2 mg naloxone hydrochloride dihydrate, about 4.4 mg of naloxone hydrochloride dihydrate, and about 8.8 mg naloxone hydrochloride dihydrate. In some embodiments, said therapeutically effective amount is about 2.2 mg of naloxone hydrochloride dihydrate. In some embodiments, said therapeutically effective amount is about 4.4 mg of naloxone hydrochloride dihydrate. In some embodiments, said therapeutically effective amount is about 8.8 mg of naloxone hydrochloride dihydrate.
  • said symptom is chosen from respiratory depression and central nervous system depression.
  • said patient exhibits any of unresponsiveness to stimulus, unconsciousness, stopped breathing; erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, and vomiting.
  • said patient is not breathing.
  • said patient is in a lying, supine, or recovery position.
  • said patient is in a lying position.
  • said patient is in a supine position.
  • said patient is a recovery position.
  • said therapeutically effective amount is equivalent to about 2 mg to about 10 mg of naloxone hydrochloride.
  • said therapeutically effective amount is equivalent to an amount chosen from about 2 mg naloxone hydrochloride, about 4 mg of naloxone hydrochloride, and about 8 mg naloxone hydrochloride.
  • said therapeutically effective amount is equivalent to about 2 mg of naloxone hydrochloride.
  • said therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride.
  • said therapeutically effective amount is equivalent to about 8 mg of naloxone hydrochloride.
  • said opioid antagonist is the only pharmaceutically active compound in said pharmaceutical composition.
  • said opioid antagonist is naloxone hydrochloride.
  • said nasally administering is accomplished using a pre-primed device adapted for nasal delivery of a pharmaceutical composition.
  • the plasma concentration versus time curve of said opioid antagonist in said patient has a t max of less than 30 minutes.
  • the plasma concentration versus time curve of said opioid antagonist in said patient has a t ma x of less than 25 minutes.
  • the plasma concentration versus time curve of said opioid antagonist in said patient has a t max of about 20 minutes.
  • said opioid overdose symptom is selected from: respiratory depression, central nervous system depression, and cardiovascular depression.
  • said opioid overdose symptom is respiratory depression induced by opioids.
  • said respiratory depression is caused by the illicit use of opioids or by an accidental misuse of opioids during medical opioid therapy.
  • said respiratory depression is induced by opioids selected from: natural and synthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocine and butorphanol.
  • said respiratory depression is induced by an opioid selected from codeine, morphine, methadone, fentanyl, oxycodone HCI, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, tapentadol.
  • an opioid selected from codeine, morphine, methadone, fentanyl, oxycodone HCI, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, tapentadol.
  • said patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
  • said patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
  • said patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
  • said patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
  • an opioid overdose symptom selected from: respiratory depression, postoperative opioid respiratory depression, altered level consciousness, miotic pupils, cardiovascular depression, hypoxemia, acute lung injury, aspiration pneumonia, sedation, and hypotension.
  • the respiratory depression is caused by the illicit use of opioids or by an accidental misuse of opioids during medical opioid therapy.
  • narcotic depression including respiratory depression, induced by opioids selected from: natural and synthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocine and butorphanol.
  • opioids selected from: natural and synthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocine and butorphanol.
  • narcotic depression, including respiratory depression is induced by an opioid agonist selected from codeine, morphine, methadone, fentanyl, oxycodone HCI, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, and tapentadol.
  • the patient is not breathing.
  • devices adapted for nasal delivery of a pharmaceutical composition to a patient comprising a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein the device is pre- primed, and wherein the therapeutically effective amount, is equivalent to about 4 mg to about 12 mg of naloxone hydrochloride.
  • the therapeutically effective amount is equivalent to about 2 mg to about 24 mg of naloxone hydrochloride.
  • the therapeutically effective amount is equivalent to about 3 mg to about 18 mg of naloxone hydrochloride.
  • the therapeutically effective amount is equivalent to about 4 mg to about 10 mg of naloxone hydrochloride.
  • the therapeutically effective amount is equivalent to about 5 mg to about 1 1 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 6 mg to about 10 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg to about 8 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 7 mg to about 9 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3.4 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride.
  • the therapeutically effective amount is equivalent to about 5 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 6 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 7 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 8 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 9 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 10 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 1 mg of naloxone hydrochloride.
  • the therapeutically effective amount is equivalent to about 12 mg of naloxone hydrochloride.
  • the opioid antagonist is the only pharmaceutically active compound in pharmaceutical composition.
  • the opioid antagonist is naloxone hydrochloride.
  • the opioid antagonist is anhydrous naloxone hydrochloride.
  • the opioid antagonist is the only pharmaceutically active compound in said pharmaceutical composition.
  • the opioid antagonist is naloxone hydrochloride.
  • the pharmaceutical composition comprises a solution of naloxone hydrochloride.
  • the nasally administering is accomplished using a device described herein.
  • the opioid overdose symptom is selected from: respiratory depression, postoperative opioid respiratory depression, altered level consciousness, miotic pupils, cardiovascular depression, hypoxemia, acute lung injury, aspiration pneumonia, sedation, and hypotension.
  • the opioid overdose symptom is respiratory depression induced by opioids.
  • the respiratory depression is caused by the illicit use of opioids or by an accidental misuse of opioids during medical opioid therapy.
  • the respiratory depression is induced by opioids selected from: natural and synthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocine and butorphanol.
  • the respiratory depression is induced by an opioid agonist selected from codeine, morphine, methadone, fentanyl, oxycodone HCI, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, and tapentadol.
  • an opioid agonist selected from codeine, morphine, methadone, fentanyl, oxycodone HCI, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, and tapentadol.
  • kits, and pharmaceutical formulations for, and methods of, treating opioid overdose or a symptom thereof comprising nasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist together and at least one known pharmaceutical agent.
  • the method comprises nasally administering to a patient in need thereof therapeutically effective amounts of a short-acting opioid antagonist and a long-acting opioid antagonist.
  • the method comprises nasally administering to a patient in need thereof therapeutically effective amounts of naloxone and naltrexone.
  • the method comprises nasally administering to a patient in need thereof therapeutically effective amounts of naloxone and methylnaltrexone.
  • the method comprises nasally administering to a patient in need thereof therapeutically effective amounts of naloxone and nalmefene.
  • kits, and pharmaceutical formulations for, and methods of, reversing the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine comprising nasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein the therapeutically effective amount is equivalent to about 2 mg to about 12 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4.4 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride dihydrate. In some embodiments, the nasally administering is accomplished using a device described herein.
  • kits, and pharmaceutical formulations for, and methods of, diagnosis of suspected acute opioid overdosage comprising nasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein the therapeutically effective amount is equivalent to about 2 mg to about 12 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4.4 mg of naloxone hydrochloride dihydrate. In some embodiments, the nasally administering is accomplished using a device described herein.
  • kits, and pharmaceutical formulations for, and methods of, treating opioid addiction comprising nasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein the therapeutically effective amount is equivalent to about 2 mg to about 12 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4.4 mg of naloxone hydrochloride dihydrate. In some embodiments, the nasally administering is accomplished using a device described herein.
  • kits, and pharmaceutical formulations for, and methods of, treating septic shock comprising nasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein the therapeutically effective amount is equivalent to about 2 mg to about 12 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4.4 mg of naloxone hydrochloride dihydrate. In some embodiments, the nasally administering is accomplished using a device described herein.
  • the therapeutically effective amount is equivalent to about 4.4 mg of naloxone hydrochloride dihydrate.
  • the therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride.
  • the patient is an opioid overdose patient. In some embodiments, the patient is not breathing.
  • the opioid antagonist is the only pharmaceutically active compound in said pharmaceutical composition. In some embodiments, the opioid antagonist is selected from naltrexone, methylnaltrexone, and nalmefene, and pharmaceutically acceptable salts thereof. In some embodiments, the opioid antagonist is naltrexone hydrochloride. In some embodiments, the opioid antagonist is methylnaltrexone bromide. In some embodiments, the opioid antagonist is nalmefene hydrochloride. In some embodiments, the nasally administering is accomplished using a device described herein.
  • the opioid overdose symptom is selected from: respiratory depression, postoperative opioid respiratory depression, altered level consciousness, miotic pupils, cardiovascular depression, hypoxemia, acute lung injury, aspiration pneumonia, sedation, and hypotension.
  • the opioid overdose symptom is respiratory depression induced by opioids.
  • the respiratory depression is caused by the illicit use of opioids or by an accidental misuse of opioids during medical opioid therapy.
  • the respiratory depression is induced by opioids selected from: natural and synthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocine and butorphanol.
  • the respiratory depression is induced by an opioid agonist selected from codeine, morphine, methadone, fentanyl, oxycodone HCI, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, and tapentadol.
  • an opioid agonist selected from codeine, morphine, methadone, fentanyl, oxycodone HCI, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, and tapentadol.
  • any embodiment above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • uses in the treatment of indications or one or more symptoms thereof as disclosed herein and uses in the manufacture of medicaments for the treatment of indications or one or more symptoms thereof as disclosed herein, equivalent in scope to any embodiment disclosed herein, or any combination thereof that is not mutually exclusive.
  • the methods and uses may employ any of the devices disclosed herein or any combination thereof that is not mutually exclusive, or any of the pharmaceutical formulations disclosed herein or any combination thereof that is not mutually exclusive.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • PET and SPECT are noninvasive imaging techniques that can give insight into the relationship between target occupancy and drug efficacy, provided a suitable radioligand is available.
  • SPECT has certain advantages (e.g., a long half-life of the radionuclides), the spatial and temporal resolution as well as the labeling possibilities of this technique are limited.
  • PET involves the administration to a subject of a positron-emitting radionuclide tracer followed by detection of the positron emission (annihilation) events in the body.
  • the radionuclide tracer is typically composed of a targeting molecule having incorporated therein one or more types of positron-emitting radionuclides.
  • Positron- emitting radionuclides include 11 C, 13 N, 15 O, 18 F, 52 Fe, 62 Cu, 64 Cu, 68 Ga, 74 As, 82 Rb, 89 Zr, 122 l, and 124 l.
  • Non-metal radionuclides may be covalently linked to the targeting molecule by reactions well known from the state of art. When the radionuclide is a metallic positron-emitter, it is understood that labeling may require the use of a chelating agent. Such chelating agents are well known from the state of the art.
  • the positron-emitter labeled compound is administered directly, e.g., IV, or indirectly, e.g., IN, into the subject's vascular system, from where it passes through the blood-brain barrier.
  • the individual is placed within in a scanning device comprising ring of scintillation detectors.
  • An emitted positron travels through the individual's tissue for a short (isotope-dependent) distance, until it interacts with an electron.
  • the interaction annihilates both the electron and the positron, producing a pair of photons moving in approximately opposite directions. These are detected when they reach a scintillator in the scanning device. Photons that do not arrive in pairs are ignored.
  • An image is then generated of the part of the individual's brain to which the compound has distributed.
  • PET studies are useful for comparing nasal delivery of naloxone using the devices and at the doses described herein, to typical nasal doses of naloxone (such as 1 -2 mg), to delivery of naloxone using other nasal devices (such as the MADTM) and by other routes of administration such IM or IV naloxone or oral naltrexone or nalmefene. Further comparisons may be made between nasal administration in the upright versus the lying or supine positions.
  • naltrexone or a novel ⁇ -opioid receptor inverse agonist (GSK1521498) (Rabiner et al., Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward- related brain activation in humans. Molecular Psychiatry (201 1 ) 16, 826-835).
  • the administered doses of GSK1521498 or naltrexone were chosen adaptively to optimize the estimation of the dose-occupancy relationship for each drug on the basis of data acquired from the preceding examinations in the study.
  • the maximum doses administered were equal to the maximum tolerated dose of GSK1521498 determined in the first-in-human study and the standard clinical dose of naltrexone used for alcohol dependence.
  • the times and doses of the two post-dose [ 11 C]-carfentanil PET scans were chosen adaptively for each subject to optimize estimation of the relationship between plasma concentration and receptor occupancy.
  • Post-dose [ 11 C]-carfentanil PET scans were acquired at 3-36 h after the administration of GSK1521498 and at 3- 88 h after the administration of naltrexone.
  • Post-dose fMRI scans were acquired within 60 min of the first post-dose PET scan. Venous blood samples were collected at regular intervals throughout the scanning sessions.
  • High-performance liquid chromatography/mass spectrometry/mass spectrometry was used to estimate the plasma concentrations of GSK1521498, naltrexone, and the major metabolite of naltrexone, 6-p-naltrexol.
  • Drug plasma concentration at the start of each PET scan was used to model the relationship between drug concentrations and ⁇ -opioid receptor occupancies.
  • Carfentanil (methyl 1 -(2-phenylethyl)-4-(phenyl(propanoyl)amino)-4- piperidinecarboxylate 3S, 5S; Advanced Biochemical Compounds, Radeberg, Germany), a potent selective ⁇ -opioid receptor agonist, was labelled with carbon-1 1 using a modification of a previously described method implemented using a semiautomated Modular Lab Multifunctional Synthetic Module (Eckert & Ziegler, Berlin, Germany). The final product was reformulated in sterile 0.9% saline containing -10% ethanol (v/v) and satisfied quality control criteria for specific activity and purity before being injected intravenously as a slow bolus over -30 s.
  • PET scanning was conducted in three-dimensional mode using a Siemens Biograph 6 Hi-Rez PET-CT for the naltrexone group and a Siemens Biograph 6 TruePoint PET-CT for the GSK1521498 group (Siemens Healthcare, Eriangen, Germany).
  • a low-dose CT scan was acquired for attenuation correction before the administration of the radiotracer.
  • Dynamic PET data were acquired for 90 min after [ 11 C]-carfentanil injection, binned into 26 frames (durations: 8 15 s, 3 ⁇ 60 s, 5 ⁇ 2 min, 5 x 5 min and 5 x 1 0 min), reconstructed using Fourier re-binning and a two-dimensional-filtered back projection algorithm and then smoothed with a two-dimensional Gaussian filter (5 mm at full width half maximum).
  • Dynamic PET images were registered to each participant's T1 -weighted anatomical MRI volume and corrected for head motion using SPM5 software (Wellcome Trust Centre for Neuroimaging).
  • Pre-selected regions of interests were defined bilaterally on the T1 - weighted anatomical volume using an in-house atlas and applied to the dynamic PET data to generate regional time-activity curves.
  • the [ 11 C]-carfentanil-specific binding was quantified as binding potential relative to the non-displaceable compartment (BP N D)
  • fND is the free fraction of the radioligand in the brain
  • KD is the affinity of [ 11 C]- carfentanil
  • B ava ii is the density of the available ⁇ -opioid receptors.
  • Regional [ 11 C]- carfentanil BP N D was estimated using a reference tissue model with the occipital cortex as the reference region. Drug related occupancy of the ⁇ -opioid receptor was quantified as a reduction of [ 11 C]-carfentanil.
  • the affinity constant for each drug at the ⁇ -opioid receptor was estimated by fitting the plasma concentration measured at the start of the PET scan, C P D rU g, to the estimated occupancy: ⁇ - ' Drug
  • [ 11 C]Diprenorphine was administered to normal volunteers in tracer amounts and, 30 min later, various bolus doses of naloxone were given (1 .5-160 pg/kg) intravenously and change in [ 11 C]diprenorphine binding monitored over the next 30 min. Approximately 13 g/kg of naloxone (approximately 1 mg in an 80 kg man) was required to produce an estimated 50% receptor occupation, consistent with the clinical dose of naloxone used to reverse opiate overdose (0.4 mg-1 .2 mg). Melichar et al., Naloxone displacement at opioid receptor sites measured in vivo in the human brain. Eur J Pharmacol. 2003 Jan 17;459(2-3):217-9).
  • delivery of the therapeutically effective amount to the patient provides occupancy at t ma x of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 90%. In some embodiments, delivery of the therapeutically effective amount to the patient, provides occupancy at t max of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 95%. In some embodiments, delivery of the therapeutically effective amount to the patient, provides occupancy at t ma x of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 99%. In some embodiments, delivery of the therapeutically effective amount to the patient, provides occupancy at t ma x of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of about 100%.
  • a system is provided herein that includes a patient device associated with a patient location and a plurality of dispenser devices.
  • Each dispenser device is associated with a dispenser of devices, kits, and pharmaceutical solutions ("product") as disclosed herein.
  • Each dispenser device is located at a dispenser location and stores dispenser information including dispenser location data, product availability data, and whether the dispenser is or is not presently in service.
  • a server is in communication with the patient device and/or the plurality of dispenser devices and is configured to receive a patient request for information about availability and location of product from the patient device, to receive the dispenser information from each of the dispenser devices, to apply a selection criteria to the received dispenser information, to determine at least one potential dispenser located proximal to the patient location and in service at the time of request, and to communicate the dispenser information for the at least one potential dispenser to the patient device.
  • the patient device is configured to receive the dispenser information for the at least one potential dispenser from the server, and to display the dispenser information for the at least one potential dispenser.
  • the server is also configured to receive a signal from the patient indicating that the patient intends to retrieve product from at least one of the indicated dispensers and to notify the dispenser device that the patient is coming to retrieve product from the dispenser.
  • a method includes storing, in each of a plurality of dispenser devices, dispenser information for an associated dispenser, including dispenser location data corresponding to a dispenser location of the associated contractor, product availability data, and whether the dispenser is or is not presently in service.
  • the method also includes receiving, with a server, a request for information about product availability in locations relative to the patient.
  • the method also includes receiving, with the server, product availability data and location data from one or more dispensers.
  • the method also includes applying, with the server, a selection criteria to the received dispenser information to determine at least one potential dispenser for the patient request based on the application of the selection criteria.
  • the method also includes communicating the dispenser information for the at least one potential dispenser to the patient device.
  • the method also includes receiving, with the patient device, the dispenser information for the at least one potential dispenser from the server.
  • the method also includes displaying, with the dispenser device, the dispenser information for the at least one potential dispenser.
  • the method also includes sending, from the patient device, a selection indicating a designated dispenser from the at least one potential dispenser to request that the dispenser make product ready and available for the patient.
  • the method also includes communicating the selection from the patient device to the server.
  • the method also includes notifying, with the server, the dispenser device for the designated dispenser of the selection.
  • Example 1 Pharmacokinetics and Safety of Intranasal Naloxone in Humans (Study 1).
  • PK pharmacokinetics
  • IM intramuscularly
  • the secondary objectives were to determine the safety of IN naloxone, specifically with respect to nasal irritation (erythema, edema, and erosion).
  • ECG ECG
  • vital signs were measured pre- dose and approximately 30, 60, 120, and 480 min post-dose.
  • the order of assessments was ECG, vital signs, then PK blood collection when scheduled at the same nominal times. ECG and vital signs were collected within the 10-min period before the nominal time of blood collections.
  • ECG and vital signs were checked once per day. Vital signs were also checked once on the day after naloxone administration.
  • Clinical laboratory measurements were repeated after the last PK blood draw prior to clinic discharge. AEs were assessed by spontaneous reports by subjects, examination of the nasal mucosa, physical examination, vital signs, ECG, and clinical laboratory parameters.
  • Naloxone given IN was at a dose of 2 mg (1 squirt in each nostril delivered 0.1 mL of 10 img/mL naloxone) and 4 mg (2 squirts in each nostril delivered 0.2 imL/nostril at 10 img/mL naloxone, using two devices).
  • IN naloxone was administered using a Pfeiffer (Aptar) BiDose liquid device with the subject in a fully supine position.
  • Naloxone was given IM at a dose of 0.4 mg in 1 .0 mL with a 23-g needle as a single injection in the gluteus maximus muscle.
  • PK Evaluation Blood was collected in sodium heparin containing tubes for naloxone PK prior to dosing and 2.5, 5, 10, 15, 20, 30, 45, 60, 120, 180, 240, 300, 360, 480, and 720 min after the start of study drug administration.
  • Non-compartmental PK parameters including C ma x, , AUC to infinity (AUCo- ⁇ ), AUC to last measurable concentration (AUC 0 -t), U/2, ⁇ ⁇ , and apparent clearance (CL/F) were determined. Values of t-i/2 were determined from the log-linear decline in plasma concentrations from 2 to 6 or 8 h.
  • Heart rate, blood pressure, and respiration rate was recorded before naloxone dosing and at approximately 30, 60, 120, and 480 min after dosing. These vital signs and temperature were also measured at screening, clinic intake, one day after each dosing session and at follow-up.
  • a 12-lead ECG was obtained prior to and approximately 60 and 480 min after each naloxone dose, as well as during screening, clinic intake, and follow-up. ECG and vital signs were taken within the 10-min period before the nominal time for blood collections.
  • AEs were recorded from the start of study-drug administration until clinic discharge. AEs were recorded relative to each dosing session to attempt to establish a relationship between the AE and type of naloxone dose administered.
  • AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 19. Preferred terms and are grouped by system, organ, class (SOC) designation. AEs are presented as a listing including the start date, stop date, severity, relationship, outcome, and duration.
  • Pharmacokinetics Results The mean dose delivered for the 2 mg IN naloxone dose was 1 .71 mg (range 1 .50 mg to 1 .80 mg) and for the 4 mg IN naloxone dose it was 3.40 mg (range 2.93 mg to 3.65 mg). This was 84-85% of the target dose. The overall % coefficient of variation (%CV) for the delivered dose from all 42 devices was 6.9% (Table 9).
  • Preparation time of the IN doses took less than one third of the time to prepare the IM injection (70 seconds for the IM injection and 20 seconds for the IN administration) (Table 8).
  • the time to prepare the IM injection did not include loading the syringe. Since the one purpose of the study was to determine if peak naloxone plasma concentrations (C ma x) and AUCs following IN 2 mg and IN 4 mg administrations were equivalent to, or greater than IM 0.4 mg dosing, AUCs and C ma x values were compared without considering the dose difference among treatments.
  • the C max , AUC 0 -t, and AUC 0 - ⁇ for both the 2 mg IN and 4 mg IN doses were statistically significantly greater than those for the 0.4 mg IM dose (p ⁇ 0.001 ).
  • the geometric least square means for C ma x were 2.18 ng/mL, 3.96 ng/mL, and 0.754 ng/mL for IN 2 mg, IN 4 mg and IM 0.4 mg, respectively.
  • the geometric least square means for AUC 0 - ⁇ were 3.32 ng-h/mL, 5.47 ng-h/mL and 1 .39 ng-h/mL for IN 2mg, IN 4 mg and IM 0.4 mg respectively.
  • the geometric least squares mean ratios for IN 2 mg/IM 0.4 mg were 290% for Cmax and 239% for AUC 0 - ⁇ .
  • the ratios for IN 4 mg/IM 0.4 mg were 525% for Cmax and 394% for AUC 0 - ⁇ .
  • the mean t ma x values did trend lower for the IN route versus IM, and for 4 mg IN versus 2 mg IN. (See Table 2).
  • the F re i estimates were 55.7% and 46.3% for IN 2 mg and 4 mg, respectively. See Table 3.
  • the study had several objectives. The first was to determine the pharmacokinetics (i.e., the C ma x, t ma x, AUCo-inf and AUC-o-t) of 4 intranasal doses - 2 mg, 4 mg (2 nostrils), 4 mg (1 nostril), and 8 mg (2 nostrils) - of naloxone compared to a 0.4 mg dose of naloxone administrated IM and to identify an appropriate IN dose that could achieve systemic exposure comparable to an approved parenteral dose. The second was to determine the pharmacokinetics of two different concentrations (20 mg/mL and 40 mg/mL) of IN naloxone. The third was to determine the safety of IN naloxone, including adverse events, vital signs, and clinical laboratory changes, specifically with respect to nasal irritation (erythema, edema, and erosion).
  • the study was an inpatient open-label, randomized, 5-period, 5- treatment, 5-sequence, crossover study involving approximately 30 healthy volunteers, randomized to have at least 24 subjects who complete all study drug administrations and blood collections for PK assessments. Subjects were assigned to one of the 5 sequences and there were 6 subjects in each.
  • Inclusion criteria were: men or women 18 to 55 years of age, inclusive; written informed consent; BMI ranging from 18 to 30 kg/m2, inclusive; adequate venous access; no clinically significant concurrent medical conditions; agreement to use a reliable double-barrier method of birth control from the start of screening until one week after completing the study (oral contraceptives are prohibited); and agreement not to ingest alcohol, drinks containing xanthine >500 mg/day, or grapefruit/grapefruit juice, or participate in strenuous exercise 72 hours prior to admission through the last blood draw of the study.
  • Exclusion criteria were: any IN conditions including abnormal nasal anatomy, nasal symptoms (i.e., blocked and/or runny nose, nasal polyps, etc.), or having a product sprayed into the nasal cavity prior to drug administration; taking prescribed or over-the-counter medications, dietary supplements, herbal products, vitamins, or recent use of opioid analgesics for pain relief (within 14 days of last use of any of these products); positive urine drug test for alcohol, opioids, cocaine, amphetamine, methamphetamine, benzodiazepines, tetrahydrocannabinol (THC), barbiturates, or methadone at screening or admission; previous or current opioid, alcohol, or other drug dependence (excluding nicotine and caffeine), based on medical history; subject consumes greater than 20 cigarettes per day on average, in the month prior to screening, or would be unable to abstain from smoking (or use of any nicotine- containing substance) for at least one hour prior to and 2 hours after naloxone dosing; on standard 12-lead
  • Naloxone for IM injection manufactured by Hospira was obtained from a licensed distributor at a concentration of 0.4 img/mL and was given IM at a dose of 0.4 mg in 1 .0 imL with a 23-g needle as a single injection in the gluteus maximus muscle.
  • Naloxone for IN administration was obtained from Lightlake Therapeutics, Inc., London, United Kingdom at two concentrations of 20 img/mL and 40 img/mL, and was given as doses of 2 mg (one 0.1 imL spray of the 20 img/mL formulation in one nostril), 4 mg (two 0.1 imL sprays of the 20 img/mL formulation in two nostrils), 4 mg (one 0.1 imL spray of the 40 img/mL formulation in one nostril) and 8 mg (two 0.1 imL sprays of the 40 img/mL formulation in two nostril).
  • IN naloxone was administered using an Aptar single dose device with the subject in a fully supine position. Subjects were to be instructed to not breathe through the nose when the IN dose of naloxone was administered.
  • the target time of the PK blood collection was considered the most important, and if the collection was more than ⁇ 1 minute from the scheduled time for the first 60 minutes of collections or more than ⁇ 5 minutes for the scheduled time points thereafter, this was considered a protocol deviation.
  • ECG and vital signs were collected within the 10 minute period before the nominal time of blood collections. At screening, admission, discharge, and follow-up, ECG and vital signs were checked once per day. Vital signs were also checked once on the day after naloxone administration. Clinical laboratory measurements were repeated after the last PK blood draw prior to clinic discharge. Adverse events were assessed by spontaneous reports by subjects, by examination of the nasal mucosa, by measuring vital signs, ECG, and clinical laboratory parameters.
  • Results are shown below in Table 10, which sets forth the mean from 28 healthy subjects (and SD, in parentheses) plasma concentrations of naloxone following single intranasal administrations and an intramuscular injection, and in Figures 3 and 4.
  • PK parameters including C max , t max , AUC 0 -inf, AUC 0 -t, U/2, ⁇ ⁇ , and apparent clearance (CL/F) were determined.
  • Pharmacokinetic parameters (C max , t max , and AUCs) for IN naloxone were compared with those for IM naloxone.
  • t max was from the time of administration (spraying into the nasal cavity or IM injection).
  • Results are shown below in Table 1 1 , which sets forth the mean plasma PK parameters from 28 healthy subjects (and % CV, in parentheses) of naloxone following single intranasal administrations and an intramuscular injection, and in Table 12, which sets forth the same PK parameters split between the 12 female and 16 male healthy subjects. Results from a replication study conducted according to substantially the same experimental protocols are shown in Table 1 1 below. Table 1 1 . Mean plasma PK parameters from 28 healthy subjects.
  • the notation a indicates median (range) is disclosed, and the notation b indicates harmonic mean is disclosed.
  • AEs were coded using the MedDRA, v. 19 preferred terms and grouped by system, organ, class (SOC) designation. Separate summaries will be provided for the 5 study periods: after the administration of each dose of study drug up until the time of the next dose of study drug or clinic discharge.
  • Listings of each individual AE including start date, stop date, severity, relationship, outcome, and duration were provided. Results are given below in Tables 14 and 15. Table 14 shows the events related to nasal irritation - erythema, edema, other, and total - observed in the nasally- treated group. Nasal irritation did not appear to be positively related to the dose of naloxone given.
  • Table 15 shows additional events related to administration either nasally or intramuscularly. Overall, few adverse events were reported.
  • Example 3 Naloxone Nasal Spray Formulations and Stability.
  • Naloxone has been formulated as a disposable Luer-Jet Luer-lock pre- filled injectable syringe. Although not approved as a combined product, this formulation is sometimes combined with an nasal atomizer kit product, comprising 1 mg/ml naloxone hydrochloride as an active agent, 8.35 mg/ml NaCI as an isotonicity agent, HCI q.s. to target pH, and purified water q.s. to 2.0 ml. Benzalkonium chloride may be added as a preservative and supports the stability of a multi-dose product. Such syringes, while functional, can be difficult to use by untrained personnel, and deliver a large volume of solution.
  • compositions comprising naloxone hydrochloride (1 , 2, or 4 % w/v, i.e., 10, 20, or 40 img/mL) were stored at 25 °C and 60% relative humidity or 40 °C and 75% relative humidity in upright clear glass vials (200 ⁇ _) stoppered with a black plunger.
  • the 2% and 4% (w/v) compositions were also tested at 40 °C and 75% relative humidity.
  • Vials of the 1 % (w/v) compositions were either nude (Batch 1 ), or mounted in the Pfeiffer BiDose device (Batch 2).
  • the pharmaceutical compositions further comprised water, benzalkonium chloride, and disodium edetate.
  • the vials were assayed at 0, 1 , 3, 6, 9, and/or 12 months for naloxone content using a high-pressure liquid chromatography method.
  • Naloxone was analyzed at each stability station using a validated (as per the International Conference on Harmonisation Guidance Q2(R1 ) (ICH Q2(R1 )) reverse phase high pressure liquid chromatography (RP-HPLC) method and ultraviolet (UV) detection.
  • the chromatographic system used a C6-phenyl chromatography column at a flow rate of 0.8 imL/min and a column temperature of 40 °C.
  • the injection volume was 10 ⁇ _; the gradient A/B 60/40 to 40/60; the mobile phase A 25 mM sodium phosphate at pH 6.8; the mobile phase B: 100% acetonitrile.
  • the ultra-violet detector wavelength was 229 nm and the runtime was 20 min.
  • the assay data in Table 18 were generated over the course of development.
  • the 25 °C/60%RH experiments were conducted with clinical batches and the 40 ⁇ /75% ⁇ experiments used later manufactured registration or stability batches. It is evident from the results of the study, reported as a percentage of the label claim in Tables 17 and 18 below, that these pharmaceutical compositions are storage-stable for at least 9-12 months at 25 °C and 60% relative humidity.
  • Table 19 Twelve month naloxone storage stability.
  • the naloxone hydrochloride nasal spray above is an aqueous solution which may be presented in a Type I glass vial closed with a chlorobutyl rubber plunger which in turn is mounted into a unit-dose nasal spray device (such as an Aptar UDS liquid UnitDose device).
  • the solution should be a clear and colorless or slightly yellow liquid.
  • the device is a non-pressurized dispenser delivering a spray containing a metered dose of the active ingredient.
  • each delivered dose contains 100 ⁇ _.
  • the droplet size distribution was investigated as a function of device age and storage according to established and validated testing methods.
  • a Malvern Spray Tec 2.0 with automated device actuation was used for determining the droplet size distribution of Naloxone Nasal Spray.
  • Spraytec laser diffraction system allows measurement of spray droplet size distributions in real-time.
  • Droplet Size Distribution As reported from the Malvern Spraytec, the distribution is a cumulative volume distribution characterized by the Dv(10), Dv(50), and Dv(90). % ⁇ 10 pm. Data concerning droplet size distribution are summarized in Tables 21 and 23.
  • the spray pattern is the shape of the plume when looking downward on the nasal spray unit as the product is emitted from the nasal spray unit.
  • Spray pattern was also investigated as a function of device age and storage. Ovality is the ratio of Dmax/Dmin, where D max and D min are the length of the longest and shortest line respectively in mm that passes through the weighted center of mass drawn within the parameter of the spray pattern.
  • a SPRAYVIEW from PROVERIS measurement systems, was used to measure spray pattern and plume geometry. Both the Sprayview and Spraytec systems have been validated. Data concerning spray pattern are summarized in Tables 22 and 24. The procedures of these tests comply with the testing contained in the FDA's Guidance for Industry ("Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products - Chemistry, Manufacturing, and Controls Documentation," July 2002).
  • Table 21 Droplet size distribution from 2 mg naloxone intranasal device.
  • Table 22 Spray pattern from 2 mg naloxone intranasal device.
  • Table 23 Droplet size distribution from 4 mg naloxone intranasal device.
  • Table 24 Spray pattern from 4 mg naloxone intranasal device.
  • compositions comprising naloxone hydrochloride (1 % w/v) were tested for stability in room temperature/light conditions, room temperature/dark conditions and in 25 "0/60 % RH (protected from light). It was tested for pH, purity, and impurities at an initial time point, 2 months and 10 months. Results are given in Table 25.
  • Example 4 Reliability of use by untrained personnel.
  • the intranasal delivery provides a quick, simple and effective solution for those bystanders, friends or family members that are in a position to give aid to an overdose victim.
  • Study 2 The second study evaluated a single device.
  • Table 26 Reliability of intranasal naloxone administration by untrained personnel.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Addiction (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Psychiatry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des produits médicamenteux conçus pour l'administration par voie nasale, comprenant un dispositif pré-amorcé rempli d'une composition pharmaceutique comprenant un antagoniste du récepteur des opioïdes. L'invention concerne également des méthodes de traitement d'une prise excessive d'opioïdes ou de ses symptômes avec les produits médicamenteux selon l'invention.
PCT/US2016/052280 2015-09-17 2016-09-16 Produits médicamenteux d'administration par voie nasale et leurs méthodes d'utilisation Ceased WO2017049181A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP16847459.1A EP3349756A4 (fr) 2015-09-17 2016-09-16 Produits médicamenteux d'administration par voie nasale et leurs méthodes d'utilisation
MX2018003349A MX2018003349A (es) 2015-09-17 2016-09-16 Productos de farmaco nasal y metodos de su uso.
CA2950687A CA2950687C (fr) 2015-09-17 2016-09-16 Produits de medicament administre par voie nasale et methodes d'utilisation associees

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562219955P 2015-09-17 2015-09-17
US62/219,955 2015-09-17
US201662274536P 2016-01-04 2016-01-04
US62/274,536 2016-01-04

Publications (1)

Publication Number Publication Date
WO2017049181A1 true WO2017049181A1 (fr) 2017-03-23

Family

ID=58289745

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/052280 Ceased WO2017049181A1 (fr) 2015-09-17 2016-09-16 Produits médicamenteux d'administration par voie nasale et leurs méthodes d'utilisation

Country Status (4)

Country Link
EP (1) EP3349756A4 (fr)
CA (1) CA2950687C (fr)
MX (1) MX2018003349A (fr)
WO (1) WO2017049181A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3675837A4 (fr) * 2017-10-09 2021-04-14 Adapt Pharma Operations Limited Solutions d'antagoniste d'opioïde stables à basse température

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150018379A1 (en) * 2011-05-13 2015-01-15 Euro-Celtique S.A. Intranasal Pharmaceutical Dosage Forms Comprising Naloxone
US20150174061A1 (en) * 2013-12-20 2015-06-25 AntiOP, Inc. Intranasal naloxone compositions and methods of making and using same
US20150258019A1 (en) * 2014-03-14 2015-09-17 Lightlake Therapeutics, Inc. Nasal drug products and methods of their use

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003296954A1 (en) * 2002-12-13 2004-07-09 The Regents Of The University Of California Analgesic combination comprising nalbuphine
CN1575795A (zh) * 2003-06-25 2005-02-09 中国人民解放军军事医学科学院毒物药物研究所 盐酸纳洛酮鼻腔喷雾剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150018379A1 (en) * 2011-05-13 2015-01-15 Euro-Celtique S.A. Intranasal Pharmaceutical Dosage Forms Comprising Naloxone
US20150174061A1 (en) * 2013-12-20 2015-06-25 AntiOP, Inc. Intranasal naloxone compositions and methods of making and using same
US20150258019A1 (en) * 2014-03-14 2015-09-17 Lightlake Therapeutics, Inc. Nasal drug products and methods of their use

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GUO ET AL.: "The Influence of Actuation Parameters on In Vitro Testing of Nasal Spray Products", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 95, 9 September 2006 (2006-09-09), XP055519728, Retrieved from the Internet <URL:https://www.researchgate.net/profile/William_Doub3/publication/6919953_The_lnfluence_of_ctuation_Parameters_on_ln_Vitro_Testing_of_Nasal_Spray_Products/links/55a009e908ae967fb3e96c37.pdf> [retrieved on 20161106] *
See also references of EP3349756A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3675837A4 (fr) * 2017-10-09 2021-04-14 Adapt Pharma Operations Limited Solutions d'antagoniste d'opioïde stables à basse température

Also Published As

Publication number Publication date
MX2018003349A (es) 2018-11-12
CA2950687A1 (fr) 2017-03-17
CA2950687C (fr) 2023-02-28
EP3349756A1 (fr) 2018-07-25
EP3349756A4 (fr) 2019-05-15

Similar Documents

Publication Publication Date Title
US9775838B2 (en) Nasal drug products and methods of their use
US20210275519A1 (en) Nasal drug products and methods of their use
US20220071896A1 (en) Nasal drug products and methods of their use
US9211253B2 (en) Nasal drug products and methods of their use
US20180169006A1 (en) Co-packaged drug products
WO2018064672A1 (fr) Traitement avec la naloxone intranasale
US20210186954A1 (en) Drug products for nasal administration and uses thereof
CA2950687C (fr) Produits de medicament administre par voie nasale et methodes d&#39;utilisation associees
HK40046528A (en) Nasal drug products and methods of their use
HK40024027A (en) Drug product for nasal delivery, pharmaceutical composition for intranasal administration and use thereof

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 2950687

Country of ref document: CA

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16847459

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: MX/A/2018/003349

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2016847459

Country of ref document: EP