WO2018064672A1 - Traitement avec la naloxone intranasale - Google Patents

Traitement avec la naloxone intranasale Download PDF

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WO2018064672A1
WO2018064672A1 PCT/US2017/054774 US2017054774W WO2018064672A1 WO 2018064672 A1 WO2018064672 A1 WO 2018064672A1 US 2017054774 W US2017054774 W US 2017054774W WO 2018064672 A1 WO2018064672 A1 WO 2018064672A1
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recited
naloxone
pharmaceutical formulation
occupancy
subject
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Roger CRYSTAL
Michael Brenner WEISS
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Opiant Pharmaceuticals Inc
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Opiant Pharmaceuticals Inc
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    • 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

Definitions

  • Opioid receptors are G protein-coupled receptors (GPCRs) that are activated both by endogenous opioid peptides and by clinically important analgesic opioid drugs such as morphine, oxycodone, hydrocodone, and codeine, as well as by illicit opioid drugs.
  • GPCRs G protein-coupled receptors
  • opioid receptors There are three principal types of opioid receptors: the ⁇ -opioid receptor, the ⁇ -opioid receptor, and the ⁇ -opioid receptor.
  • Opioids effect a wide variety of physiologic changes, some transient and some more persistent, by binding to and activating opioid receptors (in the case of opioid agonists). These include effects on regions of the brain where opioid receptors reside or exert downstream effects, such as in the regions controlling respiration and reward.
  • Opioid receptors are abundant in respiratory control centers that include, primarily, the brainstem (including medulla oblongata, pons, and midbrain), as well as higher centers such as the insula, thalamus, and anterior cingulate cortex. Brainstem structures including medullary respiratory centers are critical in sensing and responding to chemical components of the blood via chemoreceptors, and generating and maintaining respiratory rhythm. See, e.g., Pattinson, Br J Anaesth (2008) 100 (6):747-758.
  • Opioid agonists produce inhibition at the chemoreceptors via ⁇ -opioid receptors and in the medulla via ⁇ - and ⁇ -opioid receptors. Accordingly, a sufficiently high dose of an opioid agonist can cause fatal respiratory depression, especially when combined with benzodiazepines, alcohol, and other substances which facilitate the inhibitory effect of the neurotransmitter ⁇ -aminobutyric acid (GABA) at the GABAA receptor, and/or decrease the excitatory effect of the neurotransmitter glutamate at N-methyl-D-aspartate (NMD A) receptors.
  • GABA neurotransmitter ⁇ -aminobutyric acid
  • NMD A N-methyl-D-aspartate
  • Opioid receptors also play a key role in modulating mood, motivation, and desire, behaviors associated with addiction, via its role in the brain's reward circuitry.
  • the reward circuitry includes structures such as the ventral tegmental area, nucleus accumbens and other parts of the ventral striatum, dorsal striatum, substantia nigra, prefrontal cortex, anterior cingulate cortex, insular cortex, hippocampus, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, ventral pallidum, parabrachial nucleus, and amygdala.
  • the mesolimbic dopamine pathway which connects the ventral tegmental area (VTA) to the nucleus accumbens (NAcc), is an important component of the reward system that is involved in the immediate perception of the motivational component of reward and reinforcement.
  • Opioid peptides and receptors are widely distributed in reward pathways and circuitry, and the opioid system is intimately involved in reinforcement processes. Mu and, to a lesser extent, delta agonists produce positive reinforcement, whereas mu and delta antagonists can suppress the positive reinforcing properties of opioids, natural rewards (such as highly palatable foods) which trigger the release of endogenous opioid-like peptides (e.g., endorphins), and certain nonopioid drugs (e.g. alcohol) that trigger the release of opioid-like peptides.
  • endogenous opioid-like peptides e.g., endorphins
  • certain nonopioid drugs e.g. alcohol
  • Naloxone is an opioid receptor antagonist that is approved for use intranasally and by injection for the reversal of opioid overdose.
  • the onset of action of naloxone used in treating opioid overdose should be as fast as possible in order to reverse respiratory depression and restore vital processes.
  • Naloxone can also induce withdrawal and dysphoria in opioid- intoxicated or -dependent subjects, and produces conditioned aversive effects in animals; it has therefore been investigated for the treatment of reward-based disorders (though, notably, it has not been particularly successful in clinical investigations into the treatment of addictions).
  • a fast onset of action might therefore also potentially be useful in the treatment of reward-based disorders, because it would permit the user to interrupt the reward cycle at various stages in the cycle, depending on time of administration: priming, reinforcement, etc.
  • oral dosage forms comprising naloxone display a low bioavailability and are thus generally viewed as unsuitable for such purposes.
  • the administration of naloxone via injection into the blood stream or into the muscle requires trained medical personnel. Intranasal dosing, however, allows the untrained user to administer naloxone.
  • Naloxone has a relatively short half-life compared to some longer-acting opioid drugs and formulations. Accordingly, after a typical therapeutic dose of naloxone is administered to an opioid overdose patient there is often the need to re-administer naloxone, in some cases even several times, and it is important to seek immediate medical attention. Similarly, naloxone's short half life presents an opportunity to intervene at strategic time points in the reward cycle without the burden of a long-acting drug which may occupy opioid receptors for long periods of time and interfere with the natural reward system.
  • naloxone or a salt or hydrate thereof that i) achieves ⁇ -opioid receptor (MOR) occupancy by naloxone of > about 50% in the brain, or a region thereof, in less than about 15 minutes; and
  • MOR ⁇ -opioid receptor
  • ii) is cleared form the brain to a level that yields MOR occupancy by naloxone of ⁇ about 15% within six hours.
  • MOR ⁇ -opioid receptor
  • MOR ⁇ -opioid receptor
  • MOR ⁇ -opioid receptor
  • MOR ⁇ -opioid receptor
  • compositions, and devices adapted for nasal delivery of pharmaceutical formulations to a patient comprising a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts and hydrates thereof.
  • an opioid antagonist selected from naloxone and pharmaceutically acceptable salts and hydrates thereof.
  • the therapeutically effective amount of naloxone is equivalent to about 2 mg to about 12 mg, or a molar equivalent of naloxone hydrochloride.
  • an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof.
  • the therapeutically effective amount of naloxone is equivalent to about 2 mg to about 12 mg, or a molar equivalent of naloxone hydrochloride.
  • 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.
  • abusable substance includes those substances that are known to be used in amounts or using methods that are harmful to the user or others.
  • the United States National Institutes of Health maintains a list of commonly abused substances, available at www.drugabuse.gov/drugs-abuse/commonly-abused-drugs-charts.
  • Abusable substances include opioid agonists (both prescription as well as illicit narcotics), alcohol, and other substances which activate the reward circuitry via exogenous or endogenous opioids upon consumption.
  • active ingredient or "pharmaceutically active compound” is defined in the context of a “pharmaceutical formulation” and is intended to mean a component of a pharmaceutical formulation that provides the primary pharmacological effect, as opposed to an "inactive ingredient” which would generally be recognized as providing no
  • actuation refers to operation of the device such that the pharmaceutical formulation 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
  • 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 formulation to maintain microbiological stability.
  • AUC refers to the area under the drug plasma
  • AUCo refers to the area under the drug plasma concentration-time curve extrapolated to ⁇ .
  • AUCo-t D refers to the AUCo-t normalized to 0.4 mg IM naloxone.
  • AUCO- ⁇ /D refers to the AUCo- ⁇ normalized to 0.4 mg IM naloxone
  • binding potential means the ratio of Bmax (receptor density) to KD (radioligand equilibrium dissociation) or, equivalently, the product of Bmax and affinity.
  • Bmax receptor density
  • KD radioligand equilibrium dissociation
  • BPND refers to the ratio at equilibrium of specifically bound radioligand to that of nondisplaceable radioligand in tissue. BPND is the typical measurement from reference tissue methods, as it compares the concentration of radioligand in receptor-rich to receptor-free regions.
  • 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:
  • CL refers to the rate at which a drug is eliminated divided by its plasma concentration, giving a volume of plasma from which drug is completely removed per unit of time.
  • CL is equal to the elimination rate constant ( ⁇ ) multiplied by the volume of distribution (Vd), wherein “Vd” is the fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma.
  • apparent clearance (CL/F), refers to clearance that does not take into account the bioavailability of the drug. It is the ratio of the dose over the AUC.
  • Cmax refers to the maximum observed plasma
  • Cmax/Dose refers to Cmax normalized to 0.4 mg IM naloxone.
  • CV coefficient of variation
  • device refers to an apparatus capable of delivering a drug to patient in need thereof.
  • delivery time refers to the amount of time that elapses between a determination made by a healthcare professional, or an untrained individual that an individual is in need of nasal delivery of an opioid antagonist and completion of the delivery.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one or more of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • disorder as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one or more of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • condition as in medical condition
  • ⁇ ⁇ refers to the terminal phase elimination rate constant, wherein the "terminal phase” of the drug plasma concentration-time curve is a straight line when plotted on a semilogarithmic graph.
  • the terminal phase is often called the "elimination phase” because the primary mechanism for decreasing drug concentration during the terminal phase is drug elimination from the body.
  • the distinguishing characteristic of the terminal elimination phase is that the relative proportion of drug in the plasma and peripheral volumes of distribution remains constant. During this "terminal phase” drug returns from the rapid and slow distribution volumes to the plasma, and is permanently removed from the plasma by metabolism or renal excretion.
  • naloxone hydrochloride a weight of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof that is equimolar to a specified weight of naloxone hydrochloride.
  • 8 mg of anhydrous naloxone hydrochloride (molecular weight, 363.84) is equivalent to about 7.2 mg of naloxone freebase (molecular weight, 327.37), and to about 8.8 mg of naloxone hydrochloride dihydrate (molecular weight 399.87).
  • filled refers to an association between a device and a pharmaceutical formulation, for example, when a pharmaceutical formulation described herein comprising a therapeutically effective amount of an opioid antagonist is present within a reservoir that forms a part of a device described herein.
  • hydrate refers to an opioid antagonist described herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • 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 the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally.
  • naloxone refers to a compound of the following structure:
  • naloxone a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • the CAS registry number for naloxone is 465-65-6.
  • Other names for naloxone include: 17-allyl-4,5a-epoxy-3,14- dihydroxymorphinan-6-one; (-)-17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one; 4,5a- epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one; and (-)-12-allyl-7,7a,8,9- tetrahydro-3,7a-dihydroxy-4aH-8,9c-indnoethanophenanthro[4,5- )ca furan-5(6H)-one.
  • Naloxone hydrochloride may be anhydrous (CAS Reg. No. 357-08-4) and also forms a dihydrate (CAS No. 51481-60-8). It has been sold under various brand names including Narcan®, Nalone®, Nalossone®, Naloxona®, Naloxonum®, Narcanti®, and Narcon®.
  • opioid antagonist includes naloxone and pharmaceutically acceptable salts thereof.
  • the opioid antagonist is naloxone hydrochloride.
  • the opioid antagonist is naloxone hydrochloride dihydrate.
  • 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 (including postoperative opioid respiratory depression, acute lung injury, and aspiration pneumonia), 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
  • 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.
  • Opioids that may induce overdose include, codeine, morphine, methadone, fentanyl, oxycodone, hydrocodone, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, tapentadol, and certain narcotic-antagonist analgesics, such as, nalbuphine, pentazocine and butorphanol.
  • the opioid agonist is in an abuse- deterrent formulation.
  • the opioid agonist is selected from Acurox® Oxycodone DETERx®, Egalet hydrocodone, Egalet morphine, Egalet oxycodone, Exalgo®, Opana®, and Remoxy®.
  • patient refers to any subject (preferably human) afflicted with a condition likely to benefit from a treatment, e.g., with a therapeutically effective amount of intranasal naloxone.
  • absorption enhancer permeation enhancer
  • 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 formulation comprising at least one active ingredient; including but not limited to, salts, solvates and hydrates of naloxone, whereby the formulation 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 formulation 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.
  • pharmaceutically acceptable refers to a component of a pharmaceutical formulation that it compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.
  • prone refers to a patient who is lying face down.
  • 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).
  • the term "reward-based disorder,” as used herein, means a medical condition characterized by compulsive engagement in rewarding stimuli, despite adverse consequences to physical and/or mental health. Reward-based disorders include addictions.
  • the terms "addictive behavior” and “addictive stimulus,” as used herein, refer to a behavior or a stimulus, respectively, that is both rewarding and reinforcing.
  • the term "reinforcing stimuli,” as used herein refers to stimuli that increase the probability of repeating behaviors paired with them (i.e., they increase the likelihood that a person will seek repeated exposure to them).
  • Rewarding stimuli refers to stimuli that the brain interprets as intrinsically positive or desirable, or as something to be approached.
  • Stimulus-driven behavioral responses i.e., stimulus control
  • Reward-based disorders include substance use disorders, pathological gambling, and eating disorders such as binge eating and bulimia nervosa, as well as neuropsychiatric disorders in which the patient performs self-injurious and/or inappropriate behaviors which result in the release of endogenous opioids.
  • reward circuitry means those brain structures and connections involved in the experience of reward, which are known in the art and not recapitulated in detail here. Briefly, however, reward circuitry includes the cortico-basal ganglia-thalamo-cortical loop, which involves structures such as the basal ganglia, itself including the striatum (ventral/rostral, limbic/temporal/executive) and nucleus accumbens (itself the major portion of the limbic/ventral striatum), and the ventral tegmental area; the thalamus and hypothalamus; and the cortex, including the prefrontal cortex.
  • the cortico-basal ganglia-thalamo-cortical loop which involves structures such as the basal ganglia, itself including the striatum (ventral/rostral, limbic/temporal/executive) and nucleus accumbens (itself the major portion of the limbic/ventral striatum), and the ventral tegmental area
  • self-injurious and/or inappropriate behavior means a reward-based disorder which results in the release of one or more endogenous opioids.
  • self-injurious and/or inappropriate behaviors examples include self- cutting, skin picking, burning, and the like, as well as eating disorders, pathological gambling, etc.
  • the term excludes behaviors done in furtherance of suicide, and those performed due to other disorders and conditions, such as autism or schizophrenia.
  • Self-injurious and/or inappropriate behaviors include self- cutting, skin picking, burning, and the like, as well as eating disorders, pathological gambling, etc.
  • the term excludes behaviors done in furtherance of suicide, and those performed due to other disorders and conditions, such as autism or schizophrenia.
  • solvate refers to naloxone 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.
  • sterile filling refers methods of manufacturing the devices and pharmaceutical formulations described herein, such that the use of preservatives is not required.
  • 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. In an aseptic process, the drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together.
  • storage-stable refers to a pharmaceutical formulation in which at least about 95% to 99.5% of the active ingredient remains in an undegraded state after storage of the pharmaceutical formulation at specified temperature and humidity for a specified time, for example, for 12 months at 25 °C and 60% relative humidity.
  • substantially free of antimicrobial preservatives is understood by one of ordinary skill in the art to described a pharmaceutical formulation 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.
  • ti/2 or "half-life,” as used herein, refers to the amount of time required for half of a drug to be eliminated from the body or the time required for a drug concentration in the blood (and routinely measured in plasma) to decline by half.
  • Tmax refers to the time from administration of the pharmaceutical formulations described herein to maximum drug plasma concentration in blood (and routinely measured in plasma).
  • tomography refers to a process of imaging by sections.
  • the images may be looked at individually, as a series of two-dimensional slices or together, as a computer-generated three-dimensional representation.
  • tonicity agent refers to a compound which modifies the osmolality of a formulation, for example, to render it isotonic.
  • Tonicity agents include, dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxy ethyl starch, glycine and the like.
  • the term "untrained individual” refers to an individual administering to patient naloxone using a device described herein, wherein the individual is not a healthcare professional and has received no training in the use of the device, such as through an overdose education and nasal naloxone distribution (OEND) program.
  • OEND overdose education and nasal naloxone distribution
  • Naloxone specifically reverses the effects of opioid agonists but has no opioid agonist activity.
  • Naloxone is commercially available as a hydrochloride salt.
  • Naloxone hydrochloride (17- allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride), a narcotic antagonist, is a synthetic congener of oxymorphone. In structure it differs from oxymorphone in that the methyl group on the nitrogen atom is replaced by an allyl group.
  • Naloxone hydrochloride is an essentially pu re narcotic antagonist, i.e., it does not possess "agonistic" or morphine-like properties; naloxone does not produce respiratory depression, psychotomimetic effects or pupillary constriction. Naloxone has not been shown to produce tolerance or to cause physical or psychological dependence. In the presence of a physical dependence on narcotics naloxone will precipitate withdrawal symptoms.
  • naloxone hydrochloride When naloxone hydrochloride is administered intravenously the onset of action is generally apparent within two minutes; the onset of action is less rapid when it is administered subcutaneously or intramuscularly. The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride. Intramuscular administration produces a more prolonged effect than intravenous
  • naloxone hydrochloride is rapidly distributed in the body. It is metabolized in the liver, primarily by glucuronide conjugation, and excreted in urine. In one study the plasma half-life in adults following intramuscular injection was reported as 1.3 hours.. In a neonatal study the mean plasma half-life was observed to be 3.1 ⁇ 0.5 hours.
  • compositions devices adapted for nasal delivery of a pharmaceutical formulation to a patient, and methods of treatment in a patient, each 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.
  • devices adapted for nasal delivery of a pharmaceutical formulation 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.
  • 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 2 mg to about 12 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg to about 12 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 2 mg to about 8 mg of naloxone hydrochloride. In some embodiments, the
  • therapeutically effective amount is equivalent to about 5 mg to about 11 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 2 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 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 11 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 12 mg of naloxone hydrochloride. In some embodiments, the naloxone is the only pharmaceutically active compound in pharmaceutical formulation. In some embodiments, the therapeutically effective amount is equivalent to about 2, about 4, or about 8 mg of naloxone hydrochloride. In some embodiments, the opioid antagonist is anhydrous naloxone hydrochloride.
  • the opioid antagonist is naloxone hydrochloride dihydrate; in these embodiments, the amount may be a molar equivalent of an amount of naloxone disclosed herein.
  • the therapeutically effective amount is about 2.2 mg to about 13.2 mg of naloxone hydrochloride dihydrate. In some embodiments, the therapeutically effective amount is about 4.4 mg to about 11 mg of naloxone
  • the 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, the therapeutically effective amount is about 2.2 mg of naloxone hydrochloride dihydrate. In some embodiments, the therapeutically effective amount is about 4.4 mg of naloxone hydrochloride dihydrate. In some embodiments, the therapeutically effective amount is about 8.8 mg of naloxone hydrochloride dihydrate. Nasal Drug Delivery Devices and Kits
  • nasal drug delivery devices comprising a pharmaceutical formulation described herein.
  • Nasal delivery is considered an attractive route for needle-free, systemic drug delivery, especially when rapid absorption and effect are desired.
  • nasal delivery may help address issues related to poor bioavailability, slow absorption, drug degradation, and adverse events (AEs) in the gastrointestinal tract and avoids the first-pass metabolism in the liver.
  • AEs adverse events
  • Liquid nasal formulations are mainly aqueous solutions, but suspensions and emulsions can also be delivered.
  • antimicrobial preservatives are typically required to maintain microbiological stability in liquid formulations.
  • Some 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 mg/mL) and administering 1 mL 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.). This initiative is consistent with the U.S. Needlestick Safety and Prevention Act (Public Law 106-430).
  • the EMS programs recognize limitations of this system, one limitation being that it is not assembled and ready-to-use.
  • this administration mode appears to be effective in reversing narcosis, the formulation is not concentrated for retention in the nasal cavity.
  • the 1 mL 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.
  • Metered spray pumps have dominated the nasal drug delivery market since they were introduced.
  • the pumps typically deliver 100 (25-200 ⁇ ) per spray, and they offer high reproducibility of the emitted dose and plume geometry in in vitro tests.
  • the particle size and plume geometry can vary within certain limits and depend on the properties of the pump, the formulation, the orifice of the actuator, and the force applied.
  • Traditional spray pumps replace the emitted liquid with air, and preservatives are therefore required to prevent contamination.
  • pump manufacturers driven by the studies suggesting possible negative effects of preservatives, pump manufacturers have developed different spray systems that avoid the need for preservatives.
  • Metered-dose spray pumps require priming and some degree of overfill to maintain dose conformity for the labeled number of doses. They are well suited for drugs to be administered daily over a prolonged duration, but due to the priming procedure and limited control of dosing, they are less suited for drugs with a narrow therapeutic window. For expensive drugs and vaccines intended for single administration or sporadic use and where tight control of the dose and formulation is of particular importance, single-dose or bi-dose spray devices are preferred (www.aptar.com). A simple variant of a single-dose spray device (MADTM) is offered by LMA (LMA, Salt Lake City, UT, USA; www.lmana. com). A nosepiece with a spray tip is fitted to a standard syringe.
  • MADTM single-dose spray device
  • 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.
  • Products are filled and sealed in this type of environment to minimize the microbial and particulate content of the in- process product and to help ensure that the subsequent sterilization process is successful.
  • the product, container, and closure have low bioburden, but they are not sterile.
  • the product in its final container is then subjected to a sterilization process such as heat or irradiation.
  • a sterilization process such as heat or irradiation.
  • the drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together. Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment. Aseptic processing involves more variables than terminal sterilization.
  • 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.
  • naloxone hydrochloride a pharmaceutical formulation 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.
  • the opioid antagonist is naloxone hydrochloride. In some embodiments, the opioid antagonist is naloxone hydrochloride dihydrate. [084] In some embodiments, the patient is an opioid overdose patient or a suspected opioid overdose patient.
  • the patient is in a lying, supine, or recovery position. In some embodiments, the patient is in a lying position. In some embodiments, the patient is in a supine position. In some embodiments, the patient is in a recovery position.
  • the therapeutically effective amount of an opioid antagonist is delivered by an untrained individual.
  • the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical formulation.
  • the pharmaceutical formulation comprises a solution of naloxone hydrochloride, or a hydrate thereof.
  • the volume of the pharmaceutical formulation in the reservoir is not more than about 140 ⁇ .
  • about 100 of the pharmaceutical formulation in the reservoir is delivered to the patient in one actuation.
  • the device is filled with the pharmaceutical formulation using sterile filling.
  • the pharmaceutical formulation is storage-stable in the device for about twelve months at about 25 °C and about 60% relative humidity.
  • the device is a single-dose device, wherein the pharmaceutical formulation is present in one reservoir, and wherein the therapeutically effective amount of the opioid antagonist is delivered essentially by one actuation of the device into one nostril of the patient.
  • about 100 of the pharmaceutical formulation is delivered by the actuation.
  • the 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 delivery of the pharmaceutical formulation to the patient upon nasal delivery of the pharmaceutical formulation to the patient, less than about 20% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, upon nasal delivery of the pharmaceutical formulation to the patient, less than about 10% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, upon nasal delivery of the pharmaceutical formulation to the patient, less than about 5% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally.
  • the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 30 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 25 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 20 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of about 20 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 19 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of about 18.5 minutes.
  • delivery of the therapeutically effective amount to the patient provides occupancy at Tmax 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 Tmax 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 Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 99%.
  • the patient is free from respiratory depression for at least about 1 hour following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 2 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 4 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 6 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist.
  • the device is a bi-dose device, wherein a first volume of the pharmaceutical formulation is present in a first reservoir and a second volume of the pharmaceutical formulation is present in a second reservoir, and wherein the therapeutically effective amount is delivered essentially by a first actuation of the device into a first nostril of the patient and a second actuation of the device into a second nostril of the patient.
  • the first volume and the second volume combined is equal to not more than about 380 ⁇ .
  • about 100 of the first volume of the pharmaceutical formulation is delivered by the first actuation.
  • about 100 of the second volume of the pharmaceutical formulation is delivered by the second actuation.
  • the 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 delivery of the pharmaceutical formulation to the patient upon nasal delivery of the pharmaceutical formulation to the patient, less than about 20% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, upon nasal delivery of the pharmaceutical formulation to the patient, less than about 10% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, upon nasal delivery of the pharmaceutical formulation to the patient, less than about 5% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally.
  • the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 30 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 25 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of about 20 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 19 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of about 18.5 minutes.
  • delivery of the therapeutically effective amount to the patient provides occupancy at Tmax 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 Tmax 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 Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 99%.
  • the patient is free from respiratory depression for at least about 1 hour following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 2 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 4 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 6 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist.
  • 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.
  • the isotonicity agent is NaCl
  • 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 plasma concentration versus time curve of the naloxone hydrochloride in the patient has a Tmax of between about 20 and about 30 minutes.
  • the 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 delivery of the pharmaceutical formulation to the patient upon nasal delivery of the pharmaceutical formulation to the patient, less than about 20% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, upon nasal delivery of the pharmaceutical formulation to the patient, less than about 10% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or extemally. In some embodiments, upon nasal delivery of the pharmaceutical formulation to the patient, less than about 5% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally.
  • the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 30 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 25 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of about 20 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 19 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of about 18.5 minutes.
  • delivery of the therapeutically effective amount to the patient provides occupancy at Tmax 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 Tmax 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 Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 99%.
  • the patient is free from respiratory depression for at least about 1 hour following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 2 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 4 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 6 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist.
  • the device is filled with the pharmaceutical formulation using sterile filling.
  • the pharmaceutical formulation is storage-stable for about twelve months at about 25 °C and about 60% relative humidity.
  • the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical formulation.
  • 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.
  • the patient is an opioid overdose patient or a suspected opioid overdose patient.
  • the patient is in a lying, supine, or recovery position. In some embodiments, the patient is in a lying position. In some embodiments, the patient is in a supine position. In some embodiments, the patient is in a recovery position.
  • the 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 HC1, 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.
  • ADPREM Abuse Deterrent Prolonged Release Erosion Matrix
  • 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 utilizes a proprietary coating technology consisting of various polymers that can sequester an opioid antagonist (naltrexone) in fragile micropellets that are
  • 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 an abuse- deterrent formulation.
  • the opioid agonist is selected from Acurox® Oxycodone DETERx®, Egalet hydrocodone, Egalet morphine, Egalet oxycodone, Exalgo®, Opana®, and Remoxy®.
  • compositions comprising naloxone for intranasal administration.
  • the pharmaceutical formulations comprise naloxone 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 formulation comprising admixing at least one opioid antagonist and a pharmaceutically acceptable carrier. Pharmaceutical formulations 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 or a pre-primed device.
  • 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, poly oxy ethylene 20 sorbitan monolaurate, poly oxy ethylene (4) sorbitan monolaurate, poly oxy ethylene 20 sorbitan monopalmitate, poly oxy ethylene 20 sorbitan monostearate, poly oxy ethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, poly oxy ethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbit
  • carboxymethylcellulose sodium NF polyacrylic acid, magnesium aluminum silicate, xanthan gum, and the like, and mixtures thereof.
  • naloxone may optionally be provided as a pharmaceutically acceptable salt including hydrochloride. Salts may be obtained as the direct products of compound synthesis, or 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. Naloxone and its salts may form solvates with standard low molecular weight solvents, including water (to form hydrates).
  • the pharmaceutical formulation further comprises one or more excipients selected from water, an isotonicity agent, a compound which acts as a preservative, cationic surfactant, and/or permeation/penetration enhancer, a stabilizing agent, and an amount of an acid sufficient to achieve a target pH.
  • excipients selected from water, an isotonicity agent, a compound which acts as a preservative, cationic surfactant, and/or permeation/penetration enhancer, a stabilizing agent, and an amount of an acid sufficient to achieve a target pH.
  • the pharmaceutical formulation comprises one or more excipients selected from water and NaCl.
  • the pharmaceutical formulation is substantially free of antimicrobial preservatives.
  • the pharmaceutical formulation comprises a compound which is a preservative, cationic surfactant, and/or permeation/penetration enhancer.
  • the pharmaceutical formulation comprises benzalkonium chloride.
  • the benzalkonium chloride can function as a preservative (even in low amounts), a permeation/penetration enhancer, and/or a cationic surfactant (typically at a higher amount for these latter two).
  • Benzalkonium chloride is represented by the following structure:
  • n is an integer, and a mixture of more than one thereof can be used.
  • n is 8, 10, 12, 14, 16, or 18, and in certain embodiments, n is 10, 12, or 14.
  • the pharmaceutical formulation comprises about 0.005% to about 1% benzalkonium chloride.
  • the pharmaceutical formulation comprises about 0.01% to about 1% benzalkonium chloride.
  • the pharmaceutical formulation comprises about 0.005% to about 0.015% benzalkonium chloride.
  • the pharmaceutical formulation further comprises one or more excipients selected from water, NaCl, benzalkonium chloride, sodium edetate, disodium edetate, and hydrochloric acid.
  • the pharmaceutical formulation further comprises water, NaCl, benzalkonium chloride, disodium edetate, and hydrochloric acid.
  • the pharmaceutical formulation further comprises:
  • the pharmaceutical formulation comprises:
  • a compound which is a preservative, cationic surfactant, and/or permeation enhancer between about 0.005 mg and about 0.1 mg of a compound which is a preservative, cationic surfactant, and/or permeation enhancer;
  • the pharmaceutical formulation comprises:
  • the isotonicity agent is NaCl
  • 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:
  • naloxone is administered as part of a pharmaceutical formulation additionally comprising:
  • a compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer is at least one of a preservative, a cationic surfactant, and a permeation enhancer.
  • the naloxone is naloxone hydrochloride.
  • the pharmaceutical formulation comprises between about 0.2% and about 2% (w/v) of the isotonicity agent. In some embodiments, the pharmaceutical formulation comprises between about 0.2% and about 1.2% (w/v) of the isotonicity agent.
  • the pharmaceutical formulation comprises between about 0.2 to about 2.0 mg of the isotonicity agent. In some embodiments, the pharmaceutical formulation comprises between about 0.2 to about 1.2 mg of the isotonicity agent.
  • the isotonicity agent is NaCl.
  • the pharmaceutical formulation comprises about 0.005% and about 0.015% (w/v) of the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer.
  • the pharmaceutical formulation comprises about 0.005% and about 0.01 % (w/v) of the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer.
  • the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer is benzalkonium chloride.
  • the pharmaceutical formulation additionally comprises a stabilizing agent.
  • the formulation comprises between about 0.1 mg and about 0.5 mg of the stabilizing agent.
  • the stabilizing agent is disodium edetate.
  • the pharmaceutical formulation additionally comprises an amount of an acid sufficient to achieve a pH of 3.5-6.5.
  • the pharmaceutical formulation additionally comprises an amount of an acid sufficient to achieve a pH of 3.5-5.5.
  • the acid is hydrochloric acid.
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises:
  • the isotonicity agent is sodium chloride
  • the stabilizing agent is disodium edetate
  • the acid is hydrochloric acid
  • the pharmaceutical formulation comprises about 2, about 4, or about 8 mg of naloxone or a salt or hydrate thereof.
  • the pharmaceutical solution comprises:
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5.
  • the pharmaceutical formulation is storage-stable for about twelve months at about 25 °C and about 60% relative humidity.
  • compositions for intranasal administration comprising, in an aqueous solution of not more than about 140 ⁇ :
  • the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical formulation.
  • the opioid antagonist is naloxone hydrochloride, or a hydrate thereof.
  • the opioid antagonist is naloxone hydrochloride dihydrate.
  • the pharmaceutical formulation comprises an amount equivalent to about 2 mg to about 12 mg of naloxone hydrochloride. In some embodiments, 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 about 2 mg to about 8 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.
  • 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. [0183] In some embodiments, the pharmaceutical formulation comprises about 2 mg or about 4 mg naloxone hydrochloride or a hydrate thereof;
  • the pharmaceutical formulation comprises about 4 mg naloxone hydrochloride or a hydrate thereof. In some embodiments, the pharmaceutical formulations comprises about 2 mg naloxone hydrochloride or a hydrate thereof.
  • the isotonicity agent is NaCl
  • 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 is in an aqueous solution of about 100
  • the plasma concentration versus time curve of the naloxone hydrochloride in the patient has a Tmax of between about 20 and about 30 minutes.
  • the 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. [0192] In some embodiments, 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 delivery of the pharmaceutical formulation to the patient upon nasal delivery of the pharmaceutical formulation to the patient, less than about 20% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, upon nasal delivery of the pharmaceutical formulation to the patient, less than about 10% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, upon nasal delivery of the pharmaceutical formulation to the patient, less than about 5% of the pharmaceutical formulation leaves the nasal cavity via drainage into the nasopharynx or externally.
  • the plasma concentration versus time curve of the opioid antagonist in a patient has a Tmax of less than 30 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 25 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of about 20 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 19 minutes. In some embodiments, the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of about 18.5 minutes.
  • delivery of the pharmaceutical formulation to a patient provides occupancy at Tmax 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 pharmaceutical formulation to the patient, provides occupancy at Tmax 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 pharmaceutical formulation to the patient, provides occupancy at Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 99%.
  • the patient is free from respiratory depression for at least about 1 hour following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 2 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 4 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 6 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist.
  • compositions for intranasal administration comprising, in an aqueous solution of not more than about 140 ⁇ :
  • the isotonicity agent is NaCl
  • 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 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 not more than about 100 ⁇ :
  • an isotonicity agent between about 0.2 mg and about 1.2 mg of an isotonicity agent; between about 0.005 mg and about 0.015 mg of a compound which is a preservative, cationic surfactant, and/or permeation enhancer;
  • the pharmaceutical formulation comprises:
  • compositions for intranasal administration comprising, in an aqueous solution of about 100 ⁇ :
  • 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 formulation 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.
  • the pharmaceutical formulation further comprises one or more excipients selected from water and NaCl.
  • the pharmaceutical formulation is substantially free of antimicrobial preservatives.
  • the device is substantially free of benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenyl ethyl alcohol
  • the device is filled with the pharmaceutical formulation in a sterile environment.
  • the pharmaceutical formulation is storage-stable for about twelve months at about 25 °C.
  • the pharmaceutical formulation comprises less than 0.1% w/w antimicrobial preservatives.
  • the pharmaceutical formulation comprises 0.01% w/w or less antimicrobial preservatives.
  • the pharmaceutical formulation comprises 0.01% w/w - 0.001% w/w antimicrobial preservatives.
  • the pharmaceutical formulation comprises less than 0.001% w/w antimicrobial preservatives.
  • devices for "combination-therapy” comprising pharmaceutical formulations comprising at least one opioid antagonist described herein, together with at least one known pharmaceutical agent and a pharmaceutically acceptable carrier.
  • the pharmaceutical formulation comprises a short-acting opioid antagonist and a long-acting opioid antagonist.
  • the pharmaceutical formulation comprises naloxone and naltrexone.
  • the pharmaceutical formulation comprises naloxone and methylnaltrexone.
  • the pharmaceutical formulation comprises naloxone and nalmefene.
  • 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. In the mouse and rat the intravenous LD50 is 150 ⁇ 5 mg/kg and 109 ⁇ 4 mg/kg respectively.
  • 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 mg/mL 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 the 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 the 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 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 the 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.
  • the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical formulation.
  • the opioid antagonist is naloxone hydrochloride. In some embodiments, the opioid antagonist is naloxone hydrochloride dihydrate.
  • the pharmaceutical formulation comprises a solution of naloxone hydrochloride, or a hydrate thereof.
  • the patient is an opioid overdose patient or a suspected opioid overdose patient.
  • the patient is in a lying, supine, or recovery position. In some embodiments, the patient is in a lying position. In some embodiments, the patient is in a supine position. In some embodiments, the patient is in a recovery position.
  • the therapeutically effective amount of an opioid antagonist is delivered by an untrained individual.
  • 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 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 therapeutically effective amount is equivalent to about 2 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 8 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3.4 mg of naloxone hydrochloride.
  • the symptom is chosen from respiratory depression and central nervous system depression.
  • the 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.
  • the patient is not breathing.
  • the patient is in a lying, supine, or recovery position.
  • the patient is in a lying position.
  • the patient is in a supine position.
  • the patient is a recovery position.
  • the therapeutically effective amount is equivalent to about 2 mg to about 10 mg of naloxone hydrochloride.
  • the 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.
  • the therapeutically effective amount is equivalent to about 2 mg of naloxone hydrochloride.
  • the therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride.
  • the therapeutically effective amount is equivalent to about 8 mg of naloxone hydrochloride.
  • the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical formulation.
  • the opioid antagonist is naloxone hydrochloride.
  • the nasally administering is accomplished using a pre-primed device adapted for nasal delivery of a pharmaceutical formulation.
  • the nasal cavity via drainage into the nasopharynx or externally.
  • the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 30 minutes.
  • the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of less than 25 minutes.
  • the plasma concentration versus time curve of the opioid antagonist in the patient has a Tmax of about 20 minutes.
  • 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 selected from codeine, morphine, methadone, fentanyl, oxycodone HC1, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, tapentadol.
  • an opioid selected from codeine, morphine, methadone, fentanyl, oxycodone HC1, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, tapentadol.
  • the patient is free from respiratory depression for at least about
  • 1 hour following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist.
  • the patient is free from respiratory depression for at least about
  • the patient is free from respiratory depression for at least about 4 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist.
  • the patient is free from respiratory depression for at least about 6 hours following treatment comprising essentially of delivery of the therapeutically effective amount of the opioid antagonist.
  • any embodiment above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • 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, is induced by an opioid agonist selected from codeine, morphine, methadone, fentanyl, oxycodone, hydrocodone, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, and tapentadol.
  • opioid agonist selected from codeine, morphine, methadone, fentanyl, oxycodone, hydrocodone, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, and tapentadol.
  • the patient is not breathing.
  • devices adapted for nasal delivery of a pharmaceutical formulation 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 2 mg to about 12 mg of naloxone hydrochloride.
  • 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 11 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 2 mg to about 8 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 2 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. 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
  • the opioid antagonist is the only pharmaceutically active compound in pharmaceutical formulation. In some embodiments, the opioid antagonist is naloxone hydrochloride. In some embodiments, the opioid antagonist is anhydrous naloxone hydrochloride. In some embodiments, the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical formulation. In some embodiments, the opioid antagonist is naloxone hydrochloride. In some embodiments,
  • the pharmaceutical formulation comprises a solution of naloxone
  • 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 HC1, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, and tapentadol.
  • an opioid agonist selected from codeine, morphine, methadone, fentanyl, oxycodone HC1, 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.
  • 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 mg of naloxone hydrochloride dihydrate.
  • 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. In some embodiments, the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical formulation. 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. In some embodiments, 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.
  • 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 HC1, hydrocodone bitartrate, hydromorphone,
  • oxymorphone meperidine, propoxyphene, opium, heroin, tramadol, and tapentadol.
  • devices, kits, and pharmaceutical formulations for, and methods of, treating an eating disorder selected from binge eating, bulimia, and stimulus- induced over-eating comprising nasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist, wherein the therapeutically effective amount is about 2 mg to about 12 mg. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of naloxone hydrochloride.
  • the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical formulation.
  • the nasally administering is accomplished using a device described herein.
  • 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 n C, 13 N, 15 0, 18 F, 52 Fe, 62 Cu, 64 Cu, 68 Ga, 74 As, 82 Rb, 89 Zr, 122 I, and 124 I.
  • 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.
  • 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 2-12 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 other opioid antagonists, such as oral naltrexone or nalmefene. Further comparisons may be made between nasal administration in the upright versus the lying or supine positions.
  • Useful measures that may be determined in such studies are the time to onset of action, brain half-life (indirectly), the percent receptor binding or occupancy of a patient's opioid receptors, for example, the ⁇ -opioid receptors in the reward centers, or respiratory center in the medulla oblongata, and an indirect measure of how long the compound of interest remains in the brain.
  • n C]Carfentanil is a ⁇ -opioid agonist used for in vivo PET studies of ⁇ -opioid receptors.
  • One such study involved healthy male volunteers assigned at enrollment to receive either 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 (2011) 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 administered dose range was 0.4-100 mg for GSK1521498, and 2-50 mg for 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- ⁇ - 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 l-(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- 11 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, Er Weg, 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 [ n C] -carfentanil injection, binned into 26 frames (durations: 8 ⁇ 15 s, 3 ⁇ 60 s, 5 ⁇ 2 min, 5 x 5 min and 5 x 10 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 Tl -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 Tl -weighted anatomical volume using an in-house atlas and applied to the dynamic PET data to generate regional time-activity curves.
  • the [ n C]- carfentanil-specific binding was quantified as binding potential relative to the non- displaceable compartment (BPND)
  • ⁇ is the free fraction of the radioligand in the brain
  • KD is the affinity of [ N C]- carfentanil
  • Bavaii is the density of the available ⁇ -opioid receptors.
  • Regional [ N C]- carfentanil BPND 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 [ n 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 Drug, to the estimated occupancy:
  • n C]Diprenorphine was administered to normal volunteers in tracer amounts and, 30 min later, various bolus doses of naloxone were given (1.5-160 ⁇ g/kg) intravenously and change in
  • delivery of the therapeutically effective amount to the patient provides occupancy at Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of about 50% or greater. In some embodiments, delivery of the therapeutically effective amount to the patient, provides occupancy at Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 55%. In some embodiments, delivery of the therapeutically effective amount to the patient, provides occupancy at Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 60%.
  • delivery of the therapeutically effective amount to the patient provides occupancy at Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 65%. In some embodiments, delivery of the therapeutically effective amount to the patient, provides occupancy at Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 70%. In some embodiments, delivery of the therapeutically effective amount to the patient, provides occupancy at Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 75%. In some embodiments, delivery of the therapeutically effective amount to the patient, provides occupancy at Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 80%.
  • delivery of the therapeutically effective amount to the patient provides occupancy at Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 85%. In some embodiments of the devices, kits, pharmaceutical formulations, and methods disclosed above, delivery of the therapeutically effective amount to the patient, provides occupancy at Tmax 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 Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of greater than about 95%.
  • delivery of the therapeutically effective amount to the patient provides occupancy at Tmax 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 Tmax of the opioid antagonist at the opioid receptors in the respiratory control center of the patient of about 100%.
  • 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).
  • Methodology This was an inpatient open-label, randomized, 3-period, 3-treatment, 6- sequence, crossover study involving 14 healthy volunteers. Subjects were assigned to one of the 6 sequences with 2 subjects in each sequence (2 sequences had 3 subjects). Each subject received 3 naloxone doses, a single 2 mg IN dose (one spray of 0.1 mL of 10 mg/mL solution in each nostril), a single 4 mg IN dose (2 sprays of 0.1 mL per spray of 10 mg/mL solution in each nostril) and a single 0.4 mg IM dose, in the 3 dosing periods (Table 1). Subjects stayed in the inpatient facility for 11 days to complete the entire study and were discharged on the next day after the last dose.
  • 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 mg/mL naloxone) and 4 mg (2 squirts in each nostril delivered 0.2 mL/nostril at 10 mg/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 Cmax, Tmax, AUC to infinity (AUCo- ⁇ ), AUC to last measurable concentration (AUCo-t), ti/2, ⁇ , and apparent clearance (CL/F) were determined. Values of ti/ 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 most recent version of the Medical Dictionary for Regulatory Activities (MedDRA). 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.
  • MedDRA Medical Dictionary for Regulatory Activities
  • the geometric least square means for AUCo- ⁇ 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 AUCo- ⁇ .
  • the ratios for IN 4 mg/IM 0.4 mg were 525% for Cmax and 394% for AUCo
  • the mean 1 max 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.
  • PK pharmacokinetics
  • the study had several objectives. The first was to determine the pharmacokinetics (i.e., the Cmax, ⁇ max, AUCo-inf and AUCo-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 E
  • HIVb immunodeficiency virus antibody
  • Naloxone for IM injection manufactured by Hospira was obtained from a licensed distributor at a concentration of 0.4 mg/mL and 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.
  • Naloxone for IN administration was obtained from Lightlake Therapeutics, Inc., London, United Kingdom at two concentrations of 20 mg/mL and 40 mg/mL, and was given as doses of 2 mg (one 0.1 mL spray of the 20 mg/mL formulation in one nostril), 4 mg (two 0.1 mL sprays of the 20 mg/mL formulation in two nostrils), 4 mg (one 0.1 mL spray of the 40 mg/mL formulation in one nostril) and 8 mg (two 0.1 mL sprays of the 40 mg/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
  • Results are shown below in Table 9, 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.
  • Non-compartmental PK parameters including Cmax, Tmax, AUCo-inf, AUCo-t, ti/2, ⁇ ⁇ , and apparent clearance (CL/F) were determined.
  • Pharmacokinetic parameters (Cmax, Tmax, and AUCs) for IN naloxone were compared with those for IM naloxone.
  • Tmax was from the time of administration (spraying into the nasal cavity or IM injection).
  • Dose adjusted values for AUCs and Cmax were then calculated, and the relative extent of intranasal absorption (IN versus IM) estimated from the dose-corrected AUCs.
  • comparisons of ln-transformed PK parameters (Cmax and AUC) for intranasal versus IM naloxone treatments were performed.
  • the 90% confidence interval for the ratio (IN/IM) of the geometric least squares means of AUC and Cmax parameters were constructed for comparison of each treatment with IM naloxone. These 90% CIs were obtained by exponentiation of the 90% confidence intervals for the difference between the least squares means based upon an In scale.
  • Results are shown below in Table 10, 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 11, which sets forth the same PK parameters split between the 12 female and 16 male healthy subjects.
  • Tmax (h) a 0.33 0.33 0.33 0.25 0.50 0.50 0.29 0.42 0.33 0.50
  • Additional exploratory analyses could include:
  • Regulatory Activities 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 12 and 13. Table 12 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.
  • Example 3 Naloxone Nasal Spray Formulations and Stability.
  • Naloxone has been formulated as a disposable Luer-Jet Luer-lock pre-filled syringe and nasal atomizer kit product, comprising 1 mg/ml naloxone hydrochloride as an active agent, 8.35 mg/ml NaCl as an isotonicity agent, HC1 q.s. to target pH, and purified water q.s. to 2.0 ml.
  • Benzalkonium chloride may be added as a preservative, cationic surfactant, and/or permeation enhancer, and supports the stability of a multi-dose product.
  • Such syringes while functional, can be ungainly to use by untrained personnel, and deliver a large volume of solution.
  • Literature data has indicated that naloxone is sensitive to environmental factors, such as air, light and colors in certain vials, which may induce a risk for degradation.
  • compositions comprising naloxone hydrochloride (10 mg/mL) were stored at 25 °C and 60% relative humidity in upright clear glass vials (200 ⁇ ) stoppered with a black plunger. Vials 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, 3, 6, 9, and 12 months for naloxone content. It is evident from the results of the study, reported as a percentage of the label claim in Table 15 below, that these pharmaceutical compositions are storage-stable for at least 9-12 months at 25 °C and 60% relative humidity.
  • 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 ⁇ .
  • compositions comprising naloxone hydrochloride (20 or 40 mg/mL) were tested for stability in room temperature/light conditions, room temperature/dark conditions and in 25 °C/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 17.
  • Nasal naloxone administration is expected to have utility in the treatment of opioid overdose, reward-based disorders, and addictive behaviors.
  • PET Positron emission tomography
  • [ n C]carfentanil distribution and binding was expected to develop, and did develop, in 20 minutes after tracer administration (bolus dose), after which naloxone or placebo was administered intranasally and [ n C]carfentanil BiPND was determined by PET scanning for another 60 minutes.
  • the order of the PET scan days - Part 1 and Part 2 - was based on balanced randomisation.
  • participants received their IN doses of placebo and naloxone during the PET scan, at 20 min after the [ n C]carfentanil injection; PET scan data were collected until 60 min after the IN drug administration.
  • Plasma samples for the determination of naloxone concentrations and calculation of pharmacokinetic variables were collected at 3, 6, 9, 12, 15, 20, 25, 30, 40, 50, 60, 80, and 100 min, as well as at 2, 3, 4 and 6 h after IN administration of naloxone. Concentration vs.
  • time curves were generated by non-compartmental analysis with WinNonlin ® Phoenix 6.4 software (Pharsight Corporation, Mountain View, CA, USA), and pharmacokinetic parameters such as maximum concentration (Cmax) of naloxone in plasma, time to peak concentration (tmax), area under the concentration by time curve (AUC) to 6 hours (AUCo-6), AUC to the last measurable concentration (AUCo-t), elimination half-life (t1 ⁇ 2) and AUC extrapolated to infinity (AUCo- ⁇ ). Terminal time points were selected based on best-fit criteria and review of the selected points. The linear trapezoidal rule was used to estimate AUC.
  • hydrochloride and attended four study visits: a screening visit, two PET visits (day 1 and day 2) and an end-of-study visit. A wash-out period of at least 5 days between the PET visits was included. Day 1 took place 28 days' time after the screening visit and the end-of-study visit took place 14 days' time after day 2. The total maximum duration of the study for any single subject was approximately 2 months.
  • Comparative drug(s)/placebo, dose and mode of administration IN administration of saline placebo during a control PET scan were used to mimic IN administration of naloxone. Placebo containers were not identical to the IMP dispensers, but the subjects and the investigators were kept blinded to the study medication by employing an unblinded member of the study personnel to administer the medications.
  • PET was used to image CNS uptake and receptor binding of [ n C]carfentanil and to calculate the extent and time course of MOR occupancy achieved after IN naloxone administration in brain regions of interest.
  • the target radioactivity of each administered bolus injection was 500 MBq, and the carfentanil mass was not allowed to exceed 2.0 ⁇ g per injected dose.
  • PET data were acquired with a High Resolution Research Tomograph (HRRT, Siemens Medical Solutions, Knoxville, TN, USA), and image reconstruction and
  • PET data were analyzed in regions-of-interest (ROI) for binding potential relative to non-displaceable tracer uptake in brain tissue, BPND, reflecting MOR availability through the equation where fND is the fraction of the radioligand that is free in the non-displaceable compartment, Bavaii is the number of receptors available for ligand binding, and KD is the affinity of the ligand (Innis et al, 2007).
  • ROI regions-of-interest
  • the lateral occipital cortex served as a reference region, being devoid of MORs.
  • t is the time of BPND estimation under the naloxone treatment.
  • Matlab version R2011b, The MathWorks Inc., Natick, MA, USA
  • PD pharmacodynamic
  • Region-of-interest analysis was done is based on automatic parceling of the brain with the FreeSurfer.
  • Tl-weighted (Tlw) MRI data were first preprocessed using the FreeSurfer (version 5.3; available at surfer.nmr.mgh.harvard.edu) software to obtain automated cortical parcellation.
  • FreeSurfer was used to generate a high-definition cortical parcellation on the basis of the individual cortical folding patterns (Desikan et al. 2006), resulting in 35 cortical gray matter regions-of-interest (ROIs) in both hemispheres, which were subsequently combined over hemispheres to form aggregate ROIs.
  • ROIs regions-of-interest
  • the automated occipital cortex ROI was manipulated prior to reference tissue TAC extraction to minimize contribution of the specific tracer uptake and thus to allow more robust measurement of the nondisplaceable tracer uptake.
  • FreeSurfer based automated atlas In addition to cortical regions, FreeSurfer based automated atlas
  • the inverse deformation fields were employed in the individualization of subcortical ROI atlases of the striatum, thalamus, medulla oblongata and the ascending arousal network (AAN) regions, in a similar manner as described earlier in (Johansson et al. 2016a).
  • the striatal connectivity- based (CB) atlas of Tziortzi and colleagues (7 subregions, 25% probability threshold
  • the thalamic CB atlas of Behrens and colleagues (Behrens et al. 2003) (7 subregions, 25% probability threshold)
  • the Harvard AAN atlas (Edlow et al.
  • Efficacy Differences in tracer uptake between the control (placebo) condition and the naloxone treatment were considered the primary outcome variable and analysed with analysis of variance (ANOVA) and descriptive statistics. Binding data from different brain regions and data acquisition intervals was analysed to estimate the differences between the naloxone and control conditions.
  • ANOVA analysis of variance
  • Pharmacokinetics Pharmacokinetic variables of naloxone were determined from the concentration-time data using non-compartmental methods and described using descriptive statistics.
  • Results Administration of 2 mg IN naloxone to subjects resulted in a mean terminal brain mu opioid receptor (MOR) occupancy of 59 - 104 % with an average occupancy of about 74% across the top 15 brain regions.
  • Administration of 4 mg IN naloxone to subjects resulted in MOR occupancy of 82 - 102 %, with an average occupancy of about 91% across the top 15 brain regions one hour post-dose. Furthermore, there was good agreement between receptor occupancy and plasma naloxone concentrations.
  • MOR mean terminal brain mu opioid receptor
  • PET transverse imaging demonstrated that intranasally-administered naloxone at the tested 2 mg and 4 mg doses effectively displaced [ n C]carfentanil tracer from MORs in brain tissue, and occupied MORs in neural circuitry and structures involved in reward, such as the thalamus, basal ganglia, and nucleus accumbens in a dose-dependent manner.
  • MOR occupancy by naloxone was achieved rapidly after i.n. naloxone spray.
  • the ti/2 of appearance of occupancy i.e., the time at which approximately half of MOR were occupied
  • the ti/2 of appearance of occupancy was 12 - 27 minutes (average of approximately 16 minutes across the top 15 brain regions) after administering 2 mg of naloxone, and 8 - 14 minutes (average of approximately 10 minutes across the top 15 brain regions) after 4 mg of naloxone.
  • the medulla oblongata important for the regulation of breathing, was among the regions showing the fastest and strongest [l lCJcarfentanil displacement by naloxone. MOR occupancy by naloxone of 117 % and 98 % on the average was observed in the medulla oblongata one hour after administering 4 mg and 2 mg of naloxone i.n., with estimated tl/2 of appearance of naloxone occupancy of 7 minutes and 11 minutes on the average.
  • naloxone mean mu opioid appearance mean t- mean mu opioid
  • Pendunculopontine nucleus 0.24 -0.44 376 18 6.67
  • Non-compartmental PK parameters including Cmax, tmax, AUC to 6 hours (AUCo- ⁇ ), AUC to last measurable concentration (AUCo-t), and data quality allowing, also elimination rate constant ( ⁇ ), elimination half-life (t1 ⁇ 2) and AUC extrapolated to infinity (AUCo- ⁇ ) were estimated using a validated PK software program, WinNonlin® Phoenix 6.4. Selection of terminal time points was made based on the software and review of the selected points. The trapezoidal rule was used to estimate AUC, with linear calculation for increasing values and ln-transformed values used for decreasing values. The following definitions were applied to the PK parameters:
  • i) achieves ⁇ -opioid receptor (MOR) occupancy by naloxone of > about 50% in the brain, or a region thereof, in less than about 15 minutes;
  • ii) is cleared form the brain to a level that yields MOR occupancy by naloxone of ⁇ about 15% within six hours.
  • MOR ⁇ -opioid receptor
  • MOR ⁇ -opioid receptor
  • MOR ⁇ -opioid receptor
  • MOR ⁇ -opioid receptor

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Abstract

L'invention concerne des procédés d'obtention de niveaux élevés d'occupation de naltrexone des récepteurs μ-opioïdes dans le cerveau d'un sujet, ou dans une région de celui-ci, dans des points temporels spécifiques, comprenant l'administration intranasale d'une formulation de naloxone ou d'un sel ou d'un hydrate de celle-ci.
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US12194263B2 (en) 2019-03-26 2025-01-14 Pocket Naloxone Corp. Devices and methods for delivery of pharmaceutical compositions
US12268684B2 (en) 2019-07-09 2025-04-08 Orexo Ab Pharmaceutical composition for nasal delivery
US10729687B1 (en) 2019-07-09 2020-08-04 Orexo Ab Pharmaceutical composition for nasal delivery
WO2021005325A1 (fr) 2019-07-09 2021-01-14 Orexo Ab Composition pharmaceutique pour administration par voie nasale
US10898480B1 (en) 2019-07-09 2021-01-26 Orexo Ab Pharmaceutical composition for nasal delivery
US11883392B2 (en) 2019-07-09 2024-01-30 Orexo Ab Pharmaceutical composition for nasal delivery
US10653690B1 (en) 2019-07-09 2020-05-19 Orexo Ab Pharmaceutical composition for nasal delivery
US12514854B2 (en) 2020-02-05 2026-01-06 Summit Biosciences Inc. Drug products for intranasal administration and uses thereof
US11737980B2 (en) 2020-05-18 2023-08-29 Orexo Ab Pharmaceutical composition for drug delivery
US12357573B2 (en) 2020-05-18 2025-07-15 Orexo Ab Pharmaceutical composition for drug delivery
US12017026B2 (en) 2021-03-12 2024-06-25 Pocket Naloxone Corp. Drug delivery device and methods for using same
US12285581B2 (en) 2021-03-12 2025-04-29 Pocket Naloxone Corp. Drug delivery device and methods for using same
WO2022192652A1 (fr) * 2021-03-12 2022-09-15 Pocket Naloxone Corp. Naloxone destinée à l'utilisation dans le traitement d'une overdose d'opioïdes administrée par un dispositif d'administration de médicament
US12303472B2 (en) 2021-11-25 2025-05-20 Orexo Ab Pharmaceutical device for use in intranasal administration
US11957647B2 (en) 2021-11-25 2024-04-16 Orexo Ab Pharmaceutical composition comprising adrenaline
US12472154B2 (en) 2021-11-25 2025-11-18 Orexo Ab Pharmaceutical composition comprising adrenaline

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