Compositions and methods for treating opioid overdose

Abstract

To provide durable, easy-to-use, needleless devices with storage-stable formulations that enable untrained individuals to quickly deliver a therapeutically effective dose of a rapid-acting and long-lasting opioid antagonist to an opioid overdose patient.SOLUTION: The invention provides drug products suitable for nasal delivery, comprising a pre-primed device filled with a pharmaceutical composition comprising nalmefene. Methods of treating opioid overdose with the drug products are also provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 424,378, filed November 18, 2016. The disclosure of U.S. Provisional Patent Application No. 62 / 424,378 is incorporated herein by reference in its entirety and for all purposes, as if set forth herein.

[0002] Disclosed herein are methods, pharmaceutical compositions, and more particularly, pharmaceutical compositions comprising opioid antagonists and methods of use thereof. [Background technology]

[0003] Prescription opioid use and abuse have been prevalent in the United States for nearly two decades. In addition, the abuse of heroin and synthetic opioids, such as fentanyl, has dramatically increased since 2010. As a result, opioid overdose mortality rates have continued to rise dramatically. For example, an estimated 33,000 people died from opioid overdose in 2015. Currently, injectable naloxone, administered intravenously (IV), intramuscularly (IM), or subcutaneously (SC), at an initial dose of 0.4 mg–2 mg, is the accepted standard of care for opioid overdose. These injections are most commonly administered by medical personnel in emergency departments and ambulances. Recently, an intranasal (IN) formulation of naloxone was approved by the U.S. Food and Drug Administration (FDA) for the treatment of opioid overdose. Intranasal naloxone is easy to administer and is quickly becoming the preferred route of administration for first responders who are not trained or qualified to administer parenteral solutions. Furthermore, the intranasal route of administration eliminates the possibility of first responders or healthcare personnel accidentally contracting infectious diseases (e.g., Hepatitis C and HIV) through needlestick injuries.

[0004] Nalmefene and naloxone are opioid antagonists that bind to the same brain opioid receptors as opioids. Both opioid antagonists bind to these receptors with high affinity and compete with opioids (e.g., oxycodone, morphine, and heroin) at these receptor sites by mass action. Binding of opioid antagonists, such as naloxone and nalmefene, to these receptors instead of opioids can reverse the pharmacological effects of opioids, including respiratory depression and somnolence.

[0005] Naloxone has a half-life of 1-2 hours and, as a result, a short duration of action. If a patient has overdosed on a long-acting opioid (e.g., methadone, carfentanil) and / or has high levels of opioids in their system and does not receive an additional dose of naloxone, opioid-induced central nervous system depression may re-emerge. This is particularly problematic when a patient overdoses in remote / rural areas, where it may take an hour or more before emergency medical care arrives at the scene of the overdose.

[0006] Nalmefene is a 6-methylene analog of naltrexone approved by the U.S. Food and Drug Administration (FDA) for the reversal of opioid effects, including respiratory depression, sedation, and hypotension. The reported half-life of nalmefene is 8 to 10.8 hours after intravenous (IV) administration. IV administration of nalmefene is the recommended route, but if venous access is not available, nalmefene can also be given by the intramuscular (IM) and subcutaneous (SC) routes. The relative bioavailability of nalmefene by the IM and SC routes is approximately 100%, but the peak plasma concentration (C max ) occurs in 1.5 ± 1.2 hours after SC injection. Nalmefene has a longer duration of action than naloxone when tested in healthy subjects receiving continuous IV infusion of fentanyl. Although equipotent on a milligram per milligram basis, the clearance of nalmefene is slower than that of naloxone, thus resulting in a longer duration of action for nalmefene.

[0007] There are concerns about the risk of healthcare personnel being exposed to bloodborne pathogens through needlestick injuries. Furthermore, non-healthcare personnel require training to administer injectable solutions. Nalmefene administered by the intranasal (IN) route, a needle-free alternative, is significantly easier to use than injections and could have a significant impact in reducing morbidity and mortality from opioid overdose. Nalmefene may be particularly useful when the overdose is due to an opioid with a long half-life. However, the half-life of IN nalmefene and the time to peak effect (T max ) has also never been reported in the peer-reviewed literature.

[0008] Due to the longer half-life of nalmefene compared with naloxone, IN administration of nalmefene has the potential to extend the time available for first responders to help someone who has suffered an opioid overdose.

[0009] Thus, there remains a need for a durable, easy-to-use, needle-free device with a storage-stable formulation that allows an untrained person to quickly deliver a therapeutically effective dose of a fast-acting, long-lasting opioid antagonist to an opioid overdose patient. This therapeutically effective dose should be sufficient to eliminate the need for an untrained person to administer a second dose of an opioid antagonist or another medical intervention to the patient, and to stabilize the patient until professional medical care is available. The devices described herein meet this and other needs. Summary of the Invention

[0010] Provided herein are methods, compositions, and devices for treating opioid overdose, comprising administering an intranasal formulation of the opioid antagonist nalmefene.

[0011] Accordingly, in one aspect, the present invention provides a method for treating opioid overdose or symptoms thereof, comprising intranasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist (e.g., nalmefene or a pharmaceutically acceptable salt thereof), wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride or a hydrate thereof.

[0012] Also provided is a primed device suitable for nasally delivering to a patient a pharmaceutical composition comprising a therapeutically effective amount of an opioid antagonist (e.g., nalmefene and its pharmaceutically acceptable salts), wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride or a hydrate thereof.

[0013] In some embodiments, the IN formulation is administered prior to exposure to the addictive substance or behavior. In some embodiments, the IN formulation is administered about 1 to about 2 hours before exposure to the addictive substance or behavior. In some embodiments, the IN formulation is administered daily. In some embodiments, the IN formulation is administered twice daily. In some embodiments, the IN formulation is administered three times daily. In some embodiments, the IN formulation is administered four times daily. In some embodiments, the IN formulation is administered as needed by the subject throughout the day. In some embodiments, the IN formulation is administered once daily, followed by subsequent booster doses administered as needed by the subject throughout the day. In some embodiments, the IN formulation is administered simultaneously with exposure to the addictive substance or behavior. In some embodiments, the IN formulation is administered after exposure to the addictive substance or behavior. In some embodiments, the IN formulation is administered about 5 to about 15 minutes before exposure to the addictive substance or behavior.

[0014] In some embodiments, the IN formulation comprises an aqueous solution. In some embodiments, the IN formulation comprises about 4 mg of nalmefene or a salt thereof. In some embodiments, about 0.1 mL of the formulation is delivered to a subject. In some embodiments, the formulation comprises 40 mg / mL nalmefene or a salt thereof.

[0015] In some embodiments, the IN formulation is administered as a single dose into one nostril.In some embodiments, the IN formulation is administered as two doses, one into each nostril.In some embodiments, the IN formulation is administered as four doses, two into each nostril.

[0016] In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of nalmefene is administered together with an excipient. In some embodiments, the excipient is an absorption enhancer. In some embodiments, the absorption enhancer is an alkyl saccharide, such as dodecyl maltoside. In some embodiments, the absorption enhancer is an alkyl glycoside.

[0017] In some embodiments, the pharmaceutical composition comprises one or more excipients selected from sodium chloride, benzalkonium chloride, edetate disodium, and an acid, in some embodiments, the acid is sufficient to achieve a pH of about 3.5 to about 5.5.

[0018] In some embodiments, the therapeutically effective amount comprises about 1 to about 10 mg of nalmefene. In some embodiments, the therapeutically effective amount comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg of nalmefene.

[0019] In some embodiments, the therapeutically effective amount of nalmefene is administered in 4 mg doses throughout the day as needed by the subject.

[0020] In some embodiments, a therapeutically effective amount of nalmefene is administered as a first 4mg dose in the morning, and as needed, a subsequent 4mg dose is administered before exposure to an addictive substance or behavior.In some embodiments, a therapeutically effective amount of nalmefene is administered as a first 4mg dose in the morning, and as needed, a subsequent 4mg dose is administered simultaneously with exposure to an addictive substance or behavior.In some embodiments, a therapeutically effective amount of nalmefene is administered as a first 4mg dose in the morning, and as needed, a subsequent 4mg dose is administered after / before exposure to an addictive substance or behavior.

[0021] Disclosed herein is a method for achieving a therapeutically effective plasma concentration of nalmefene for treating opioid overdose in a patient in need thereof while maintaining a plasma concentration of 6β-naltrexol below about 4 ng / mL, the method comprising intranasal administration of a pharmaceutical formulation comprising about 2 mg to about 16 mg of nalmefene, or a salt or hydrate thereof.

[0022] C of at least 5 ng / mL within 40 minutes max Also disclosed herein is an intranasal pharmaceutical formulation comprising nalmefene, which achieves [The present invention 1001] In about 50 to about 250 μL of aqueous solution, Approximately 1 to 10 mg of nalmefene hydrochloride or its hydrate; about 0.2 to about 2.0 mg of an isotonic agent; and absorption enhancers 1. A pharmaceutical formulation for intranasal administration comprising: [The present invention 1002] 1001. A pharmaceutical formulation of the present invention comprising about 3 mg of nalmefene hydrochloride or a hydrate thereof. [The present invention 1003] 1001. The pharmaceutical formulation of claim 1001, wherein said absorption enhancer is benzalkonium chloride. [The present invention 1004] 1003. The pharmaceutical formulation of the present invention, comprising about 0.005% to about 0.015% benzalkonium chloride. [The present invention 1005] 1001. The pharmaceutical formulation of claim 1001, wherein the absorption enhancer is an alkyl saccharide, an alkyl glycoside, a sucrose ester of a fatty acid, a cyclodextrin, or a bile salt. [The present invention 1006] 1005. The pharmaceutical formulation of claim 10, wherein the absorption enhancer is an alkyl saccharide. [The present invention 1007] 1005. The pharmaceutical formulation of claim 10, wherein the absorption enhancer is dodecyl maltoside or tetradecyl maltoside. [The present invention 1008] 1005. The pharmaceutical formulation of claim 10, wherein said absorption enhancer is Intravail® (dodecyl maltoside). [The present invention 1009] 1008. A pharmaceutical formulation of the present invention comprising about 0.05% to about 2.5% Intravail® (dodecyl maltoside). [The present invention 1010] 1008. A pharmaceutical formulation of the present invention comprising about 0.1% to about 0.5% Intravail® (dodecyl maltoside). [The present invention 1011] 1001. The pharmaceutical formulation of the present invention, comprising about 0.1 to about 0.5 mg of a stabilizer. [The present invention 1012] 1001. A pharmaceutical formulation of this invention comprising a sufficient amount of acid or base to achieve a pH of 3.5 to 5.5. [The present invention 1013] 1001. A pharmaceutical formulation of this invention comprising a sufficient amount of acid or base to achieve a pH of 3.5 to 4.5. [The present invention 1014] 1012. The pharmaceutical formulation of the present invention, comprising about 0.1 to about 0.5 mg of a stabilizer. [The present invention 1015] 1001. The pharmaceutical formulation of claim 1001, wherein said isotonic agent is NaCl. [The present invention 1016] 1008. The pharmaceutical formulation of claim 10, wherein said stabilizer is edetate disodium. [The present invention 1017] 1012. The pharmaceutical formulation of claim 1011, wherein said acid is hydrochloric acid or said base is sodium hydroxide. [The present invention 1018] 1014. The pharmaceutical formulation of claim 1014, wherein the isotonic agent is NaCl, the absorption enhancer is benzalkonium chloride, the stabilizer is edetate disodium, and the acid is hydrochloric acid or the base is sodium hydroxide. [The present invention 1019] In about 100 μL of aqueous solution, Approximately 3 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; Approximately 0.01 mg of benzalkonium chloride; Approximately 0.2 mg of edetate disodium; and Hydrochloric acid or sodium hydroxide in sufficient quantity to achieve a pH of 3.5 to 5.5 1014. A pharmaceutical formulation of the present invention comprising: [The present invention 1020] 1014. A pharmaceutical formulation of invention 1014, wherein the isotonic agent is NaCl, the absorption enhancer is Intravail® (dodecyl maltoside), the stabilizer is edetate disodium, and the acid is hydrochloric acid or the base is sodium hydroxide. [The present invention 1021] In about 100 μL of aqueous solution, Approximately 3 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; approximately 0.25 mg of Intravail® (dodecyl maltoside); Approximately 0.2 mg of edetate disodium; and Hydrochloric acid or sodium hydroxide in sufficient quantity to achieve a pH of 3.5 to 5.5 1016. The pharmaceutical formulation of the present invention comprising: [The present invention 1022] 1014. A pharmaceutical formulation of claim 10, wherein the pharmaceutical formulation comprises two absorption enhancers, the isotonicity agent is NaCl, the absorption enhancers are benzalkonium chloride and Intravail® (dodecylmaltoside), the stabilizer is edetate disodium, and the acid is hydrochloric acid or the base is sodium hydroxide. [The present invention 1023] In about 100 μL of aqueous solution, Approximately 3 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; Approximately 0.01 mg of benzalkonium chloride; approximately 0.25 mg of Intravail® (dodecyl maltoside); Approximately 0.2 mg of edetate disodium; and Hydrochloric acid or sodium hydroxide in sufficient quantity to achieve a pH of 3.5 to 5.5 1018. A pharmaceutical formulation of the present invention comprising: [The present invention 1024] 1. A disposable, primed device suitable for nasal delivery of a pharmaceutical composition to a patient, wherein operation of the device delivers the pharmaceutical composition into one nostril of the patient, the device comprising: Approximately 1 to 10 mg of nalmefene hydrochloride or its hydrate; about 0.1 mg to about 5.0 mg of an isotonic agent; and absorption enhancers The device contains a pharmaceutical composition which is about 50 to about 250 μL of an aqueous solution containing the above. [The present invention 1025] 1024. The device of claim 10, comprising about 3 mg of nalmefene hydrochloride or a hydrate thereof. [The present invention 1026] 1024. The device of claim 1024, wherein the absorption enhancer is benzalkonium chloride. [The present invention 1027] 1024. The device of claim 1024, comprising about 0.005% to about 0.015% benzalkonium chloride. [The present invention 1028] 1024. The device of claim 1024, wherein the absorption enhancer is an alkyl saccharide, an alkyl glycoside, a sucrose ester of a fatty acid, a cyclodextrin, or a bile salt. [The present invention 1029] The device of claim 1024, wherein the absorption enhancer is an alkyl saccharide. [The present invention 1030] The device of claim 1024, wherein the absorption enhancer is Intravail® (dodecyl maltoside). [The present invention 1031] 1024. A device of the present invention comprising about 0.05% to about 2.5% Intravail® (dodecyl maltoside). [The present invention 1032] A device of the present invention 1024 comprising about 0.1% to about 0.5% Intravail® (dodecyl maltoside). [The present invention 1033] 1024. The device of claim 1024, wherein the isotonic agent is NaCl. [The present invention 1034] stabilizers; and Sufficient acid or base to achieve a pH between 3.5 and 5.5 1024 devices of the present invention, including: [This invention 1035] The device of claim 1034, wherein the isotonic agent is NaCl, the absorption enhancer is benzalkonium chloride, the stabilizer is edetate disodium, and the acid is hydrochloric acid or the base is sodium hydroxide. [The present invention 1036] About 100 μL of the aqueous solution Approximately 3 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; Approximately 0.01 mg of benzalkonium chloride; Approximately 0.2 mg of edetate disodium; and Hydrochloric acid or sodium hydroxide in sufficient quantity to achieve a pH of 3.5 to 5.5 1024 devices of the present invention, including: [This invention 1037] The device of claim 1034, wherein the isotonic agent is NaCl, the absorption enhancer is Intravail® (dodecyl maltoside), the stabilizer is edetate disodium, and the acid is hydrochloric acid or the base is sodium hydroxide. [The present invention 1038] About 100 μL of the aqueous solution Approximately 3 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; approximately 0.25 mg of Intravail® (dodecyl maltoside); Approximately 0.2 mg of edetate disodium; and Hydrochloric acid or sodium hydroxide in sufficient quantity to achieve a pH of 3.5 to 5.5 1024 devices of the present invention, including: [This invention 1039] The device of claim 1034, wherein the pharmaceutical composition comprises two absorption enhancers, the isotonicity agent is NaCl, the absorption enhancers are benzalkonium chloride and Intravail® (dodecyl maltoside), the stabilizer is edetate disodium, and the acid is hydrochloric acid or the base is sodium hydroxide. [The present invention 1040] About 100 μL of the aqueous solution Approximately 3 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; Approximately 0.01 mg of benzalkonium chloride; approximately 0.25 mg of Intravail® (dodecyl maltoside); Approximately 0.2 mg of edetate disodium; and Hydrochloric acid or sodium hydroxide in sufficient quantity to achieve a pH of 3.5 to 5.5 1024 devices of the present invention, including: [The present invention 1041] The device of the present invention 1024 can be operated with one hand. [The present invention 1042] 1024. The device of claim 1024, wherein the reservoir has a volume of about 140 μL or less. [This invention 1043] The device of the present invention 1024, wherein approximately 100 μL of the aqueous solution in the reservoir is delivered to the patient in a single operation. [This invention 1044] A device of the present invention 1035, wherein the 90% confidence interval for the dose delivered per actuation is about ±2%. [This invention 1045] A device of the present invention 1041, wherein the 95% confidence interval for the dose delivered per actuation is about ±2.5%. [The present invention 1046] The device of the present invention 1041, wherein the delivery time is less than about 25 seconds. [This invention 1047] The device of the present invention 1041, wherein the delivery time is less than about 20 seconds. [This invention 1048] The device of claim 1041, wherein when said pharmaceutical composition is delivered nasally to said patient, less than about 20% of said pharmaceutical composition leaves the nasal cavity by flowing into or out of the nasopharynx. [This invention 1049] The device of claim 1043, wherein when said pharmaceutical composition is delivered nasally to said patient, less than about 10% of said pharmaceutical composition leaves the nasal cavity by flowing into or out of the nasopharynx. [The present invention 1050] 1049. The device of claim 1049, wherein when said pharmaceutical composition is delivered nasally to said patient, less than about 5% of said pharmaceutical composition leaves the nasal cavity by flowing into or out of the nasopharynx. [This invention 1051] T of the plasma concentration versus time curve of nalmefene hydrochloride in the patient max The device of the present invention 1024, wherein the time is about 10 to about 30 minutes. [This invention 1052] The device of invention 1036, 1038, or 1040, wherein the patient is an opioid overdose patient or a patient suspected of having an opioid overdose. [This invention 1053] The device of the present invention 1052, wherein the patient exhibits one or more symptoms selected from respiratory depression, central nervous system depression, cardiovascular depression, altered level of consciousness, miosis, hypoxemia, acute lung injury, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimuli, unconsciousness, respiratory arrest; irregular pulse or cessation of pulse, choking or gurgling sound, blue or purple nails or lips, decreased muscle tone, pupil constriction, and vomiting. [This invention 1054] The device of the present invention 1053, wherein the patient exhibits respiratory depression. [This invention 1055] The device of claim 1054, wherein said respiratory depression is caused by illicit use of opioids or by accidental misuse of opioids during medical opioid therapy. [This invention 1056] 1054. The device of claim 1054, wherein said patient is free of respiratory depression for at least about 4 hours after treatment essentially comprising delivery of said therapeutically effective amount of said opioid antagonist. [This invention 1057] 1054. The device of claim 1054, wherein said patient is free of respiratory depression for at least about 8 hours after treatment essentially comprising delivery of said therapeutically effective amount of said opioid antagonist. [This invention 1058] 1054. The device of claim 1054, wherein said patient is free of respiratory depression for at least about 12 hours after treatment essentially comprising delivery of said therapeutically effective amount of said opioid antagonist. [This invention 1059] 1054. The device of claim 1054, wherein said patient is free of respiratory depression for at least about 14 hours after treatment essentially comprising delivery of said therapeutically effective amount of said opioid antagonist. [The present invention 1060] The device of the present invention 1052, wherein the patient is in a supine, recumbent, or recovery position. [The present invention 1061] A disposable, primed device suitable for nasal delivery of a pharmaceutical formulation to a patient, wherein operation of the device delivers the pharmaceutical formulation into the patient's nostrils, and the device contains a pharmaceutical composition according to any one of claims 1001 to 1023. [The present invention 1062] A primed, two-dose device suitable for nasal delivery of a pharmaceutical formulation to a patient, wherein operation of the device delivers the pharmaceutical formulation into at least one nostril of the patient, the device comprising a first volume of the pharmaceutical composition of any of claims 1001 to 1023 present in a first reservoir and a second volume of the pharmaceutical composition of any of claims 1001 to 1023 present in a second reservoir. [The present invention 1063] A method for treating an opioid overdose or symptoms thereof in a patient, comprising the step of intranasally administering to a patient in need thereof a pharmaceutical formulation of any one of claims 1001 to 1023, or intranasally administering a dose of nalmefene using a device of any one of claims 1024 to 1062, thereby treating an opioid overdose or symptoms thereof in the patient. [The present invention 1064] A method for inducing complete or partial recovery from opioid-induced narcotic depression or respiratory depression in a patient, comprising the step of intranasally administering to a patient in need thereof any of the pharmaceutical formulations of inventions 1001 to 1023, or intranasally administering a dose of nalmefene using any of the devices of inventions 1024 to 1062, thereby inducing complete or partial recovery from opioid-induced narcotic depression or respiratory depression in the patient. [This invention 1065] A method for treating an opioid overdose or symptoms thereof in a patient within 15 minutes of the onset of the condition, comprising the step of administering to a patient in need thereof a pharmaceutical formulation of any one of claims 1001 to 1023, or administering a dose of nalmefene intranasally using a device of any one of claims 1024 to 1062, thereby treating the opioid overdose or symptoms thereof in the patient. [The present invention 1066] A method for treating an opioid overdose or symptoms thereof in a patient for at least 3 hours, comprising the step of administering to a patient in need thereof a pharmaceutical formulation of any one of claims 1001 to 1023, or administering a dose of nalmefene intranasally using a device of any one of claims 1024 to 1062, thereby treating an opioid overdose or symptoms thereof in the patient. [This invention 1067] A method for treating an opioid overdose or its symptoms in a patient within 15 minutes of onset and for at least 3 hours, comprising the step of intranasally administering to a patient in need thereof a pharmaceutical formulation of any of inventions 1001 to 1023, or intranasally administering a dose of nalmefene using a device of any of inventions 1024 to 1062, thereby treating an opioid overdose or its symptoms in the patient. [The present invention 1068] A method for treating an opioid overdose or symptoms thereof in a patient, comprising the step of administering to a patient in need thereof a pharmaceutical formulation of any one of claims 1001 to 1023 or a dose of nalmefene intranasally using a device of any one of claims 1024 to 1062, thereby treating an opioid overdose or symptoms thereof in the patient and increasing the T of nalmefene plasma concentration. max is less than 20 minutes. [The present invention 1069] A method for treating an opioid overdose or symptoms thereof in a patient, comprising the step of administering to a patient in need thereof a pharmaceutical formulation of any one of claims 1001 to 1023 or a dose of nalmefene intranasally using a device of any one of claims 1024 to 1062, thereby treating an opioid overdose or symptoms thereof in the patient and increasing the T of nalmefene plasma concentration. max is 15 minutes or less. [The present invention 1070] A method for treating an opioid overdose or symptoms thereof in a patient, comprising the step of administering to a patient in need thereof a pharmaceutical formulation of any one of claims 1001 to 1023, or administering a dose of nalmefene intranasally using a device of any one of claims 1024 to 1062, thereby treating an opioid overdose or symptoms thereof in the patient, wherein the half-life of the drug in plasma is greater than 6 hours. [This invention 1071] A pharmaceutical composition for treating opioid overdose or symptoms thereof, comprising about 1 to 10 mg of nalmefene hydrochloride or a hydrate thereof, formulated for intranasal administration, which produces a plasma concentration versus time curve having an area under the curve (AUC) that is about 60% of the AUC of 1.5 mg IM nalmefene. [Brief explanation of the drawings]

[0023] [Figure 1A] 1 is a graph showing the mean plasma concentrations of nalmefene after a single intramuscular injection compared to IN administration with and without 0.25% Intravail® (dodecylmaltoside). [Figure 2A] 1 is a graph showing the mean plasma concentrations of nalmefene after a single intramuscular injection compared to IN administration with and without 0.25% Intravail® (dodecylmaltoside). [Figure 3A] FIG. 1B is a semi-logarithmic plot of the data shown in FIG. 1A. [Figure 4A]1 is a graph showing the plasma concentrations of 4 mg naloxone IN (0.1 mL of a 40 mg / ml solution) compared to 3 mg nalmefene IN (0.1 mL of a 30 mg / ml solution) with and without 0.25% Intravail. These data were obtained from a previous study. In the previous study, the Tmax was 0.5 hours (30 minutes). [Figure 5A] This is a semi-logarithmic plot of the data shown in Figure 4A. These data were obtained from a previous study. In the previous study, Tmax was 0.5 hours (30 minutes). These data were obtained from a previous study. In the previous study, Tmax was 0.5 hours (30 minutes). DETAILED DESCRIPTION OF THE INVENTION

[0024] Detailed Description Disclosed herein are methods and compositions for treating opioid overdose, comprising administering an intranasal formulation of an opioid antagonist. Disclosed herein are methods and compositions for treating opioid receptor-mediated diseases, disorders, addictions, symptoms, or conditions, comprising administering an intranasal formulation of an opioid antagonist, alone or in combination with an absorption enhancer. For clarity and consistency, the following definitions are used throughout this patent document.

[0025] Opioid receptors are G protein-coupled receptors (GPCRs) activated by endogenous opioid peptides, clinically important alkaloid analgesics such as morphine, and synthetic analgesics such as methadone and fentanyl. There are three major types of opioid receptors: delta-, kappa-, and mu-opioid receptors. Opioids inhibit respiration, which is primarily controlled by peripheral input from chemoreceptors and other sources through the medullary respiratory center. Opioids exert their inhibition via mu-opioid receptors at chemoreceptors and via mu- and delta-opioid receptors in the medulla. Many neurotransmitters mediate respiratory control, with glutamate being the primary excitatory neurotransmitter and gamma-aminobutyric acid (GABA) the primary inhibitory neurotransmitter. This explains the potential interactions between opioids and benzodiazepines and alcohol. That is, both benzodiazepines and alcohol stimulate GABA A Alcohol also decreases the excitatory action of glutamate at NMDA receptors, whereas it enhances the inhibitory action of GABA at the receptors. Oxycodone and other opioid analgesics (e.g., hydrocodone and fentanyl), as well as heroin and methadone, are all implicated in fatal overdoses.

[0026] In 2016, approximately 64,000 people died from drug overdoses. At least 14,400 of these deaths involved prescription opioid painkillers, nearly 3,300 of these deaths involved methadone, 15,400 of these deaths involved heroin, and over 20,000 of these deaths were attributed to fentanyl and related synthetic opioids. Collectively, the number of opioid-related overdose deaths in 2016 far exceeded the peak number of HIV-related deaths and the peak number of firearm-related deaths.

[0027] Provided is a primed device suitable for nasally delivering to a patient a pharmaceutical composition comprising a therapeutically effective amount of the opioid antagonist nalmefene and pharmaceutically acceptable salts thereof, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride.

[0028] Also provided is a method for treating opioid overdose or symptoms thereof, comprising the step of intranasally administering to a patient in need thereof a therapeutically effective amount of the opioid antagonist nalmefene and pharmaceutically acceptable salts thereof, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride.

[0029] As used herein, the following terms have the meanings indicated.

[0030] When a range of values ​​is disclosed and the notation "from n1 to n2" or "n1-n2" is used, where n1 and n2 are numbers, this notation is intended to include the numbers themselves and the range between the numbers unless otherwise specified. The range may be integer or continuous, between and including the end values. As an example, carbon is expressed in integer units, so the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons. As an example, compare the range "1 to 3 μM (micromolar)," which is intended to include 1 μM, 3 μM, and all concentrations in between to any significant figure (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0031] As used herein, the term "about" is intended to modify the numerical value it modifies, indicating that such value is variable within a range. When a range is not described, such as an error bar or standard deviation for a mean value given in a graph or table of data, the term "about" should be understood to mean the larger of the range that includes the stated value, a range that is included by rounding up or down to take into account significant digits, and a range that includes the stated value ±20%.

[0032] As used herein, the term "absorption enhancer" refers to a functional excipient included in a formulation to improve the absorption of a pharmacologically active drug. This term typically refers to an agent that functions to enhance absorption by enhancing permeation through the nasal mucosa rather than by increasing solubility. Thus, such agents are sometimes referred to as permeation enhancers. In particular, the absorption enhancers described herein may improve paracellular transport (i.e., passage through intercellular spaces and tight junctions), transcellular transport (i.e., passive diffusion or active transport across cell membranes), or transcytosis (i.e., uptake of cellular vesicles). Ozsoy et al., Molecules 14:3754-79, 2009.

[0033] Examples of absorption enhancers include aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoylcarnitine, dodecylmaltoside, EDTA, glycocholic acid, glycodeoxycholic acid, glycofurol, glycosylated sphingosine, glycyrrhetinic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroylcarnitine, sodium lauryl sulfate, lysophosphatidylcholine, menthol, poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol, quillaja saponin, salicylic acid, sodium salt, β-sitosterol β-D-glucoside, sucrose coconut oil, cocoate), taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid, and alkyl saccharides, including, but not limited to, dodecyl maltoside, dodecyl-β-D-maltoside, tetradecyl maltoside, tetradecyl-β-D-maltoside, and sucrose dodecanoate. Alkyl saccharides (e.g., nonionic alkyl saccharide surfactants, e.g., alkyl glycosides, which consist of an aliphatic hydrocarbon chain attached to a sugar moiety by a glycosidic bond, and sucrose esters of fatty acids, which consist of an aliphatic hydrocarbon chain attached to a sugar moiety by an ester bond), cyclodextrins (cyclic oligosaccharides composed of six or more monosaccharide units with a central cavity, which form inclusion bodies with hydrophobic molecules and have been used primarily to increase drug solubility and dissolution and to enhance the absorption of low-molecular-weight drugs), chitosan (a linear cationic polysaccharide derived from the deacetylation of chitin), and bile salts and their derivatives (e.g., sodium glycocholate, sodium taurocholate, and sodium taurodihydrofusidate) tend to be among the best-tolerated absorption enhancers. See, e.g., Aungst, AAPS Journal 14(1):10-8, 2011; and Maggio, J. Excipients and Food Chem. 5(2):100-12, 2014.

[0034] The term "alkyl saccharide" as used herein refers to an absorption enhancer. As used herein, alkyl saccharide refers to any sugar linked by any hydrophobic alkyl linkage, as known in the art. Alkyl saccharides include alkyl saccharides such as octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl-α- or β-D-maltoside, -glucoside, or -sucroside; alkyl thiomaltosides such as heptyl-, octyl-, dodecyl-, tridecyl-, and tetradecyl-β-D-thiomaltoside; alkyl thioglucosides such as heptyl- or octadecyl-α- or β-D-maltoside; These may include, but are not limited to, octyl 1-thio α- or β-D-glucopyranoside; alkylthiosucrose; alkylmaltotriosides; long-chain aliphatic carbonic acid amides of sucrose β-amino-alkyl ethers; derivatives of palatinose and isomaltamine linked to the alkyl chain by an amide bond; derivatives of isomaltamine linked to the alkyl chain by a urea bond; long-chain aliphatic ureido carbonates of sucrose β-amino-alkyl ethers; and long-chain aliphatic carbonic acid amides of sucrose β-amino-alkyl ethers. Depending on the desired hydrophobicity and hydrophilicity of the saccharide moiety, any desired size of hydrophobic alkyl can be selected. For example, one preferred range for the alkyl chain is from about 9 to about 24 carbon atoms. A more preferred range is from about 9 to about 16 or about 14 carbon atoms. Similarly, some preferred sugars include maltose, sucrose, and glucose linked by glycosidic bonds to alkyl chains of 9, 10, 12, 13, 14, 16, 18, 20, 22, or 24 carbon atoms, e.g., nonyl-, decyl-, dodecyl-, and the like, as well as tetradecyl sucroside, glucoside, and maltoside.

[0035] As used herein, "sugars" includes monosaccharides, linear or cyclic oligosaccharides or polysaccharides, or combinations thereof to form sugar chains. Oligosaccharides are sugars having two or more monosaccharide residues. Sugars may be selected from, for example, any currently commercially available sugar species, or may be synthesized. Some examples of the many possible sugars that can be used include glucose, maltose, maltotriose, maltotetraose, sucrose, and trehalose. Preferred sugars include maltose, sucrose, and glucose.

[0036] The term "active ingredient" or "pharmaceutically active compound" is defined in the context of a "pharmaceutical composition" and is intended to mean the component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to "inactive ingredients," which are generally recognized as not providing any pharmaceutical benefit.

[0037] As used herein, the term "operating" refers to manipulating a device to deliver a pharmaceutical composition from the device.

[0038] As used herein, the term "agonist" refers to a moiety that interacts with and activates a receptor, thereby initiating a physiological or pharmacological response characteristic of that receptor. As used herein, the term "antagonist" refers to a moiety that competitively binds to the same receptor site as an agonist (e.g., an endogenous ligand) but does not activate the intracellular response initiated by the activated form of the receptor, thereby inhibiting the intracellular response induced by an agonist or partial agonist. An antagonist does not reduce the baseline intracellular response in the absence of an agonist or partial agonist. The term "inverse agonist" refers to a moiety that binds to the endogenous form of a receptor or a constitutively activated form of a receptor and inhibits the baseline intracellular response initiated by the activated form of the receptor below the normal basal level of activity observed in the absence of an agonist or partial agonist.

[0039] As used herein, the term "antimicrobial preservative" refers to a pharmaceutically acceptable excipient with antimicrobial properties that is added to a pharmaceutical composition to maintain microbiological stability.

[0040] As used herein, the term "AUC" refers to the area under the drug plasma concentration-time curve. 0-t The term "AUC" refers to the area under the drug plasma concentration-time curve from t=0 to the last measurable concentration. 0-∞ The term "AUC" refers to the area under the drug plasma concentration-time curve extrapolated to infinity. 0-t / D The term "AUC" refers to the AUC normalized to 0.4 mg IN nalmefene. 0-t As used herein, "AUC 0-∞ / D The term "AUC" is the AUC normalized to 1.5 mg IM nalmefene. 0-∞ Refers to...

[0041] As used herein, the term "bioavailability (F)" refers to the fraction of a drug dose that is absorbed from the administration site and reaches the systemic circulation intact. The term "absolute bioavailability" is used when the fraction of a drug absorbed is related to its IV bioavailability, which is expressed by the following formula: The relative bioavailability (F rel The term "(dose)" is used to compare two different routes of extravascular drug administration and is expressed as follows: This can be calculated using TIFF0007730443000002.tif10128.

[0042] As used herein, the term "clearance (CL)" refers to the rate at which a drug is eliminated divided by the plasma concentration of the drug, and represents the volume of plasma from which the drug is completely removed per unit time. CL is calculated by multiplying the elimination rate constant (λ) by the volume of distribution (V d ) multiplied by V dis the fluid volume required to contain the amount of drug present in the body at the same concentration as in plasma. As used herein, the term "apparent clearance (CL / F)" refers to the clearance without taking into account the bioavailability of the drug. It is the ratio of the dose over the AUC.

[0043] As used herein, "C max The term "C" refers to the peak plasma concentration observed. max / D The term "C" refers to the C normalized to 1.5 mg IM nalmefene. max Refers to...

[0044] As used herein, the term "coefficient of variation (CV)" refers to the ratio of the sample standard deviation to the sample mean. The "coefficient of variation (CV)" is often expressed as a percentage.

[0045] As used herein, the term "confidence interval" refers to a range of values ​​that contains, with a specified percentage probability, the true mean value of a parameter.

[0046] As used herein, the term "device" refers to an apparatus capable of delivering a drug to a patient in need thereof.

[0047] As used herein, the term "time of delivery" refers to the amount of time that elapses from the determination by a medical professional or untrained person that an individual requires nasal delivery of an opioid antagonist until delivery is completed.

[0048] As used herein, the term "disease" is generally synonymous with the terms "disorder," "syndrome," and "condition" (such as a medical condition), and is intended to be used interchangeably with these terms, as they all reflect an abnormal condition of the human or animal body or parts thereof that impairs normal function, is typically manifested by well-characterized signs and symptoms, and results in a reduction in duration or quality of life for the human or animal.

[0049] As used herein, the term "elimination rate constant (λ)" refers to the rate, expressed in fractions, at which a drug is eliminated from the body. This rate is first order, constant, and independent of the drug concentration in the body. λ is the slope of the plasma concentration-time line (on a logarithmic y scale). As used herein, "λ" refers to the rate at which a drug is eliminated from the body, expressed in fractions. This rate is first order, constant, and independent of the drug concentration in the body. λ is the slope of the plasma concentration-time line (on a logarithmic y scale). z The term "terminal phase" refers to the terminal elimination rate constant. The "terminal phase" of a drug plasma concentration-time curve is a straight line when plotted on a semi-logarithmic graph. Because the primary mechanism that reduces drug concentrations during the terminal phase is drug elimination from the body, the terminal phase is often also called the "elimination phase." A characteristic of the terminal elimination phase is that the relative proportions of drug in the plasma and in the peripheral volume of distribution remain constant. During this "terminal phase," the drug returns to plasma from the rapid and slow volumes of distribution and is permanently removed from plasma by metabolism or renal excretion.

[0050] As used herein, the term "equivalent" refers to a molar amount of an opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts, equivalent to the specified weight of nalmefene hydrochloride.

[0051] As used herein, the term "excipient" refers to a natural or synthetic substance that is formulated with an active ingredient of a drug for the purpose of long-term stabilization, increasing the bulk of a solid formulation, or to impart a therapeutic enhancement to the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or increasing solubility.

[0052] As used herein, the term "loaded" refers to the association between the device and the pharmaceutical composition, for example, when a pharmaceutical composition described herein comprising a therapeutically effective amount of an opioid antagonist is present in a reservoir that becomes part of the device described herein.

[0053] As used herein, the term "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.

[0054] The terms "in need of treatment" and "in need of treatment" when referring to treatment are used interchangeably and refer to the judgment of a caregiver (e.g., physician, nurse, nurse practitioner) that the patient will benefit from treatment. Individuals "at risk for opioid overdose" include those who have used opioids illicitly, those who have accidentally ingested opioids, and those at risk for accidental misuse of opioids during medical opioid treatment.

[0055] As used herein, two embodiments are "mutually exclusive" when one is defined as something different from the other. For example, an embodiment specifying an amount of nalmefene hydrochloride of 4 mg is mutually exclusive with an embodiment specifying an amount of nalmefene hydrochloride of 2 mg. However, an embodiment specifying an amount of nalmefene hydrochloride of 4 mg is not mutually exclusive with an embodiment in which less than about 10% of the pharmaceutical composition leaves the nasal cavity by flowing into or out of the nasopharynx.

[0056] As used herein, the term "nalmefene" has the following structure: This refers to the compound TIFF0007730443000003.tif40128, 17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol.

[0057] Nalmefene hydrochloride (CAS Reg. No. 58895-64-0) is sold under the trade names Nalmetrene®, Cervene®, Revex®, Arthrene®, and Incystene®.

[0058] As used herein, the term "naloxone" has the following structure: This refers to the compound TIFF0007730443000004.tif39128, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. The CAS Registry Number for naloxone is 465-65-6. Other names for naloxone include 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one; (-)-17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one; 4,5α-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one; and (-)-12-allyl-7,7a,8,9-tetrahydro-3,7a-dihydroxy-4aH-8,9c-iminoethanophenanthro[4,5-bcd]furan-5(6H)-one. Naloxone hydrochloride can be anhydrous (CAS Reg. No. 357-08-4) or form a dihydrate (CAS No. 51481-60-8). Naloxone hydrochloride is sold under various trade names, including Narcan®, Nalone®, Nalossone®, Naloxona®, Naloxonum®, Narcanti®, and Narcon®.

[0059] As used herein, the term "naltrexone" has the following structure: This refers to the compound TIFF0007730443000005.tif37128, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. The CAS registry number for naltrexone is 16590-41-3. Other names for naltrexone include 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one; (5α)-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epoxymorphinan-6-one; and (1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10-trien-14-one. Naltrexone hydrochloride (CAS Reg. No. 16676-29-2) is sold under the trade names Antaxone®, Depade®, Nalorex®, Revia®, Trexan®, Vivitrex®, and Vivitrol®.

[0060] As used herein, the term "methylnaltrexone" has the following structure: TIFF0007730443000006.tif41128 refers to a pharmaceutically acceptable salt containing the compound cation (5α)-17-(cyclopropylmethyl)-3,14-dihydroxy-17-methyl-4,5-epoxymorphinanium-17-ium-6-one, wherein X - is a pharmaceutically acceptable anion. Methylnaltrexone bromide (CAS Reg. No. 75232-52-7) is sold under the trade name Relistor®.

[0061] As used herein, the term "nostril" is synonymous with "naris."

[0062] The term "opioid antagonist" includes naloxone, naltrexone, and nalmefene, and pharmaceutically acceptable salts thereof. In some embodiments, the opioid antagonist is nalmefene hydrochloride. In some embodiments, intranasal administration is performed using a device described herein.

[0063] As used herein, the term "opioid overdose" refers to an acute medical condition caused by excessive use of one or more opioids. Symptoms of opioid overdose include respiratory depression (including postoperative opioid respiratory depression, acute lung injury, and aspiration pneumonia), central nervous system depression (which may include sedation, altered level of consciousness, miosis (pupil constriction)), and cardiovascular depression (which may include hypoxemia and hypotension). Visible signs of an opioid overdose or suspected opioid overdose include unresponsiveness and / or loss of consciousness (unresponsive to stimuli such as shouting, shaking, or rubbing a knuckle against the sternum); slow, irregular breathing, or cessation of breathing; slow, irregular, or cessation of pulse; low-pitched snoring or choking / gurgling sounds; blue or purple fingernails or lips; pale and / or cold, clammy face; decreased muscle tone; constricted pupils; and vomiting. Because opioid overdose can be difficult to diagnose and / or quantify, especially by laypersons, the term "treatment of opioid overdose," as used herein, is intended to include treatment of suspected opioid overdose in opioid-addicted patients. Opioids that can induce overdose include codeine, morphine, methadone, fentanyl, oxycodone HCl, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, tapentadol, and certain opioid antagonist analgesics, such as nalbuphine, pentazocine, and butorphanol. In some embodiments, the opioid agonist is in an abuse-deterrent formulation. In some embodiments, the opioid agonist is in a tamper-resistant formulation. In some embodiments, the opioid agonist is selected from Acurox® oxycodone DETERx®, Egalet hydrocodone, Egalet morphine, Egalet oxycodone, Exalgo®, Opana®, and Remoxy®.

[0064] The term "patient" refers to any subject, preferably a human, suffering from a condition that is likely to benefit from treatment with a therapeutically effective amount of an opioid antagonist.

[0065] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one active ingredient, including, but not limited to, salts, solvates, and hydrates of an opioid antagonist described herein, and applicable for use in a mammal (e.g., but not limited to, a human) to achieve a specified effective outcome. In some embodiments, the opioid antagonist is nalmefene.

[0066] The term "pharmaceutically acceptable," as used herein, refers to a component of a pharmaceutical composition that is compatible with the other ingredients of the formulation and not unduly harmful to the recipient thereof.

[0067] As used herein, the term "primed" refers to a device, such as a nasal spray, in which delivery of a pharmaceutical composition to a patient in need thereof can be achieved on the first actuation of the spray pump, i.e., without priming the pump prior to dosing (e.g., by pressing the pump one or more times until a spray is dispensed).

[0068] As used herein, the term "prone" refers to a patient lying face down.

[0069] As used herein, the term "protective packaging" refers to an overwrap.

[0070] The term "receptor binding or occupancy" refers to the characterization of the kinetics between the radiopharmaceutical and receptors or other binding sites throughout the body, and the characterization of the binding affinity of the radiopharmaceutical to these receptors.

[0071] As used herein, the term "recovery position" refers to a human body position in which the patient is lying on their side with their feet or knees forward (e.g., to prevent them from rolling over onto their stomach) and at least one hand supporting their head (e.g., to elevate their face to facilitate breathing and prevent inhaling vomit).

[0072] The term "providing," in the context of providing a co-packaged drug product disclosed herein to an individual, includes co-packaging the drug products, prescribing the co-packaged drug product, and administering the co-packaged drug product. The providing step may be done directly to the individual (e.g., an individual suitable for administering an opioid agonist prescription drug or an individual otherwise at risk of opioid overdose) or to a second individual.

[0073] As used herein, the term "solvate" refers to an opioid antagonist or salt thereof described herein that further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and / or acceptable for human administration in trace amounts.

[0074] As used herein, the term "aseptic filling" refers to a method of manufacturing the devices and pharmaceutical compositions 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 typically involves filling and sealing a product container under high-quality environmental conditions. In an aseptic process, the drug product, container, and closure are first subjected to sterilization separately, if appropriate, and then combined.

[0075] As used herein, the term "storage-stable" refers to a pharmaceutical composition in which at least about 90% to 99.5% of the active ingredient remains undegraded after storage at a specified temperature and humidity for a specified period of time, e.g., after storage for 12 months at 25°C and 60% relative humidity.

[0076] As used herein, the term "subject" is intended to be synonymous with "patient" and refers to any mammal, preferably a human, suffering from a condition that is likely to benefit from treatment with a therapeutically effective amount of the opioid antagonist nalmefene.

[0077] The term "substantially free of antimicrobial preservatives" will be understood by those skilled in the art to refer to pharmaceutical compositions that contain less than 1% w / w of antimicrobial preservatives.

[0078] As used herein, the term "supine" refers to a patient lying face up.

[0079] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose" refers to the amount or dose of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, or individual sought by a researcher, healthcare provider, or individual. A therapeutically effective amount may, but need not, eliminate one, more, or all symptoms of the disease, disorder, or condition being treated. A therapeutically effective amount may also prevent disease progression and may also prevent the appearance of further symptoms.

[0080] As used herein, "t 1 / 2 The term "half-life" or "half-life" refers to the amount of time required for half of a drug (e.g., an opioid or opioid antagonist) to be eliminated from the body, or the time required for the drug concentration to decrease by half.

[0081] As used herein, the term "tonicity agent" refers to a compound that alters the osmolality of a formulation, e.g., makes the formulation isotonic. Tonicity agents include dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, and the like.

[0082] As used herein, the term "tomography" refers to a cross-sectional imaging process. The images may be viewed individually, as a series of two-dimensional slices, or together as a computer-generated three-dimensional representation.

[0083] As used herein, "T max " refers to the time from administration of a pharmaceutical composition described herein to peak plasma concentration of the drug.

[0084] The term "untrained person" refers to a person who administers an opioid antagonist to a patient using a device described herein, but who is not a medical professional and is not trained in using the device.

[0085] Opioid antagonists Provided is a drug product of opioid receptor antagonist suitable for nasal delivery.Opioid receptor antagonist is a well-known class of chemicals.Opioid receptor antagonist has been described in detail in scientific and patent literature.Opioid antagonist such as nalmefene is a drug that specifically reverses the action of opioid agonist but does not have opioid agonist activity.

[0086] Nalmefene, available commercially as the hydrochloride salt, is a 6-methylene analog of naltrexone. Nalmefene hydrochloride (17-(cyclopropylmethyl)-4,5-(-epoxy-6-methylenemorphinan-3,14-diol) is approved for the reversal of opioid overdose and can be used to prevent euphoria-inducing effects in the treatment of patients with opioid dependence. It reverses opioid effects, including respiratory depression, sedation, and hypotension, but patients do not develop tolerance or dependence to nalmefene.

[0087] Provided are pharmaceutical compositions, devices suitable for nasal delivery of the pharmaceutical compositions to a patient, kits containing the same, and methods of using the same in treatment, each comprising a therapeutically effective amount of an opioid antagonist selected from nalmefene and pharmaceutically acceptable salts thereof, wherein the device is primed, and the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride.

[0088] In some embodiments, the therapeutically effective amount is equivalent to about 0.5 mg to about 12 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 0.5 mg to about 10 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg to about 12 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg to about 9 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg to about 8 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg to about 7 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg to about 6 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg to about 5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg to about 4 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg to about 3 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg to about 2 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1.5 mg to about 10 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2 mg to about 10 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3 mg to about 10 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg to about 10 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 5 mg to about 10 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2 mg to about 8 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2 mg to about 6 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3 mg of nalmefene hydrochloride.In some embodiments, the therapeutically effective amount is equivalent to about 3.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 6 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 7 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 8 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 9 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 10 mg of nalmefene hydrochloride. In some embodiments, a therapeutically effective amount is equivalent to about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.2 mg, about 1.4 mg, about 1.6 mg, about 1.8 mg, about 2 mg, about 2.2 mg, about 2.4 mg, about 2.6 mg, about 2.8 mg, about 3 mg, about 3.2 mg, about 3.4 mg, about 3.6 mg, about 3.8 mg, or about 4 mg of nalmefene hydrochloride. In some embodiments, a therapeutically effective amount is equivalent to about 0.5 to about 1.0 mg, about 0.5 to about 1.5 mg, about 1.5 to about 2.0 mg, about 1.5 to about 2.5 mg, about 1.5 to about 3.0 mg, about 1.5 to about 3.5 mg, or about 1.5 to about 4.0 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to less than 10 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to less than 5 mg of nalmefene hydrochloride.

[0089] In some embodiments, the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical composition. In some embodiments, the opioid antagonist is nalmefene hydrochloride. In some embodiments, the opioid antagonist is anhydrous nalmefene hydrochloride.

[0090] Provided herein are methods of treatment using intranasal delivery to a patient of a pharmaceutical composition comprising a therapeutically effective amount of the opioid antagonist nalmefene. In some embodiments, the therapeutically effective amount is equivalent to about 2 to about 16 mg of nalmefene. In some embodiments, the therapeutically effective amount is equivalent to about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, or about 16 mg of nalmefene. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of nalmefene hydrochloride. In some embodiments, the opioid antagonist is nalmefene hydrochloride. In some embodiments, the opioid antagonist is anhydrous nalmefene hydrochloride. In some embodiments, the opioid antagonist is nalmefene hydrochloride dihydrate.

[0091] Thus, provided herein are pharmaceutical formulations for intranasal administration comprising nalmefene. In certain embodiments, the formulation is an aqueous solution. In certain embodiments, the formulation comprises about 25 to about 200 μL of aqueous solution per dose. In certain embodiments, the formulation comprises about 50 to about 200 μL of aqueous solution per dose. In certain embodiments, the formulation comprises about 140 μL or less per dose. In certain embodiments, the formulation comprises about 100 μL or less per dose. The formulation may comprise about 25 μL, about 50 μL, about 75 μL, about 100 μL, about 125 μL, about 150 μL, about 175 μL, or about 200 μL of aqueous solution per dose.

[0092] In certain embodiments, the formulation comprises about 1% (w / v) to about 16% (w / v) of the opioid antagonist nalmefene. In certain embodiments, the formulation comprises about 2% (w / v) to about 12% (w / v) nalmefene. In certain embodiments, the formulation comprises about 2% (w / v) to about 10% (w / v) nalmefene. In certain embodiments, the formulation comprises about 2% (w / v) to about 8% (w / v) nalmefene. In certain embodiments, the formulation comprises about 2% (w / v) to about 4% (w / v) nalmefene. In certain embodiments, the formulation comprises about 1% (w / v), about 2% (w / v), about 3% (w / v), about 4% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), or about 8% (w / v) nalmefene. In certain embodiments, the formulation comprises about 1% (w / v) nalmefene, in certain embodiments, about 2% (w / v) nalmefene, in certain embodiments, about 4% (w / v) nalmefene.

[0093] In certain embodiments, the formulation contains about 1 mg to about 16 mg of the opioid antagonist nalmefene. In certain embodiments, the formulation contains about 2 mg to about 12 mg of nalmefene. In certain embodiments, the formulation contains about 2 mg to about 10 mg of nalmefene. In certain embodiments, the formulation contains about 2 mg to about 8 mg of nalmefene. In certain embodiments, the formulation contains about 2 mg to about 4 mg of nalmefene. In certain embodiments, the formulation contains about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg of nalmefene. In certain embodiments, the formulation contains about 1 mg of nalmefene. In certain embodiments, the formulation contains about 2 mg of nalmefene. In certain embodiments, the formulation contains about 4 mg of nalmefene.

[0094] In certain embodiments, provided herein is a pharmaceutical formulation for intranasal administration comprising about 2 mg to about 16 mg of nalmefene; and about 0.2 mg to about 1.2 mg of an isotonic agent in about 140 μL or less of an aqueous solution.

[0095] In certain embodiments, provided herein is a pharmaceutical formulation for intranasal administration comprising about 2% (w / v) to about 16% (w / v) nalmefene; and about 0.2% (w / v) to about 1.2% (w / v) isotonic agent in about 140 μL or less of an aqueous solution.

[0096] In certain embodiments, the pharmaceutical formulation comprises about 2 mg or about 4 mg of nalmefene hydrochloride or a hydrate thereof; and about 0.2 mg to about 1.2 mg of an isotonicity agent.

[0097] In certain embodiments, the pharmaceutical formulation comprises about 2% (w / v) or about 4% (w / v) nalmefene hydrochloride or a hydrate thereof; and about 0.2% (w / v) to about 1.2% (w / v) of an isotonicity agent.

[0098] In certain embodiments, the isotonic agent is sodium chloride.

[0099] In certain embodiments, the pharmaceutical formulation comprises about 2 mg or about 4 mg of nalmefene hydrochloride; and about 0.74 mg of sodium chloride.

[0100] In certain embodiments, the pharmaceutical formulation comprises about 4 mg of nalmefene hydrochloride; and about 0.74 mg of sodium chloride.

[0101] In certain embodiments, the pharmaceutical formulation comprises about 100 μL or less of an aqueous solution.

[0102] In certain embodiments, the pharmaceutical formulation comprises about 4 mg or about 4% (w / v) of nalmefene hydrochloride or a hydrate thereof. In certain embodiments, the pharmaceutical formulation comprises about 2 mg or about 2% (w / v) of nalmefene hydrochloride or a hydrate thereof. In certain embodiments, the nalmefene hydrochloride is provided as nalmefene hydrochloride dihydrate.

[0103] In certain embodiments, the pharmaceutical formulation further comprises an absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises about 0.005% to about 2.5% of the absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises about 0.05% to about 2.5% of the absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises about 0.1% to about 0.5% of the absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises about 0.25% of the absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises about 0.18% of the absorption enhancer. In certain embodiments, the absorption enhancer is an alkyl saccharide. In certain embodiments, the alkyl saccharide is selected from dodecyl maltoside, tetradecyl maltoside (TDM), and sucrose dodecanoate.

[0104] In certain embodiments, the alkyl saccharide is Intravail® (dodecyl maltoside). Intravail® is the alkyl saccharide 1-On-dodecyl-β-D-maltopyranoside (alternatively referred to as lauryl-β-D-maltopyranoside, dodecyl maltopyranoside, and DDM; C24H46Q11). Alkyl saccharides are used in commercial food and personal care products and are designated as generally recognized as safe (GRAS) for food use. Alkyl saccharides are tasteless, odorless, nontoxic, nonmutagenic, non-sensitizing, and non-irritating transmucosal absorption enhancers up to 25% concentration in the Draize assay. Alkyl saccharides increase absorption by increasing paracellular permeability, as indicated by a decrease in transepithelial electrical resistance. Alkyl saccharides may also increase transcytosis. This effect is short-lived. Other alkyl saccharides include tetradecyl maltoside (TDM) and sucrose dodecanoate.

[0105] In certain embodiments, the pharmaceutical formulation comprises about 0.005% to about 0.05% (w / v) of an absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises about 0.005% to about 0.015% (w / v) of an absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises about 0.01% (w / v) of an absorption enhancer. In certain embodiments, the absorption enhancer is benzalkonium chloride.

[0106] In certain embodiments, the intranasal formulation contains about 0.05% to about 2.5% (w / v) Intravail®. In certain embodiments, the intranasal formulation contains about 0.1% to about 0.5% (w / v) Intravail®. In certain embodiments, the intranasal formulation contains about 0.15% to about 0.35% (w / v) Intravail®. In certain embodiments, the intranasal formulation contains about 0.15% to about 0.2% (w / v) Intravail®. In certain embodiments, the intranasal formulation contains about 0.18% (w / v) Intravail®. In certain embodiments, the intranasal formulation contains about 0.2% to about 0.3% (w / v) Intravail®. In certain embodiments, the intranasal formulation contains about 0.25% (w / v) Intravail®.

[0107] When 0.18% Intravail® was added to an intranasal formulation of sumatriptan, peak plasma concentrations increased nearly fourfold compared to Imitrex nasal spray, and Tmax decreased from 1-2 hours to 8-10 minutes. Total exposure, as measured by area under the concentration-time curve (AUC), increased by 32%. Nalmefene intranasal formulations may be used without needles or extended-release formulations. The inclusion of Intravail® may improve pharmacokinetic parameters in some applications.

[0108] In certain embodiments, the pharmaceutical formulation further comprises an isotonicity agent. The intranasal formulation may comprise about 0.2% (w / v) to about 1.2% (w / v) of the isotonicity agent, for example, about 0.2% (w / v), about 0.3% (w / v), about 0.4% (w / v), about 0.5% (w / v), about 0.6% (w / v), about 0.7% (w / v), about 0.8% (w / v), about 0.9% (w / v), about 1.0% (w / v), about 1.1% (w / v), or about 1.2% (w / v). The intranasal formulation may comprise more than about 0.1% (w / v) of the isotonicity agent. The intranasal formulation may comprise less than about 1.2% (w / v) of the isotonicity agent.

[0109] In certain embodiments, provided herein is a pharmaceutical formulation for intranasal administration comprising about 2 mg to about 16 mg of nalmefene; about 0.05 mg to about 2.5 mg of an absorption enhancer; and about 0.2 mg to about 1.2 mg of an isotonic agent in about 140 μL or less of an aqueous solution.

[0110] In certain embodiments, provided herein is a pharmaceutical formulation for intranasal administration comprising about 2% (w / v) to about 16% (w / v) nalmefene; about 0.05% (w / v) to about 2.5% (w / v) absorption enhancer; and about 0.2% (w / v) to about 1.2% (w / v) isotonicity agent in about 140 μL or less of an aqueous solution.

[0111] In certain embodiments, the pharmaceutical formulation comprises about 2 mg or about 4 mg of nalmefene hydrochloride or a hydrate thereof; about 0.05 mg to about 2.5 mg of an absorption enhancer; and about 0.2 mg to about 1.2 mg of an isotonicity agent.

[0112] In certain embodiments, the pharmaceutical formulation comprises about 2% (w / v) or about 4% (w / v) nalmefene hydrochloride or its hydrate; about 0.05% (w / v) to about 2.5% (w / v) of an absorption enhancer; and about 0.2% (w / v) to about 1.2% (w / v) of an isotonicity agent.

[0113] In certain embodiments, the pharmaceutical formulation comprises about 100 μL or less of an aqueous solution.

[0114] In certain embodiments, provided herein is a pharmaceutical formulation for intranasal administration comprising about 2 mg to about 16 mg of nalmefene; about 0.005 mg to about 0.015 mg of an absorption enhancer; and about 0.2 mg to about 1.2 mg of an isotonic agent in about 140 μL or less of an aqueous solution.

[0115] In certain embodiments, provided herein is a pharmaceutical formulation for intranasal administration comprising about 2% (w / v) to about 16% (w / v) nalmefene; about 0.005% (w / v) to about 0.015% (w / v) of an absorption enhancer; and about 0.2% (w / v) to about 1.2% (w / v) of an isotonic agent in about 140 μL or less of an aqueous solution.

[0116] In certain embodiments, the pharmaceutical formulation comprises about 2 mg or about 4 mg of nalmefene hydrochloride or a hydrate thereof; about 0.005 mg to about 0.015 mg of an absorption enhancer; and about 0.2 mg to about 1.2 mg of an isotonicity agent.

[0117] In certain embodiments, the pharmaceutical formulation comprises about 2% (w / v) or about 4% (w / v) nalmefene hydrochloride or its hydrate; about 0.005% (w / v) to about 0.015% (w / v) of an absorption enhancer; and about 0.2% (w / v) to about 1.2% (w / v) of an isotonicity agent.

[0118] In certain embodiments, the pharmaceutical formulation comprises about 100 μL or less of an aqueous solution.

[0119] In certain embodiments, the isotonic agent is sodium chloride.

[0120] In certain embodiments, the absorption enhancer is Intravail® (dodecyl maltoside).

[0121] In certain embodiments, the pharmaceutical formulation comprises about 2 mg or about 4 mg of nalmefene hydrochloride; about 0.25 mg of Intravail® (dodecylmaltoside); and about 0.74 mg of sodium chloride.

[0122] In certain embodiments, the pharmaceutical formulation comprises about 4 mg of nalmefene hydrochloride; about 0.25 mg of Intravail® (dodecylmaltoside); and about 0.74 mg of sodium chloride.

[0123] In certain embodiments, the absorption enhancer is benzalkonium chloride.

[0124] In certain embodiments, the pharmaceutical formulation comprises about 2 mg or about 4 mg of nalmefene hydrochloride; about 0.01 mg of benzalkonium chloride; and about 0.74 mg of sodium chloride.

[0125] In certain embodiments, the pharmaceutical formulation comprises about 4 mg of nalmefene hydrochloride; about 0.01 mg of benzalkonium chloride; and about 0.74 mg of sodium chloride.

[0126] In certain embodiments, the pharmaceutical formulation comprises about 100 μL or less of an aqueous solution.

[0127] In certain embodiments, the pharmaceutical formulation comprises about 4 mg or about 4% (w / v) of nalmefene hydrochloride or a hydrate thereof. In certain embodiments, the pharmaceutical formulation comprises about 2 mg or about 2% (w / v) of nalmefene hydrochloride or a hydrate thereof. In certain embodiments, nalmefene hydrochloride is provided as nalmefene hydrochloride dihydrate.

[0128] In certain embodiments, the pharmaceutical formulation further comprises a compound that is a preservative and / or a surfactant.

[0129] In certain embodiments, the preservative and / or surfactant is selected from benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenylethyl alcohol, and the like, and mixtures thereof; surfactants, such as polysorbate 80NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate, and the like, and mixtures thereof.

[0130] In certain embodiments, the pharmaceutical formulation further comprises a stabilizer.

[0131] In certain embodiments, the stabilizer is edetate disodium (EDTA).

[0132] In some embodiments, the acid or base is sufficient to achieve a pH of about 3.5-4.0. In some embodiments, the acid or base is sufficient to achieve a pH of about 3.5-4.5. In some embodiments, the acid or base is sufficient to achieve a pH of about 4.0-4.5. In some embodiments, the acid or base is sufficient to achieve a pH of about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, or about 7.

[0133] In some embodiments, the preservative, absorption enhancer, and / or cationic surfactant is selected from benzalkonium chloride, cyclodextrin, alkyl saccharides (e.g., nonionic alkyl saccharide surfactants, e.g., alkyl glycosides consisting of an aliphatic hydrocarbon chain linked to a sugar moiety by a glycosidic bond, and sucrose esters of fatty acids consisting of an aliphatic hydrocarbon chain linked to a sugar moiety by an ester bond), fusidic acid derivatives, phosphatidylcholine, microspheres and liposomes, and bile salts. In certain embodiments, the preservative, absorption enhancer, and / or cationic surfactant is benzalkonium chloride.

[0134] In some embodiments, the pharmaceutical composition further comprises one or more excipients selected from water, NaCl, benzalkonium chloride, sodium edetate, disodium edetate, and hydrochloric acid. In some embodiments, the pharmaceutical composition further comprises water, NaCl, benzalkonium chloride, disodium edetate, and hydrochloric acid.

[0135] In some embodiments, pharmaceutical compositions comprise benzalkonium chloride.Benzalkonium chloride can function as a preservative (even in small amounts), as an absorption enhancer, and / or as a cationic surfactant (typically, the latter two can function in greater amounts than preservatives).Benzalkonium chloride has the following structure: TIFF0007730443000007.tif12128, where n is an integer and mixtures thereof can be used. In some embodiments, n is 8, 10, 12, 14, 16, or 18, and in some embodiments, n is 10, 12, or 14. In some embodiments, the pharmaceutical composition comprises about 0.005% to about 1% benzalkonium chloride.

[0136] As a surfactant, benzalkonium chloride not only affects the surface tension of droplets from the delivered nasal spray plume, resulting in spherical or substantially spherical particles with a narrow droplet size distribution (DSD), but can also affect the viscosity of the liquid formulation.

[0137] In some embodiments, the absorption enhancer is benzalkonium chloride. The pharmaceutical composition may contain about 0.01% to about 1% benzalkonium chloride. In some embodiments, the pharmaceutical composition contains about 0.005% to about 0.015% benzalkonium chloride. In some embodiments, the pharmaceutical composition contains about 0.01% benzalkonium chloride.

[0138] In some embodiments, the absorption enhancer is an alkyl saccharide, e.g., a nonionic alkyl saccharide surfactant, e.g., an alkyl glycoside consisting of an aliphatic hydrocarbon chain linked to a sugar moiety by a glycosidic bond, and a sucrose ester of a fatty acid consisting of an aliphatic hydrocarbon chain linked to a sugar moiety by an ester bond. In some embodiments, the absorption enhancer is an alkyl maltoside (e.g., tetradecyl maltoside (TDM), dodecyl maltoside, etc.). In some embodiments, the absorption enhancer is sucrose dodecanoate. Alkyl saccharides are used in commercially available food and personal care products and are designated as generally regarded as safe (GRAS) substances for food use. Alkyl saccharides are tasteless, odorless, nontoxic, nonmutagenic, and non-sensitizing transmucosal absorption enhancers that are non-irritating up to 25% concentration in the Draize test. Without being bound by theory, alkyl saccharides are believed to increase absorption by increasing paracellular permeability, as indicated by a decrease in transepithelial electrical resistance. Alkyl saccharides may also increase transcytosis, an effect that may be short-lived.

[0139] In some embodiments, the absorption enhancer is Intravail®, alkyl saccharide 1-On-dodecyl-β-D-maltopyranoside (alternatively lauryl-β-D-maltopyranoside, dodecylmaltopyranoside, dodecylmaltoside, and DDM;C 24 H 46 Q 11 (referred to as "Intravail®"). In certain embodiments, the intranasal formulation contains about 0.01% to about 2.5% Intravail®. In certain embodiments, the intranasal formulation contains about 0.1% to about 0.5% Intravail®. In certain embodiments, the intranasal formulation contains about 0.15% to about 0.35% Intravail®. In certain embodiments, the intranasal formulation contains about 0.15% to about 0.2% Intravail®. In certain embodiments, the intranasal formulation contains about 0.18% Intravail®. In certain embodiments, the intranasal formulation contains about 0.2% to about 0.3% Intravail®. In certain embodiments, the intranasal formulation contains about 0.25% Intravail®.

[0140] 1. A method of reducing the risk of opioid overdose in an individual at risk of opioid overdose, comprising providing a therapeutically effective amount of nalmefene hydrochloride or a hydrate thereof to the individual at risk of opioid overdose, wherein the nalmefene hydrochloride or a hydrate thereof is contained in a primed bi-dose device suitable for nasal delivery of a pharmaceutical composition to a patient, wherein a first volume of the pharmaceutical composition is in a first reservoir and a second volume of the pharmaceutical composition is in a second reservoir, and wherein a therapeutically effective amount of an opioid antagonist is delivered from the first reservoir into a nostril of the patient by a first actuation of the drug delivery device and from the second reservoir into a nostril of the patient by a second actuation of the drug delivery device, each reservoir comprising: Nalmefene hydrochloride or its hydrate; about 0.2 mg to about 1.2 mg of an isotonic agent; benzalkonium chloride in an amount effective to function as an absorption enhancer and / or cationic surfactant; stabilizers; and Sufficient acid or base to achieve a pH between 3.5 and 5.5 Also provided herein is a method comprising the steps of:

[0141] In certain embodiments, the absorption enhancer is selected from the group consisting of benzalkonium chloride, chitosan, cyclodextrin, deoxycholic acid, dodecylmaltoside, glycocholic acid, laureth-9, taurocholic acid, and taurodihydrofusidic acid. In certain embodiments, the absorption enhancer is Intravail®. In certain embodiments, the stabilizer is edetate disodium; and edetate disodium. In certain embodiments, the acid is hydrochloric acid.

[0142] In certain embodiments, the pharmaceutical formulation comprises about 2 mg or about 4 mg of nalmefene hydrochloride or its hydrate; about 0.74 mg of sodium chloride; about 0.01 mg of benzalkonium chloride; about 0.25 mg of Intravail® (dodecylmaltoside); about 0.2 mg of edetate disodium; and a sufficient amount of hydrochloric acid to achieve a pH of 3.5 to 5.5.

[0143] In certain embodiments, the pharmaceutical formulation comprises about 2 mg or about 4 mg of nalmefene hydrochloride or its hydrate; about 0.74 mg of sodium chloride; about 0.01 mg of benzalkonium chloride; about 0.2 mg of edetate disodium; and a sufficient amount of hydrochloric acid or base to achieve a pH of 3.5 to 5.5.

[0144] In certain embodiments, the pharmaceutical formulation comprises about 2 mg or about 4 mg of nalmefene hydrochloride or its hydrate; about 0.74 mg of sodium chloride; about 0.25 mg of Intravail® (dodecylmaltoside); about 0.2 mg of edetate disodium; and a sufficient amount of hydrochloric acid to achieve a pH of 3.5 to 5.5.

[0145] In certain embodiments, the pharmaceutical formulation contains about 4 mg of nalmefene hydrochloride or a hydrate thereof. In certain embodiments, the pharmaceutical formulation contains about 2.5 mg to about 8 mg of nalmefene hydrochloride or a hydrate thereof. In certain embodiments, the pharmaceutical formulation contains about 2 mg of nalmefene hydrochloride or a hydrate thereof. In certain embodiments, the pharmaceutical formulation contains about 2.5 mg of nalmefene hydrochloride or a hydrate thereof. In certain embodiments, the pharmaceutical formulation contains about 4 mg of nalmefene hydrochloride dihydrate.

[0146] Also provided herein is a pharmaceutical formulation for intranasal administration comprising, in about 100 μL of aqueous solution, about 4 mg of nalmefene hydrochloride or a hydrate thereof; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.005 mg to about 0.015 mg of a compound which is a preservative and / or cationic surfactant; about 0.00 to about 0.50 mg of sodium hydroxide, a compound which is an absorption enhancer; about 0.1 mg to about 0.5 mg of a stabilizer; and an acid in an amount sufficient to achieve a pH of 3.5 to 5.5.

[0147] Also provided herein is a pharmaceutical formulation for intranasal administration comprising, in about 100 μL of aqueous solution, about 4 mg of nalmefene hydrochloride or a hydrate thereof; about 0.2 mg to about 1.2 mg of an isotonic agent; optionally, about 0.005 mg to about 0.015 mg of a compound that is a preservative and / or cationic surfactant; about 0.005 to about 0.50 mg of a compound that is an absorption enhancer; optionally, about 0.1 mg to about 0.5 mg of a stabilizer; and an acid in an amount sufficient to achieve a pH of 3.5 to 5.5.

[0148] Also provided herein is a pharmaceutical formulation for intranasal administration comprising, in about 100 μL of aqueous solution, about 4 mg of nalmefene hydrochloride or a hydrate thereof; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.005 mg to about 0.015 mg of a compound that is a preservative and / or cationic surfactant; about 0.05 to about 0.50 mg of a compound that is an absorption enhancer; about 0.1 mg to about 0.5 mg of a stabilizer; and an acid in an amount sufficient to achieve a pH of 3.5 to 5.5.

[0149] In certain embodiments, the pharmaceutical formulation comprises about 4 mg of nalmefene hydrochloride or a hydrate thereof; about 0.74 mg of sodium chloride; about 0.01 mg of benzalkonium chloride; about 0.18 mg of Intravail® (dodecylmaltoside); about 0.2 mg of edetate disodium; and a sufficient amount of hydrochloric acid to achieve a pH of 3.5 to 5.5.

[0150] Also provided herein is a pharmaceutical formulation for intranasal administration comprising, in about 100 μL of aqueous solution, about 2 mg nalmefene hydrochloride or a hydrate thereof; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.005 mg to about 0.015 mg of a compound that is a preservative and / or cationic surfactant; about 0.00 to about 0.50 mg of a compound that is an absorption enhancer; about 0.1 mg to about 0.5 mg of a stabilizer; and an acid in an amount sufficient to achieve a pH of 3.5 to 5.5.

[0151] In certain embodiments, the pharmaceutical formulation comprises about 2 mg of nalmefene hydrochloride dihydrate; about 0.74 mg of sodium chloride; about 0.01 mg of benzalkonium chloride; about 0.18 mg of Intravail® (dodecylmaltoside); about 0.2 mg of edetate disodium; and a sufficient amount of hydrochloric acid to achieve a pH of 3.5 to 5.5.

[0152] In certain embodiments, the therapeutically effective amount comprises about 2 to about 16 mg of nalmefene. In certain embodiments, the pharmaceutical formulation comprises an amount equivalent to about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, or about 16 mg of nalmefene hydrochloride. In certain embodiments, the pharmaceutical formulation comprises an amount equivalent to about 4 mg to about 8 mg of naloxone hydrochloride. In certain embodiments, the pharmaceutical formulation comprises an amount equivalent to about 16 mg of naloxone hydrochloride.

[0153] Nasal drug delivery devices and kits Also provided is a nasal drug delivery device comprising the pharmaceutical composition described herein. Provided herein is a pharmaceutical composition in a device suitable for nasal delivery to a subject suffering from opioid overdose; or an opioid receptor-mediated disease, disorder, addiction, symptom, or condition, comprising administering an intranasal formulation of nalmefene. In some embodiments, the device is pre-primed. In some embodiments, the device can be primed before use. In some embodiments, the device can be operated with one hand.

[0154] Nasal delivery is considered an attractive, safe, and easy-to-administer route for needle-free systemic drug delivery, especially when rapid absorption and action are desired. Furthermore, nasal delivery may help address issues associated with poor bioavailability, slow absorption, drug degradation, and adverse events (AEs) in the gastrointestinal tract, and avoids first-pass metabolism in the liver.

[0155] Liquid nasal formulations are primarily aqueous solutions, although suspensions and emulsions can also be delivered. Traditional spray pump systems typically require antimicrobial preservatives to maintain microbiological stability in liquid formulations.

[0156] Several emergency medical services (EMS) programs have developed systems for intranasal administration of the opioid antagonist naloxone using existing technology and medical devices for approved drugs, albeit in a manner not approved by the FDA. This has been accomplished by using an injectable formulation (1 mg / mL) and administering 1 mL per nostril via a commercially available nasal atomizer / nebulizer device. This system combines an FDA-approved naloxone injection product (with a Luer-fitting tip and no needle) with a commercially available medical device called the Mucosal Atomization Device (MAD™ Nasal, Wolfe Tory Medical, Inc.). This initiative is consistent with the US Needlestick Safety and Prevention Act (Public Law 106-430). EMS programs have acknowledged limitations of this system, including the fact that it is not preassembled and ready to use. While this method of administration appears to be effective in reversing narcosis, the formulation is not concentrated enough to be retained in the nasal cavity. The delivery volume of 1 mL per nostril is larger than the delivery volume that is usually used for intranasal drug administration.Therefore, the drug is lost from the nasal cavity by flowing into the nasopharynx or out of the nasal cavity.The device described herein is an improved ready-to-use product that is optimized, concentrated, and formulated for nasal delivery.

[0157] Metered dose spray pumps have dominated the nasal drug delivery market since their introduction. These pumps typically deliver 100 μL (range 25-200 μL) per spray and demonstrate highly reproducible emitted dose and plume shape in in vitro studies.

[0158] Metered-dose spray pumps have dominated the nasal drug delivery market since their introduction. These pumps typically deliver 100 μL (or other volumes ranging from 25 to 200 μL and even larger) per spray and demonstrate highly reproducible emitted dose and plume shape in in vitro studies.

[0159] Examples of standard metered dose spray pumps include those supplied by Aptar Pharma, Inc., such as the multi-dose "classic technology platform" nasal spray device. Such devices include a reservoir holding multiple doses (e.g., 50, 100, 150, 200, 60, or 120 doses) of a nasal spray formulation, a closure (e.g., screw, crimp, or snap-on), and an actuator that delivers 45 to 1000 μL (e.g., 50 μL, 100 μL, 140 μL, 150 μL, or 200 μL) of fluid per actuation to comprise a single dose. The actuator may be configured to count doses, deliver a gel formulation, deliver in an upside-down configuration, etc.

[0160] Conventional spray pump systems typically require antimicrobial preservatives to maintain the microbiological stability of liquid formulations. However, preservative-free systems are also available, such as Aptar's Advanced Preservative-Free (APF) system. These systems are vented, have a filter membrane for airflow to prevent contamination, have a metal-free fluid path for oxidizing the formulation, and can be used in any orientation. Additional nasal spray devices, such as Aptar, are optimized with anti-clogging dispenser tips (useful for high-viscosity and high-volatility formulations) and actuators that do not require repriming after extended periods of non-use.

[0161] The particle size and plume shape may vary within certain limits and depend on the pump characteristics, formulation, actuator orifice, and applied force. The droplet size distribution of nasal sprays is an important parameter because it significantly influences in vivo drug deposition in the nasal cavity. Droplet size is influenced by the device's operating parameters and formulation. The typical median droplet size should be approximately 30 to approximately 100 μm. If droplets are too large (>approximately 120 μm), deposition occurs primarily in the anterior part of the nose. If droplets are too small (<approximately 10 μm), they may be inhaled and reach the lungs. This must be avoided for safety reasons. As a surfactant, benzalkonium chloride not only affects the surface tension of droplets from the delivered nasal spray plume, resulting in spherical or substantially spherical particles with a narrow droplet size distribution (DSD), but also affects the viscosity of liquid formulations.

[0162] The plume shape, droplet size, and DSD of the plume delivered after spraying can be measured under specified experimental and instrumental conditions by suitable, validated, and / or calibrated analytical procedures known in the art. These include photography, laser diffraction, and impaction systems (cascade impaction, NGI). Plume shape, droplet size, and DSD can be measured by C max , T max These may affect pharmacokinetic outcomes such as steroid use and linear dose-proportionality.

[0163] The droplet size distribution can be controlled by the range of D10, D50, D90, span [(D90-D10) / D50], and the percentage of droplets less than 10 mm. In certain embodiments, the formulation has a narrow DSD. In certain embodiments, the formulation has a D(v,50) of 30-70 μm and a D(v,90) of <100 μm.

[0164] In certain embodiments, the percentage of droplets less than 10 μm is less than 10%. In certain embodiments, the percentage of droplets less than 10 μm is less than 5%. In certain embodiments, the percentage of droplets less than 10 μm is less than 2%. In certain embodiments, the percentage of droplets less than 10 μm is less than 1%.

[0165] In certain embodiments, the formulation, when actuated and dispensed from the device, produces a uniform, circular plume with an ovality ratio close to 1. The ovality ratio is the maximum diameter (D) of the spray pattern perpendicular to the direction of the spray stream (e.g., from the "top") max ) and minimum diameter (D min ) In certain embodiments, the ellipticity ratio is less than ±2.0. In certain embodiments, the ellipticity ratio is less than ±1.5. In certain embodiments, the ellipticity ratio is less than ±1.3. In certain embodiments, the ellipticity ratio is less than ±1.2. In certain embodiments, the ellipticity ratio is less than ±1.1. In certain embodiments, the ellipticity ratio is about ±1.0.

[0166] Details of particle generation and mechanical principles for different types of nasal aerosol devices have been described. See Vidgren and Kublik, Adv. Drug Deliv. Rev. 29:157-77, 1998. Traditional spray pumps replace the expelled liquid with air, and therefore require preservatives to prevent contamination. However, prompted by research suggesting the possible adverse effects of preservatives, pump manufacturers have developed various spray systems that do not require preservatives. These systems use collapsible bags, movable pistons, or compressed gas to compensate for the expelled liquid volume (www.aptar.com and www.rexam.com). Solutions using collapsible bags and movable pistons to compensate for the expelled liquid volume have the added advantage that they can be expelled upside down without the risk of air being drawn into the dip tube and compromising the subsequent spray. This can be useful for some products where patients are bedridden and head-down use is recommended. Another method used to avoid preservatives is to have the air replacing the released liquid filtered through a sterile air filter. Additionally, some systems have a ball valve at the tip to prevent contamination of the liquid within the applicator tip (www.aptar.com). More recently, a side-actuation pump has been designed and introduced to deliver fluticasone furoate for the indications of seasonal and perennial allergic rhinitis. This pump was designed with a shorter tip to avoid contact with sensitive mucosal surfaces. New designs are available to reduce the need for priming and repriming, as well as pumps incorporating pressure point features to improve dose reproducibility and dose counters, and lockout mechanisms to enhance dose control and safety (www.rexam.com and www.aptar.com).

[0167] Conventional simple metered dose spray pumps require priming and some degree of overfill to maintain dose consistency with the labeled number of doses. While conventional simple metered dose spray pumps are well suited for drugs administered daily over a long period of time, the priming procedure and poor dosing control make them less suitable for drugs with a narrow therapeutic window, especially when used infrequently, unless a specialized device is selected. For expensive drugs and vaccines intended for single administration or single use, and when strict control of dose and formulation is important, single-dose or bi-dose spray devices are preferred (www.aptar.com). A simple variation of the single-dose spray device (MAD™) is offered by LMA (LMA, Salt Lake City, UT, USA; www.lmana.com). A nosepiece with a spray tip is fitted onto a standard syringe. First, the liquid drug to be delivered is drawn into the syringe, and then the spray tip is fitted onto the syringe. This device has been used in academic research to deliver topical steroids in patients with chronic sinusitis, for example, and in vaccine research. A single- or two-dose prefilled device based on the same principle (Accuspray™, Becton Dickinson Technologies, Research Triangle Park, NC, USA; www.bdpharma.com) is used to deliver the influenza vaccine FluMist™ (www.flumist.com) and is approved for both adults and children on the US market. A similar two-dose device for delivering another influenza vaccine was marketed by a Swiss company ten years ago.

[0168] Pre-primed single-dose and double-dose devices are also available and consist of a reservoir, piston, and swirl chamber (see, e.g., Aptar, formerly Pfeiffer's UDS UnitDose™ and BDS BiDose™ devices). A spray is formed as the liquid is forced through the swirl chamber. These devices are held between the second and third fingers, with the thumb on the actuator. Pressure point mechanisms incorporated into some devices ensure repeatability of actuation force and emitted plume characteristics. Currently, over-the-counter nasal migraine medications such as Imitrex® (www.gsk.com) and Zomig® (www.az.com; Pfeiffer / Aptar single-dose device), the over-the-counter influenza vaccine Flu-Mist (www.flumist.com; Becton Dickinson single-dose spray device), and the opioid overdose rescue intranasal formulation of naloxone, Narcan Nasal® (narcan.com; Adapt Pharma), are delivered using this type of device.

[0169] In certain embodiments, the 90% confidence interval for the dose delivered per actuation is about ±2%. In certain embodiments, the 95% confidence interval for the dose delivered per actuation is about ±2.5%.

[0170] Historically, intranasal administration of large volumes of drugs, for example, from a syringe fitted with a mucosal atomizer device, has encountered difficulties due to the tendency of some of the formulation to drip out of the nostrils or down the nasopharynx. Thus, in certain embodiments, when the pharmaceutical composition is delivered to the patient via the nose, less than about 20% of the pharmaceutical composition leaves the nasal cavity by flowing into or outside the nasopharynx. In certain embodiments, when the pharmaceutical composition is delivered to the patient via the nose, less than about 10% of the pharmaceutical composition leaves the nasal cavity by flowing into or outside the nasopharynx. In certain embodiments, when the pharmaceutical composition is delivered to the patient via the nose, less than about 5% of the pharmaceutical composition leaves the nasal cavity by flowing into or outside the nasopharynx.

[0171] Current container closure system designs for inhalation spray drug products include both pre-metered and device-metered presentations that use mechanical or power assistance and / or energy from patient inspiration for spray plume generation. Pre-metered presentations comprise a pre-measured dose or dose fraction in some type of unit (e.g., one or more blisters or other cavities) that is then inserted into the device during manufacture or by the patient prior to use. A typical device-metering unit has a reservoir containing enough formulation for multiple doses that are delivered as a metered spray by the device itself upon patient activation.

[0172] A new nasal drug delivery method is breath-powered Bi-Directional™ technology, which can be adapted to any type of dispersion technology, both liquid and powder. This concept utilizes the natural functional aspects of the upper airway to provide a delivery method that can overcome many of the inherent limitations of conventional nasal devices. The Breath-powered Bi-Directional™ device consists of a mouthpiece and a sealing nosepiece with an optimized frustoconical shape and a comfortable surface that mechanically widens the first portion of the nasal valve. The user slides the sealing nosepiece into one nostril until it seals the flexible soft tissue of the nostril opening, mechanically widening the narrow, slit-shaped portion of the triangular nasal valve. The user then exhales through the attached mouthpiece. As the user exhales into the mouthpiece against the resistance of the device, the soft palate (or velum) automatically rises due to oropharyngeal positive pressure, isolating the nasal cavity from the rest of the respiratory system. This mechanism allows for the release of liquid or powder particles into a stream of air that enters one nostril, passes completely through the nasal septum, and exits through the opposite nostril.

[0173] Aseptic filling does not require the use of preservatives in primed devices, but overfilling is required, resulting in a waste fraction similar to that of metered-dose multidose sprays. To deliver 100 μL, devices used for the intranasal migraine medications Imitrex™ (sumatriptan) and Zomig™ (zolmitriptan) (Pfeiffer / Aptar single-dose devices) are filled with a volume of 125 μL, and two-dose designs are filled approximately half that amount. Sterile drug products may be produced using aseptic processing or terminal sterilization. Terminal sterilization typically involves filling and sealing product containers under high-quality environmental conditions. Products are filled and sealed in this type of environment to minimize the microbial and particulate content of the in-process product and to aid in the success of subsequent sterilization processes. In most cases, the product, container, and closure have low levels of bioburden but are not sterile. The product in the final container is then subjected to a sterilization process, such as heat or irradiation. In aseptic processing, the drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then combined. Because there is no process that sterilizes the product inside the final container, it is important that the container be filled and sealed in an extremely high-quality environment. Aseptic processing involves more variables than terminal sterilization. Before being aseptically assembled into the final product, the individual parts of the final product are typically subjected to various sterilization processes. For example, glass containers are subjected to dry heat, rubber closures to moist heat, and liquid dosage forms to filtration. Each of these manufacturing processes requires validation and control.

[0174] The devices described herein can be used with any pharmaceutical formulation and are useful in all of the methods disclosed herein.

[0175] Thus, provided herein is a primed device suitable for nasal delivery of a pharmaceutical composition to a patient, the device comprising a reservoir containing a therapeutically effective amount of an opioid antagonist (selected from nalmefene and its pharmaceutically acceptable salts). In some embodiments, the opioid antagonist is nalmefene hydrochloride. In some embodiments, the opioid antagonist is anhydrous nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to any of the amounts of nalmefene hydrochloride provided above, for example, about 1 mg to about 10 mg of nalmefene hydrochloride.

[0176] In some embodiments, the relative bioavailability (dose-corrected AUC after IN administration) of nalmefene in the formulations disclosed herein is 0-inf and dose-adjusted AUC for IM formulation 0-inf (compared to ) is about 40% to about 80%. In some embodiments, the relative bioavailability is about 45% to about 75%. In some embodiments, the relative bioavailability is about 50% to about 70%. In some embodiments, the relative bioavailability is about 5% to about 65%. In some embodiments, the relative bioavailability is about 60%.

[0177] In some embodiments, the pharmaceutical composition contains approximately 1-10 mg of nalmefene hydrochloride or its hydrate formulated for intranasal administration and produces a plasma concentration versus time curve with an area under the curve (AUC) that is approximately 60% of the AUC of 1.5 mg IM nalmefene. While Intravail® did not alter the AUC of IN nalmefene, results with naltrexone were different. With naltrexone, the AUC increased significantly. This significant difference could not have been predicted based on the structure of opioid antagonists or the function of these moieties as opioid antagonists.

[0178] In some embodiments, the patient is an opioid overdose patient or a patient suspected of having an opioid overdose.

[0179] In some embodiments, the patient is in a supine, recumbent, or recovery position. In some embodiments, the patient is in a supine position. In some embodiments, the patient is in a recovery position.

[0180] In some embodiments, the therapeutically effective amount of the opioid antagonist is delivered by an untrained person.

[0181] In some embodiments, the therapeutically effective amount is equivalent to about 1 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 5 mg of nalmefene hydrochloride.

[0182] In some embodiments, the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical composition.

[0183] In some embodiments, the pharmaceutical composition comprises a solution of nalmefene hydrochloride or a hydrate thereof.

[0184] In some embodiments, the volume of the pharmaceutical composition in the reservoir is about 140 μL or less.

[0185] In some embodiments, about 100 μL of the pharmaceutical composition in the reservoir is delivered to the patient in one actuation.

[0186] In some embodiments, the pharmaceutical composition further comprises one or more excipients selected from water and NaCl.

[0187] In some embodiments, the pharmaceutical composition is substantially free of antimicrobial preservatives.

[0188] In some embodiments, the pharmaceutical composition further comprises a compound that acts as a preservative, an absorption enhancer and / or a cationic surfactant; an isotonicity agent; a stabilizer; and an acid or base or base in an amount sufficient to achieve a pH of about 3.5 to about 5.5. The use of absorption enhancers, such as alkyl saccharides, cyclodextrins, and chitosan, can increase the rate at which nalmefene is absorbed. Generally, absorption enhancers provide improved pharmacokinetic outcomes, e.g., C, compared to intramuscular and intranasal formulations that do not contain absorption enhancers. max Increase in T max Without being bound by theory, such absorption enhancers typically work by affecting the two main mechanisms for nasal absorption: paracellular transport through openings in tight junctions between cells, and transcellular transport or transcytosis through cells via vesicular carriers.

[0189] For example, alkyl saccharides are used in commercial food and personal care products and are designated as generally regarded as safe (GRAS) for food use. Alkyl saccharides are tasteless, odorless, nontoxic, nonmutagenic, and non-irritating transmucosal absorption enhancers that are non-sensitizing up to 25% concentration in the Draize assay. Alkyl saccharides increase absorption by increasing paracellular permeability, as indicated by a decrease in transepithelial electrical resistance. Alkyl saccharides may also increase transcytosis. This effect is short-lived.

[0190] Adding alkyl saccharides to intranasal formulations can increase peak plasma concentrations several-fold compared to Imitrex nasal spray, shortening Tmax from hours to minutes. Total exposure, as measured by area under the concentration-time curve (AUC), increases by approximately 30%. This increase in naltrexone AUC could not be predicted by those skilled in the art, because structurally similar drugs, such as nalmefene, do not increase AUC under these same conditions. Naltrexone intranasal formulations have the potential to be used to treat AUD without needles or extended-release formulations.

[0191] Some absorption-enhancing excipients can alter the paracellular and / or transcellular pathways, while others can extend residence time in the nasal cavity or prevent metabolic transformation. While the molecular weight limit for nasal absorption without an absorption enhancer is approximately 1 kDa, administration of drugs with an absorption enhancer allows absorption of molecules ranging from 1 to 30 kDa. However, intranasal administration of most absorption enhancers can cause nasal mucosal damage. (Maggio, J. Excipients and Food Chem. 5(2):100-12, 2014) Examples of absorption enhancers include aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoylcarnitine, EDTA, glycocholic acid, glycodeoxycholic acid, glycofurol, glycosylated sphingosine, glycyrrhetinic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroylcarnitine, lauryl sulfate, lysophosphatidylinositol, methylparaben ... Alcoholic acid, menthol, poloxamer 407, poloxamer F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol, quillaja saponin, salicylic acid, β-sitosterol-β-D-glucoside, sucrose cocoate, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid, and alkyl saccharides such as dodecyl maltoside, tetradecyl maltoside, and sucrose dodecanoate.

[0192] The opioid antagonist naltrexone described herein can be formulated into pharmaceutical compositions using techniques well known to those skilled in the art. Suitable pharmaceutically acceptable carriers other than those mentioned herein are known in the art.

[0193] The opioid antagonist nalmefene described herein may optionally exist as a pharmaceutically acceptable salt, including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.Representative acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, etc. Acid addition salts may be obtained as direct products of compound synthesis. Alternatively, the free base may be dissolved in a suitable solvent containing a suitable acid and the salt isolated by evaporating the solvent or by otherwise separating the salt and solvent. The opioid antagonist nalmefene described herein can form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

[0194] Thus, a drug product comprising a therapeutically effective amount of nalmefene hydrochloride or a hydrate thereof, wherein the nalmefene hydrochloride or a hydrate thereof is contained in a disposable, primed device suitable for nasal delivery of a pharmaceutical composition to a patient, wherein a single actuation of the device delivers the pharmaceutical composition into one nostril of the patient; Nalmefene hydrochloride or its hydrate; benzalkonium chloride in an amount effective to function as an absorption enhancer and / or cationic surfactant; Isotonic agents; stabilizers; and Sufficient acid or base to achieve a pH between 3.5 and 5.5 Provided herein is a drug product comprising a reservoir containing a pharmaceutical composition that is about 100 μL of an aqueous solution comprising:

[0195] In some embodiments, a disposable, primed device suitable for nasal delivery of a pharmaceutical composition to a patient comprises any amount of nalmefene hydrochloride provided above, for example, about 1 mg to about 10 mg of nalmefene hydrochloride or a hydrate thereof.

[0196] In some embodiments, a disposable, primed device suitable for nasal delivery of a pharmaceutical composition to a patient contains the equivalent of about 1 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 1.5 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 2 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 2.5 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 3 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 3.5 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 4 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 4.5 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 5 mg of nalmefene hydrochloride.

[0197] In some embodiments, the aqueous solution comprises: about 1 mg to about 10 mg of nalmefene hydrochloride or its hydrate; about 0.005% to about 1% benzalkonium chloride; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.1 mg to about 0.5 mg of a stabilizer; and Sufficient acid or base to achieve a pH between 3.5 and 5.5 Includes:

[0198] In some embodiments, The isotonic agent is NaCl, The stabilizer is edetate disodium, The acid is hydrochloric acid.

[0199] In some embodiments, the aqueous solution comprises: Approximately 3 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; about 0.005% to about 1% benzalkonium chloride; Approximately 0.2 mg of edetate disodium; and Sufficient hydrochloric acid to achieve a pH of 3.5 to 5.5 Includes:

[0200] In some embodiments, the aqueous solution comprises: About 1 mg to about 10 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; about 0.005% to about 1% benzalkonium chloride; Approximately 0.2 mg of edetate disodium; and Sufficient hydrochloric acid to achieve a pH of 3.5 to 5.5 Includes:

[0201] 1. A drug product comprising a therapeutically effective amount of nalmefene hydrochloride or a hydrate thereof, the nalmefene hydrochloride or a hydrate thereof being contained within a primed, two-dose device suitable for nasal delivery of the pharmaceutical composition to a patient, wherein a first volume of the pharmaceutical composition is in a first reservoir and a second volume of the pharmaceutical composition is in a second reservoir, and wherein a therapeutically effective amount of an opioid antagonist is delivered from the first reservoir into a nostril of the patient by a first actuation of the drug delivery device and from the second reservoir into a nostril of the patient by a second actuation of the drug delivery device, each reservoir comprising: Nalmefene hydrochloride or its hydrate; Isotonic agents; benzalkonium chloride in an amount effective to function as an absorption enhancer and / or cationic surfactant; stabilizers; and Sufficient acid or base to achieve a pH between 3.5 and 5.5 Also provided herein is a drug product comprising a pharmaceutical composition which is about 100 μL of an aqueous solution comprising:

[0202] In some embodiments, each reservoir of a primed, two-dose device suitable for nasal delivery of a pharmaceutical composition to a patient contains any amount of nalmefene hydrochloride provided above, e.g., about 1 mg to about 10 mg of nalmefene hydrochloride or a hydrate thereof.

[0203] In some embodiments, each reservoir of a primed, two-dose device suitable for nasal delivery of a pharmaceutical composition to a patient contains the equivalent of about 1 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 1.5 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 2 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 2.5 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 3 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 3.5 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 4 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 4.5 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 5 mg of nalmefene hydrochloride.

[0204] In some embodiments, the aqueous solution comprises: about 1 mg to about 10 mg of nalmefene hydrochloride or its hydrate; about 0.005% to about 1% benzalkonium chloride; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.1 mg to about 0.5 mg of a stabilizer; and Sufficient acid or base to achieve a pH between 3.5 and 5.5 Includes:

[0205] In some embodiments, The isotonic agent is NaCl, The stabilizer is edetate disodium, The acid is hydrochloric acid.

[0206] In some embodiments, the aqueous solution Approximately 1 mg or approximately 10 mg of nalmefene hydrochloride; about 0.005% to about 1% benzalkonium chloride; Approximately 0.2 mg of edetate disodium; and Sufficient hydrochloric acid to achieve a pH of 3.5 to 5.5 Includes:

[0207] In some embodiments, each reservoir contains about 3 mg of nalmefene hydrochloride.

[0208] 1. A method of reducing the risk of opioid overdose in an individual at risk of opioid overdose, comprising providing to the individual at risk of opioid overdose a therapeutically effective amount of nalmefene hydrochloride or a hydrate thereof, wherein the nalmefene hydrochloride or a hydrate thereof is contained within a disposable, primed device suitable for nasal delivery of a pharmaceutical composition to a patient, wherein a single actuation of the device delivers the pharmaceutical composition into one nostril of the patient; Nalmefene hydrochloride or its hydrate; isotonic agents, benzalkonium chloride in an amount effective to function as an absorption enhancer and / or cationic surfactant; stabilizers; and Sufficient acid or base to achieve a pH between 3.5 and 5.5 Also provided herein are methods comprising a reservoir containing a pharmaceutical composition that is about 100 μL of an aqueous solution comprising:

[0209] In some embodiments, a disposable, primed device suitable for nasal delivery of a pharmaceutical composition to a patient comprises any amount of nalmefene hydrochloride provided above, for example, about 1 mg to about 10 mg of nalmefene hydrochloride or a hydrate thereof.

[0210] In some embodiments, a disposable, primed device suitable for nasal delivery of a pharmaceutical composition to a patient contains the equivalent of about 1 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 1.5 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 2 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 2.5 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 3 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 3.5 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 4 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 4.5 mg of nalmefene hydrochloride. In some embodiments, the device contains the equivalent of about 5 mg of nalmefene hydrochloride.

[0211] In some embodiments, the aqueous solution comprises: about 1 mg to about 10 mg of nalmefene hydrochloride or its hydrate; about 0.005% to about 1% benzalkonium chloride; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.1 mg to about 0.5 mg of a stabilizer; and Sufficient acid or base to achieve a pH between 3.5 and 5.5 Includes:

[0212] In some embodiments, The isotonic agent is NaCl, The stabilizer is edetate disodium, The acid is hydrochloric acid.

[0213] In some embodiments, the aqueous solution comprises: Approximately 3 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; about 0.005% to about 1% benzalkonium chloride; Approximately 0.2 mg of edetate disodium; and Sufficient hydrochloric acid to achieve a pH of 3.5 to 5.5 Includes:

[0214] In some embodiments, the aqueous solution comprises: About 1 to about 10 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; about 0.005% to about 1% benzalkonium chloride; Approximately 0.2 mg of edetate disodium; and Sufficient hydrochloric acid to achieve a pH of 3.5 to 5.5 Includes:

[0215] In some embodiments, a disposable, primed device suitable for nasal delivery of a pharmaceutical composition to a patient comprises any amount of nalmefene hydrochloride provided above, for example, about 1 mg to about 10 mg of nalmefene hydrochloride or a hydrate thereof.

[0216] In some embodiments, each reservoir of a primed, two-dose device suitable for nasal delivery of a pharmaceutical composition to a patient contains the equivalent of about 1 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 1.5 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 2 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 2.5 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 3 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 3.5 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 4 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 4.5 mg of nalmefene hydrochloride. In some embodiments, each reservoir of the device contains the equivalent of about 5 mg of nalmefene hydrochloride.

[0217] In some embodiments, the aqueous solution comprises: about 1 mg to about 10 mg of nalmefene hydrochloride or its hydrate; about 0.005% to about 1% benzalkonium chloride; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.1 mg to about 0.5 mg of a stabilizer; and Sufficient acid or base to achieve a pH between 3.5 and 5.5 Includes:

[0218] In some embodiments, The isotonic agent is NaCl, The stabilizer is edetate disodium, The acid is hydrochloric acid or the base is sodium hydroxide.

[0219] In some embodiments, each reservoir comprises: Approximately 1 mg or approximately 10 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; about 0.005% to about 1% benzalkonium chloride; and Approximately 0.2 mg of edetate disodium Includes:

[0220] In some embodiments, the pharmaceutical composition further comprises one or more excipients selected from water, NaCl, benzalkonium chloride, sodium edetate, disodium edetate, and hydrochloric acid.

[0221] In some embodiments, the pharmaceutical composition further comprises water, NaCl, benzalkonium chloride, edetate disodium, and hydrochloric acid.

[0222] In some embodiments, the pharmaceutical composition comprises: isotonic agents, Preservatives; stabilizers; Sufficient acid or base to achieve a pH of 3.5 to 5.5; and Enough water to achieve a final volume of approximately 100 μL Further includes:

[0223] In some embodiments, the pharmaceutical composition comprises: about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.005 mg to about 0.015 mg of a compound that is a preservative, a cationic surfactant, and / or an absorption enhancer; about 0.1 mg to about 0.5 mg of a stabilizer; Sufficient acid or base to achieve a pH of 3.5 to 5.5; and Enough water to achieve a final volume of approximately 100 μL Includes:

[0224] In some embodiments, The isotonic agent is NaCl, the compound that is a preservative, cationic surfactant, and / or absorption enhancer is benzalkonium chloride; The stabilizer is edetate disodium, The acid is hydrochloric acid or the base is sodium hydroxide.

[0225] In some embodiments, the pharmaceutical composition comprises: approximately 0.74 mg NaCl; Approximately 0.01 mg of benzalkonium chloride; Approximately 0.2 mg of edetate disodium; Hydrochloric acid or sodium hydroxide in an amount sufficient to achieve a pH of 3.5 to 5.5; and Enough water to achieve a final volume of approximately 100 μL Includes:

[0226] In some embodiments, the device is filled with the pharmaceutical composition using sterile filling.

[0227] In some embodiments, the pharmaceutical composition is stable to storage at about 25° C. and about 60% relative humidity for about 12 months.

[0228] In some embodiments, the device is a single-dose device, the pharmaceutical composition is present in one reservoir, and a therapeutically effective amount of the opioid antagonist is delivered into one nostril of the patient by essentially one actuation of the device.

[0229] In some embodiments, the actuation delivers about 100 μL of the pharmaceutical composition.

[0230] In some embodiments, the device is operable with one hand.

[0231] In some embodiments, the delivery time is less than about 30 seconds. In some embodiments, the delivery time is less than about 25 seconds. In some embodiments, the delivery time is less than about 20 seconds. In some embodiments, the delivery time is less than about 15 seconds.

[0232] In some embodiments, the 90% confidence interval for the dose delivered per actuation is about ±2%. In some embodiments, the 95% confidence interval for the dose delivered per actuation is about ±2.5%.

[0233] In some embodiments, when the pharmaceutical composition is delivered to a patient via the nose, less than about 20% of the pharmaceutical composition leaves the nasal cavity by flowing into or outside the nasopharynx. In some embodiments, when the pharmaceutical composition is delivered to a patient via the nose, less than about 15% of the pharmaceutical composition leaves the nasal cavity by flowing into or outside the nasopharynx. In some embodiments, when the pharmaceutical composition is delivered to a patient via the nose, less than about 10% of the pharmaceutical composition leaves the nasal cavity by flowing into or outside the nasopharynx. In some embodiments, when the pharmaceutical composition is delivered to a patient via the nose, less than about 5% of the pharmaceutical composition leaves the nasal cavity by flowing into or outside the nasopharynx.

[0234] In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 30 minutes. maxIn some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 25 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 20 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 15 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 10 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 5 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 25 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 20 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is about 15 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 10 minutes. max is about 5 minutes.

[0235] In some embodiments, upon delivery of a therapeutically effective amount to a patient, T max At T , greater than about 90% occupancy of the opioid antagonist occurs at opioid receptors in the patient's respiratory control center. In some embodiments, upon delivery of a therapeutically effective amount to the patient, T max In some embodiments, delivery of a therapeutically effective dose to a patient results in greater than about 95% occupancy of the opioid antagonist at opioid receptors in the patient's respiratory control center. max This results in greater than 99% occupancy of opioid antagonists at opioid receptors in the patient's respiratory control center.

[0236] In some embodiments, a patient is spared from respiratory depression for at least about 1 hour after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is spared from respiratory depression for at least about 2 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is spared from respiratory depression for at least about 3 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is spared from respiratory depression for at least about 4 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is spared from respiratory depression for at least about 6 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is spared from respiratory depression for at least about 7 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is spared from respiratory depression for at least about 8 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is free from respiratory depression for at least about 10 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is free from respiratory depression for at least about 12 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is free from respiratory depression for at least about 14 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is free from respiratory depression for at least about 16 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is free from respiratory depression for at least about 1 hour to at least about 15 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, a patient is free from respiratory depression for at least about 3 hours to at least about 15 hours after treatment involving delivery of a therapeutically effective amount of an opioid antagonist. In some embodiments, the patient is free from respiratory depression for at least about 3 hours to at least about 12 hours after treatment comprising delivery of a therapeutically effective amount of an opioid antagonist.In some embodiments, the patient is free from respiratory depression for at least about 3 hours to at least about 10 hours after treatment comprising delivery of a therapeutically effective amount of an opioid antagonist, hi some embodiments, the patient is free from respiratory depression for at least about 3 hours to at least about 8 hours after treatment comprising delivery of a therapeutically effective amount of an opioid antagonist.

[0237] 1. A disposable, primed device suitable for nasal delivery of a pharmaceutical composition to a patient, wherein a single actuation of the device delivers into one nostril of the patient, the device comprising: About 1 mg or about 10 mg of nalmefene hydrochloride or its hydrate; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.005 mg to about 0.015 mg of a compound acting as a preservative, cationic surfactant, and / or absorption enhancer; about 0.1 mg to about 0.5 mg of a stabilizer; Sufficient acid or base to achieve a pH between 3.5 and 5.5 Also provided herein is such a device having one reservoir containing about 100 μL of a pharmaceutical composition which is an aqueous solution comprising:

[0238] In some embodiments, the device contains any amount of nalmefene hydrochloride provided above, for example, about 1 mg to about 10 mg of nalmefene hydrochloride or a hydrate thereof, hi some embodiments, the device contains about 3 mg of nalmefene hydrochloride or a hydrate thereof.

[0239] In some embodiments, The isotonic agent is NaCl, the compound that is a preservative, cationic surfactant, and / or absorption enhancer is benzalkonium chloride; The stabilizer is edetate disodium, The acid is hydrochloric acid or the base is sodium hydroxide.

[0240] In some embodiments, the device comprises: Approximately 1 mg or approximately 10 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; Approximately 0.01 mg of benzalkonium chloride; Approximately 0.2 mg of edetate disodium; and Hydrochloric acid or sodium hydroxide in sufficient quantity to achieve a pH of 3.5 to 5.5 Includes:

[0241] In some embodiments, the device contains about 1 mg of nalmefene hydrochloride. In some embodiments, the device contains about 1.5 mg of nalmefene hydrochloride. In some embodiments, the device contains about 2 mg of nalmefene hydrochloride. In some embodiments, the device contains about 2.5 mg of nalmefene hydrochloride. In some embodiments, the device contains about 3 mg of nalmefene hydrochloride. In some embodiments, the device contains about 3.5 mg of nalmefene hydrochloride. In some embodiments, the device contains about 4 mg of nalmefene hydrochloride. In some embodiments, the device contains about 4.5 mg of nalmefene hydrochloride. In some embodiments, the device contains about 5 mg of nalmefene hydrochloride.

[0242] In some embodiments, as provided above, when a pharmaceutical composition is nasally delivered to a patient, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the pharmaceutical composition leaves the nasal cavity by flowing into or out of the nasopharynx.

[0243] In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient, as provided above, max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 30 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 30 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 25 minutes. maxIn some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 20 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is about 15 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 10 minutes. max is about 5 minutes.

[0244] In some embodiments, the device is operable with one hand.

[0245] In some embodiments, the delivery time is less than about 30 seconds. In some embodiments, the delivery time is less than about 25 seconds. In some embodiments, the delivery time is less than about 20 seconds. In some embodiments, the delivery time is less than about 15 seconds.

[0246] In some embodiments, the 90% confidence interval for the dose delivered per actuation is about ±2%. In some embodiments, the 95% confidence interval for the dose delivered per actuation is about ±2.5%.

[0247] In some embodiments, as provided above, when a pharmaceutical composition is nasally delivered to a patient, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the pharmaceutical composition leaves the nasal cavity by flowing into or out of the nasopharynx.

[0248] In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient, as provided above, max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 30 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 30 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 25 minutes. maxIn some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 20 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is about 15 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 10 minutes. max is about 5 minutes.

[0249] In some embodiments, upon delivery of a therapeutically effective amount to a patient, T max , resulting in greater than about 90%, greater than about 95%, or greater than about 99% occupancy of the opioid antagonist at opioid receptors in the patient's respiratory control center.

[0250] In some embodiments, the patient is free from respiratory depression for at least about 1 hour to at least about 8 hours after treatment comprising delivery of a therapeutically effective amount of an opioid antagonist, as provided above, hi some embodiments, the patient is free from respiratory depression for at least about 3 hours to at least about 8 hours after treatment comprising delivery of a therapeutically effective amount of an opioid antagonist.

[0251] In some embodiments, the device is filled with the pharmaceutical composition using sterile filling.

[0252] In some embodiments, the pharmaceutical composition is stable upon storage at about 25° C. and about 60% relative humidity for about 12 months.

[0253] In some embodiments, the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical composition.

[0254] Also provided is a device according to any one of the preceding aspects for use in treating a symptom of opioid overdose selected from respiratory depression, post-operative opioid respiratory depression, altered level of consciousness, miosis, cardiovascular depression, hypoxemia, acute lung injury, aspiration pneumonia, sedation, and hypotension.

[0255] There is also provided a device according to any one of the preceding aspects for use in reversing opioid-induced respiratory depression.

[0256] In some embodiments, the respiratory depression is caused by illicit use of opioids or by accidental misuse of opioids during medical opioid therapy.

[0257] Also provided is a device according to any one of the preceding aspects for use in full or partial recovery from narcotic depression, including respiratory depression, induced by opioids selected from natural and synthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocine, and butorphanol.

[0258] In some embodiments, the patient is an opioid overdose patient or a patient suspected of having an opioid overdose.

[0259] In some embodiments, the patient is in a supine, recumbent, or recovery position. In some embodiments, the patient is in a supine position. In some embodiments, the patient is in a recovery position.

[0260] In some embodiments, the therapeutically effective amount of the opioid antagonist is delivered by an untrained person.

[0261] In some embodiments, the device is a two-dose device, wherein a first volume of the pharmaceutical composition is in a first reservoir and a second volume of the pharmaceutical composition is in a second reservoir, and the therapeutically effective amount is essentially delivered into a first nostril of the patient by a first actuation of the device and into a second nostril of the patient by a second actuation of the device.

[0262] In some embodiments, the first volume and the second volume combined equal about 380 μL or less.

[0263] In some embodiments, the first volume of the pharmaceutical composition is delivered by the first actuation, the first volume being about 100 μL.

[0264] In some embodiments, the second volume of the pharmaceutical composition is delivered by the second actuation, the second volume being about 100 μL.

[0265] In some embodiments, the dual-dose device is operable with one hand.

[0266] In some embodiments, the delivery time is less than about 30 seconds. In some embodiments, the delivery time is less than about 25 seconds. In some embodiments, the delivery time is less than about 20 seconds. In some embodiments, the delivery time is less than about 15 seconds.

[0267] In some embodiments, the 90% confidence interval for the dose delivered per actuation is about ±2%. In some embodiments, the 95% confidence interval for the dose delivered per actuation is about ±2.5%.

[0268] In some embodiments, when the pharmaceutical composition is delivered intranasally to a patient, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the pharmaceutical composition leaves the nasal cavity by spilling into or out of the nasopharynx. In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient, as provided above, is max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 30 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 30 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 25 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 20 minutes. maxIn some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is about 15 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 10 minutes. max is about 5 minutes.

[0269] In some embodiments, upon delivery of a therapeutically effective amount to a patient, T max , resulting in greater than about 90%, greater than about 95%, or greater than about 99% occupancy of the opioid antagonist at opioid receptors in the patient's respiratory control center.

[0270] In some embodiments, the patient is free from respiratory depression for at least about 1 hour to at least about 8 hours after treatment comprising delivery of a therapeutically effective amount of an opioid antagonist, as provided above, hi some embodiments, the patient is free from respiratory depression for at least about 3 hours to at least about 8 hours after treatment comprising delivery of a therapeutically effective amount of an opioid antagonist.

[0271] Pharmaceutical Compositions Pharmaceutical compositions containing one or more opioid antagonists are also provided. In some embodiments, the pharmaceutical composition comprises an opioid antagonist and a pharmaceutically acceptable carrier. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not undue harmful to the recipient. Some embodiments of the present disclosure include a method for producing a pharmaceutical composition, comprising mixing at least one opioid antagonist with a pharmaceutically acceptable carrier. The pharmaceutical composition is applied directly to the nasal cavity using a device described herein. In the case of a spray, this may be accomplished, for example, by a metered-dose spray pump.

[0272] Liquid preparations include solutions, suspensions, and emulsions, such as water or water-propylene glycol solutions. Additional ingredients in liquid preparations include antibacterial preservatives, such as benzalkonium chloride (which can also act as a cationic surfactant and / or absorption enhancer), methylparaben, sodium benzoate, benzoic acid, phenylethyl alcohol, and mixtures thereof; surfactants, such as polysorbate 80NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene sorbitan monooleate, polyoxyethylene ... Examples of suitable surfactants include ethylene 20 sorbitan monoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate, and mixtures thereof; isotonic agents such as dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, and mixtures thereof; and suspending agents such as crystalline cellulose, sodium carboxymethylcellulose NF, polyacrylic acid, magnesium aluminum silicate, xanthan gum, and mixtures thereof.

[0273] The opioid antagonists described herein can be formulated into pharmaceutical compositions using techniques well known to those skilled in the art.

[0274] The opioid antagonists described herein may optionally be present as pharmaceutically acceptable salts, including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.Representative acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, etc.For example, pharmaceutically acceptable salts are listed in Berge et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977). Acid addition salts may be obtained as the direct product of compound synthesis. Alternatively, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or by otherwise separating the salt and solvent. The opioid antagonists described herein can form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

[0275] Therefore, in an aqueous solution of about 140 μL or less, about 1 mg to about 10 mg of an opioid antagonist; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.005 mg to about 0.015 mg of a compound that is a preservative, a cationic surfactant, and / or an absorption enhancer; about 0.1 mg to about 0.5 mg of a stabilizer; Sufficient acid or base to achieve a pH between 3.5 and 5.5 Provided herein is a pharmaceutical formulation for intranasal administration comprising:

[0276] In some embodiments, the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical composition.

[0277] In some embodiments, the opioid antagonist is nalmefene hydrochloride, or a hydrate thereof.

[0278] In some embodiments, the opioid antagonist is nalmefene hydrochloride.

[0279] As provided above, the pharmaceutical formulation may contain any amount of nalmefene hydrochloride (e.g., equivalent to about 1 mg to about 10 mg). In some embodiments, the therapeutically effective amount is equivalent to about 1 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 5 mg of nalmefene hydrochloride.

[0280] In some embodiments, the pharmaceutical formulation is in about 100 μL of aqueous solution.

[0281] In some embodiments, as provided above, when a pharmaceutical composition is nasally delivered to a patient, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the pharmaceutical composition leaves the nasal cavity by flowing into or out of the nasopharynx.

[0282] In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient, as provided above, max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 30 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 30 minutes. maxIn some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 25 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 20 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is about 15 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 10 minutes. max is about 5 minutes.

[0283] In some embodiments, the device is operable with one hand.

[0284] In some embodiments, the delivery time is less than about 30 seconds. In some embodiments, the delivery time is less than about 25 seconds. In some embodiments, the delivery time is less than about 20 seconds. In some embodiments, the delivery time is less than about 15 seconds.

[0285] In some embodiments, the 90% confidence interval for the dose delivered per actuation is about ±2%. In some embodiments, the 95% confidence interval for the dose delivered per actuation is about ±2.5%.

[0286] In some embodiments, as provided above, when a pharmaceutical composition is nasally delivered to a patient, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the pharmaceutical composition leaves the nasal cavity by flowing into or out of the nasopharynx.

[0287] In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient, as provided above, max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 30 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 30 minutes. maxIn some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 25 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 20 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is about 15 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 10 minutes. max is about 5 minutes.

[0288] In some embodiments, upon delivery of a therapeutically effective amount to a patient, T max , resulting in greater than about 90%, greater than about 95%, or greater than about 99% occupancy of the opioid antagonist at opioid receptors in the patient's respiratory control center.

[0289] In some embodiments, the patient is free from respiratory depression for at least about 1 hour to at least about 8 hours after treatment comprising delivery of a therapeutically effective amount of an opioid antagonist, as provided above, hi some embodiments, the patient is free from respiratory depression for at least about 3 hours to at least about 8 hours after treatment comprising delivery of a therapeutically effective amount of an opioid antagonist.

[0290] In an aqueous solution of about 140 μL or less, About 1 mg or about 10 mg of nalmefene hydrochloride or its hydrate; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.005 mg to about 0.015 mg of a compound that is a preservative, a cationic surfactant, and / or an absorption enhancer; about 0.1 mg to about 0.5 mg of a stabilizer; Hydrochloric acid or sodium hydroxide in sufficient quantity to achieve a pH of 3.5 to 5.5 Also provided herein is a pharmaceutical formulation for intranasal administration comprising:

[0291] In some embodiments, The isotonic agent is NaCl, the compound that is a preservative, cationic surfactant, and / or absorption enhancer is benzalkonium chloride; The stabilizer is edetate disodium, The acid is hydrochloric acid or the base is sodium hydroxide.

[0292] In some embodiments, the pharmaceutical formulation comprises: about 2 mg or about 3 mg or about 4 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; Approximately 0.01 mg of benzalkonium chloride; Approximately 0.2 mg of edetate disodium; and Hydrochloric acid or sodium hydroxide in sufficient quantity to achieve a pH of 3.5 to 5.5 Includes:

[0293] In some embodiments, the pharmaceutical formulation comprises about 4 mg of nalmefene hydrochloride or a hydrate thereof. In some embodiments, the pharmaceutical formulation comprises about 3 mg of nalmefene hydrochloride or a hydrate thereof.

[0294] In about 100 μL of aqueous solution, Approximately 3 mg of nalmefene hydrochloride or its hydrate; Approximately 0.2 mg to 1.2 mg of isotonic agent. about 0.005 mg to about 0.015 mg of a compound that is a preservative, a cationic surfactant, and / or an absorption enhancer; about 0.1 mg to about 0.5 mg of a stabilizer; Sufficient acid or base to achieve a pH between 3.5 and 5.5 Also provided herein is a pharmaceutical formulation for intranasal administration comprising:

[0295] In some embodiments, the pharmaceutical formulation comprises: About 1 mg to about 10 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; Approximately 0.01 mg of benzalkonium chloride; Approximately 0.2 mg of edetate disodium; and Hydrochloric acid or sodium hydroxide in sufficient quantity to achieve a pH of 3.5 to 5.5 Includes:

[0296] In about 100 μL of aqueous solution, Approximately 3 mg of nalmefene hydrochloride or its hydrate; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.005 mg to about 0.015 mg of a compound that is a preservative, a cationic surfactant, and / or an absorption enhancer; about 0.1 mg to about 0.5 mg of a stabilizer; Sufficient acid or base to achieve a pH between 3.5 and 5.5 Also provided herein is a pharmaceutical formulation for intranasal administration comprising:

[0297] In some embodiments, the pharmaceutical formulation comprises: Approximately 3 mg of nalmefene hydrochloride; approximately 0.74 mg NaCl; Approximately 0.01 mg of benzalkonium chloride; Approximately 0.2 mg of edetate disodium; and Hydrochloric acid or sodium hydroxide in sufficient quantity to achieve a pH of 3.5 to 5.5 Includes:

[0298] In about 100 μL of aqueous solution, about 1 to about 10 mg of nalmefene hydrochloride or its hydrate; about 0.2 mg to about 1.2 mg of an isotonic agent; about 0.005 mg to about 0.015 mg of a compound that is a preservative, a cationic surfactant, and / or an absorption enhancer; about 0.1 mg to about 0.5 mg of a stabilizer; Sufficient acid or base to achieve a pH between 3.5 and 5.5 Also provided herein is a pharmaceutical formulation for intranasal administration comprising:

[0299] Provided is a primed device suitable for nasally delivering to a patient a pharmaceutical composition comprising a therapeutically effective amount of an opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts, as provided above, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 5 mg of nalmefene hydrochloride.

[0300] In some embodiments, the pharmaceutical composition comprises a solution prepared from nalmefene hydrochloride. In some embodiments, the pharmaceutical composition further comprises one or more excipients selected from water and NaCl. In some embodiments, the pharmaceutical composition is substantially free of antimicrobial preservatives. In some embodiments, the device is substantially free of benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, and phenylethyl alcohol. In some embodiments, the device is filled with the pharmaceutical composition in a sterile environment. In some embodiments, the pharmaceutical composition is stable for storage at about 25°C for about 12 months. In some embodiments, the pharmaceutical composition comprises less than 0.1% w / w of an antimicrobial preservative. In some embodiments, the pharmaceutical composition comprises 0.01% w / w or less of an antimicrobial preservative. In some embodiments, the pharmaceutical composition comprises 0.01% w / w to 0.001% w / w of an antimicrobial preservative. In some embodiments, the pharmaceutical composition comprises less than 0.001% w / w of an antimicrobial preservative.

[0301] Also provided are aspects in which any of the above aspects may be combined with any one or more of these aspects, provided that the combinations are not mutually exclusive.

[0302] Indications Also provided are devices for use in treating opioid overdose and its symptoms, and methods of using said devices.Nalmefene blocks or reverses the effects of opioids, including respiratory depression, sedation, and hypotension.

[0303] Accordingly, also provided herein is a method for treating opioid overdose or symptoms thereof, comprising intranasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride or its hydrate. In some embodiments, the therapeutically effective amount of the opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts is delivered dissolved in about 140 μL or less of an aqueous carrier solution.

[0304] Also provided herein in some embodiments is a method for treating opioid overdose or symptoms thereof, comprising intranasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride or a hydrate thereof in about 140 μL or less of an aqueous carrier solution.

[0305] In some embodiments, provided are methods for treating opioid overdose or symptoms thereof, comprising the step of intranasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts using a spray device capable of spraying droplets having a median droplet size of about 30 to about 100 μm.

[0306] In some embodiments, the spray device is capable of spraying formulations with a D(v,50) of 30-70 μm and a D(v,90)<100 μm.

[0307] In some embodiments, the spray device can spray so that the percentage of droplets less than 10 μm is less than 10%. In some embodiments, the percentage of droplets less than 10 μm is less than 5%. In some embodiments, the percentage of droplets less than 10 μm is less than 2%. In some embodiments, the percentage of droplets less than 10 μm is less than 1%.

[0308] In some embodiments, the spray device is capable of spraying a uniform, circular plume with an ellipticity ratio close to 1. The ellipticity ratio is determined by the maximum diameter (D) of the spray pattern perpendicular to the direction of the spray flow (e.g., from the "top"). max ) and minimum diameter (D min ) In some embodiments, the ellipticity ratio is less than ±2.0. In some embodiments, the ellipticity ratio is less than ±1.5. In some embodiments, the ellipticity ratio is less than ±1.3. In some embodiments, the ellipticity ratio is less than ±1.2. In some embodiments, the ellipticity ratio is less than ±1.1. In some embodiments, the ellipticity ratio is about ±1.0.

[0309] Also provided herein in some embodiments is a method of treating an opioid overdose or a symptom thereof, comprising: intranasally administering to a patient in need thereof a single dose of a therapeutically effective amount of an opioid antagonist selected from nalmefene and a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride or a hydrate thereof in about 140 μL or less of an aqueous carrier solution.

[0310] In some embodiments, the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical composition.

[0311] In some embodiments, the opioid antagonist is nalmefene hydrochloride.

[0312] In some embodiments, the pharmaceutical composition comprises a solution of nalmefene hydrochloride or a hydrate thereof.

[0313] In some embodiments, the patient is an opioid overdose patient or a patient suspected of having an opioid overdose.

[0314] In some embodiments, the patient is in a supine, recumbent, or recovery position. In some embodiments, the patient is in a supine position. In some embodiments, the patient is in a recovery position.

[0315] In some embodiments, the therapeutically effective amount of the opioid antagonist is delivered by an untrained person.

[0316] In some embodiments, as provided above, the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 5 mg of nalmefene hydrochloride.

[0317] In some embodiments, the symptom is selected from respiratory depression and central nervous system depression.

[0318] In some embodiments, the patient exhibits any of the following: unresponsiveness to stimuli, unconsciousness, respiratory arrest; irregular or stopped pulse, choking or gurgling sounds, blue or purple nails or lips, decreased muscle tone, constricted pupils, and vomiting.

[0319] In some embodiments, the patient is not breathing.

[0320] In some embodiments, the patient is in a recumbent, supine, or recovery position.

[0321] In some embodiments, the patient is in a recumbent position.

[0322] In some embodiments, the patient is in a supine position.

[0323] In some embodiments, the patient is in the recovery position.

[0324] In some embodiments, the therapeutically effective amount is equivalent to about 2 mg to about 10 mg of nalmefene hydrochloride.

[0325] In some embodiments, the therapeutically effective amount is equivalent to an amount selected from about 1 mg nalmefene hydrochloride, about 1.5 mg nalmefene hydrochloride, about 2 mg nalmefene hydrochloride, about 2.5 mg nalmefene hydrochloride, about 3 mg nalmefene hydrochloride, about 3.5 mg nalmefene hydrochloride, about 4 mg nalmefene hydrochloride, about 4.5 mg nalmefene hydrochloride, and about 5 mg nalmefene hydrochloride.

[0326] In some embodiments, the therapeutically effective amount is equivalent to about 2 mg of nalmefene hydrochloride.

[0327] In some embodiments, the therapeutically effective amount is equivalent to about 3 mg of nalmefene hydrochloride.

[0328] In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of nalmefene hydrochloride.

[0329] In some embodiments, the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical composition.

[0330] In some embodiments, the nasal administering step is accomplished using a primed device suitable for nasal delivery of the pharmaceutical composition.

[0331] In some embodiments, as provided above, when a pharmaceutical composition is nasally delivered to a patient, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the pharmaceutical composition leaves the nasal cavity by flowing into or out of the nasopharynx.

[0332] In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient, as provided above, max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is less than 30 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 30 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 25 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 20 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in the patient is about 15 minutes. max In some embodiments, the T of the plasma concentration versus time curve of the opioid antagonist in a patient is about 10 minutes. max is about 5 minutes.

[0333] In some embodiments, the symptoms of opioid overdose are selected from respiratory depression, central nervous system depression, and cardiovascular depression.

[0334] In some embodiments, the symptom of opioid overdose is opioid-induced respiratory depression.

[0335] In some embodiments, the respiratory depression is caused by illicit use of opioids or accidental misuse of opioids during medical opioid therapy.

[0336] In some embodiments, the respiratory depression is induced by an opioid selected from natural and synthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocine, and butorphanol.

[0337] In some embodiments, the respiratory depression is induced by an opioid selected from codeine, morphine, methadone, fentanyl, oxycodone HCl, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, tapentadol.

[0338] In some embodiments, the patient is free from respiratory depression for at least about 1 hour to at least about 8 hours after treatment comprising delivery of a therapeutically effective amount of an opioid antagonist, as provided above, hi some embodiments, the patient is free from respiratory depression for at least about 3 hours to at least about 8 hours after treatment comprising delivery of a therapeutically effective amount of an opioid antagonist.

[0339] Also provided are aspects in which any of the above aspects may be combined with any one or more of these aspects, provided that the combinations are not mutually exclusive.

[0340] Also provided are devices, pharmaceutical compositions, kits, and treatment methods described herein for use in treating symptoms of opioid overdose selected from respiratory depression, post-operative opioid respiratory depression, altered level of consciousness, miosis, cardiovascular depression, hypoxemia, acute lung injury, aspiration pneumonia, sedation, and hypotension.Also provided are devices, pharmaceutical compositions, kits, and treatment methods described herein for use in recovering from opioid-induced respiratory depression.In some embodiments, respiratory depression is caused by illicit use of opioids or accidental misuse of opioids during medical opioid therapy.

[0341] Also provided are the devices, pharmaceutical compositions, kits, and treatment methods described herein for use in full or partial recovery from narcotic depression, including respiratory depression, induced by opioids selected from natural and synthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocine, and butorphanol. In some embodiments, the narcotic depression, including respiratory depression, is induced by an opioid agonist selected from codeine, morphine, methadone, fentanyl, oxycodone HCl, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, and tapentadol.

[0342] Also provided are devices, pharmaceutical formulations, and kits for treating opioid overdose or its symptoms, and methods for treating opioid overdose or its symptoms, comprising intranasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride. In some embodiments, the patient is not breathing. Also provided are primed devices suitable for intranasally delivering to a patient a pharmaceutical composition comprising a therapeutically effective amount of an opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride, as provided above.

[0343] In some embodiments, the therapeutically effective amount is equivalent to about 1 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 1.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 2.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 3.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 4.5 mg of nalmefene hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to about 5 mg of nalmefene hydrochloride.

[0344] In some embodiments, the opioid antagonist is the only pharmaceutically active compound in the pharmaceutical composition. In some embodiments, the opioid antagonist is nalmefene hydrochloride. In some embodiments, the opioid antagonist is anhydrous nalmefene hydrochloride. In some embodiments, the pharmaceutical composition comprises a solution of nalmefene hydrochloride. In some embodiments, the nasal administration step is performed using a device described herein. In some embodiments, the symptoms of opioid overdose are selected from respiratory depression, post-operative opioid respiratory depression, altered level of consciousness, miosis, cardiovascular depression, hypoxemia, acute lung injury, aspiration pneumonia, sedation, and hypotension. In some embodiments, the symptoms of opioid overdose are opioid-induced respiratory depression. In some embodiments, the respiratory depression is caused by illicit opioid use or accidental misuse of opioids during medical opioid treatment. In some embodiments, the respiratory depression is induced by an opioid selected from natural and synthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocine, and butorphanol. In some embodiments, the respiratory depression is induced by an opioid agonist selected from codeine, morphine, methadone, fentanyl, oxycodone HCl, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, and tapentadol.

[0345] Also provided are devices, kits, and pharmaceutical formulations for reversing the psychotomimetic and dysphoric effects of agonist-antagonists, such as pentazocine, and methods for reversing the psychotomimetic and dysphoric effects of agonist-antagonists, such as pentazocine, comprising the step of intranasally administering to a patient in need of reversal a therapeutically effective amount of an opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride, as provided above.

[0346] Also provided are devices, kits, and pharmaceutical formulations for diagnosing suspected acute opioid overdose, and a method for diagnosing suspected acute opioid overdose, comprising the step of intranasally administering to a patient in need of diagnosis a therapeutically effective amount of an opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride, as provided above.

[0347] Also provided are devices, kits, and pharmaceutical formulations for treating opioid addiction, and a method for treating opioid addiction, comprising intranasally administering to a patient in need of treatment a therapeutically effective amount of an opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride, as provided above.

[0348] Also provided are devices, kits, and pharmaceutical formulations for treating septic shock, and a method for treating septic shock, comprising intranasally administering to a patient in need of treatment a therapeutically effective amount of an opioid antagonist selected from nalmefene and its pharmaceutically acceptable salts, wherein the therapeutically effective amount is equivalent to about 1 mg to about 10 mg of nalmefene hydrochloride, as provided above.

[0349] Also provided are devices, kits, and pharmaceutical formulations for treating opioid overdose or its symptoms, reversing the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine, diagnosing suspected acute opioid overdose, treating opioid addiction, or treating septic shock, as well as methods for treating opioid overdose or its symptoms, reversing the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine, diagnosing suspected acute opioid overdose, treating opioid addiction, or treating septic shock, comprising intranasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist, wherein the therapeutically effective amount is from about 1 mg to about 10 mg, as provided above.

[0350] Other Aspects The detailed description set forth above is provided to aid those skilled in the art in practicing the present disclosure. However, the scope of the disclosure described and claimed herein should not be limited by the specific embodiments disclosed herein, as these embodiments are intended to illustrate certain aspects of the present disclosure. Any equivalent embodiments are intended to be within the scope of the present disclosure. Indeed, various modifications of the present disclosure, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description without departing from the spirit or scope of the inventive findings. Such modifications are also intended to be within the scope of the appended claims.

[0351] Also provided are embodiments in which any of the above-mentioned embodiments can be combined with any one or more of these embodiments, provided that these combinations are not mutually exclusive. Also provided herein are uses in treating one or more of the indications or symptoms thereof disclosed herein and in manufacturing medicaments for treating one or more of the indications or symptoms thereof, which are equivalent in scope to any of the above-disclosed embodiments, or any combination thereof that is not mutually exclusive. The methods and uses can use any of the devices disclosed herein, or any combination thereof that is not mutually exclusive, or any pharmaceutical preparations disclosed herein, or any combination thereof that is not mutually exclusive. [Example]

[0352] The following examples are included to demonstrate preferred embodiments of the present disclosure. The following examples are provided merely as examples and to assist those skilled in the art in using the present disclosure. The examples are not intended to limit the scope of the present disclosure in any way. In light of the present disclosure, those skilled in the art will understand that many changes can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present disclosure.

[0353] Example 1: Overview of the protocol for the phase 1 pharmacokinetic evaluation of nalmefene administered intranasally to healthy volunteers The following is a summary of a single-center study conducted at Vince & Associates Clinical Research, Overland Park, Kansas. The National Institute on Drug Abuse (NIDA) was the IND sponsor for this study. The drug used in this study was nalmefene hydrochloride (nalmefene). The study was designed to enroll approximately 14 healthy volunteers, with at least 10 subjects completing all study drug administrations and blood draws for PK assessments. If fewer than 10 subjects completed the study with the first cohort of 14, additional subjects were screened and enrolled until a total of at least 10 subjects had completed the study.

[0354] The objectives of this study were to compare the pharmacokinetics of nalmefene administered IN with and without an absorption enhancer compared with IM injection, and to determine the safety and tolerability of IN nalmefene, particularly with respect to rhinitis (erythema, edema, and erosion).

[0355] The primary endpoint was the pharmacokinetic parameter C of nalmefene for the three IN treatment regimens. max , T max , AUC 0-t , and AUC 0-inf The objective of this study was to compare nalmefene administered intravenously with IM administration of nalmefene. Treatment regimens were 3 mg nalmefene IN; 3 mg nalmefene + 0.25% Intravail IN; 1.5 mg nalmefene IN; and 1.5 mg nalmefene IM.

[0356] The study was designed as an inpatient, double-blind (for IN administration), randomized, four-period, four-treatment, six-sequence, crossover study involving 14 healthy volunteers. Subjects were assigned to one of six dosing sequences, with at least two subjects per dosing sequence. Each subject received four treatments during four dosing periods: 3 mg nalmefene IN, 3 mg nalmefene + 0.25% Intravail IN, 1.5 mg nalmefene IN, and 1.5 mg nalmefene IM. If fewer than 10 subjects completed the study, additional subjects were screened and enrolled until a total of at least 10 subjects completed. Subjects remained in the inpatient facility for 17 days to complete the entire study and were discharged at the end of the final period after completing discharge procedures. Three to five days after discharge, subjects received a telephone call to review any adverse events (AEs) and concomitant medications since discharge.

[0357] After obtaining informed consent, subjects were screened for eligibility to participate in the study, including a medical history, physical examination, clinical chemistry tests, coagulation markers, hematology tests, infectious disease serology tests, urinalysis, urine toxicology screen for drugs and alcohol, vital signs, and an ECG. The day after admission, subjects received IN-formulated medication in a randomized order with four days between doses. During the fourth (final) treatment period, an IM dose of nalmefene was administered.

[0358] To obtain nalmefene PK data, blood samples were taken predose and at 2.5, 5, 10, 15, 20, 30, and 45 minutes, and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, and 72 hours after study drug administration. On study drug administration days, 12-lead ECGs were taken approximately 1 hour predose and approximately 1 and 8 hours postdose. Vital signs were measured predose and approximately 0.5, 1, 2, and 8 hours postdose. The order of assessments on dosing days was ECG, vital signs, and then PK blood samples when scheduled at the same nominal time. The target time for PK blood samples was considered most critical. If blood draws deviated from the scheduled time by more than ±1 minute during the first 60 minutes of blood draw or by more than ±5 minutes thereafter, this was considered a protocol deviation. ECGs and vital signs were collected within 15 minutes before the nominal time of blood draw. ECGs and vital signs were checked once daily at screening, admission, discharge, and follow-up. Vital signs were also checked approximately 24, 48, and 72 hours after study drug administration. Clinical laboratory measurements were repeated after the final PK blood draw before discharge. AEs were assessed by subject spontaneous reporting, nasal mucosal examination, and measurement of vital signs, ECGs, and clinical laboratory parameters.

[0359] The inclusion and exclusion criteria and the protocol for safety assessment in this study are detailed in the Examples below.

[0360] The study drug and design were as follows: cGMP nalmefene was obtained from Rusan Pharma Ltd. The study drug was provided to the study site pharmacy. Detailed instructions for prescribing the study drug were provided to the pharmacist. The four formulations were: a) 30 mg nalmefene HCl / mL water for injection (WFI); b) 30 mg nalmefene HCl / mL WFI + 0.25% Intravail; c) 15 mg nalmefene HCl / mL WFI; d) 1.0 mg nalmefene / mL saline for injection.

[0361] The three IN formulations were administered as a single 0.1 mL spray into one nostril using an Aptar multi-dose nasal spray device to subjects in a reclining position. Subjects were instructed not to breathe through their nose when the IN dose was administered. The IM formulation was administered as a 1.5 mL dose into the arm opposite the arm from which the blood sample was obtained.

[0362] For pharmacokinetic (PK) evaluation, blood samples were collected into tubes containing sodium heparin at baseline and at 2.5, 5, 10, 15, 20, 30, and 45 minutes after study drug administration, and at 1, 2, 4, 6, 8, 12, 16, 24, 30, 36, 48, and 72 hours. Plasma samples were stored at or below -60°C until analysis. Nalmefene plasma concentrations were determined by liquid chromatography and tandem mass spectrometry.

[0363] The analytical plan was as follows: C of nalmefene max , AUC 0-t , AUC 0-inf , and T max The relative IN bioavailability of nalmefene was calculated as the dose-corrected AUC 0-inf and dose-corrected AUC of the IM formulation 0-inf was obtained by comparing

[0364] Within the framework of analysis of variance (ANOVA), natural log-transformed PK parameters (dose-normalized C max Comparisons of C and AUC were performed using a mixed effects model in which administration sequence, duration, and treatment modality were independent factors. max We constructed 90% confidence intervals for the ratio of least squares geometric means of AUC and σ. These 90% confidence intervals were obtained by exponentiation of the 90% confidence intervals of the differences between least squares means on the ln scale.

[0365] AEs were coded using the latest version of the Medical Dictionary for Regulatory Affairs (MedDRA) Preferred Terms and grouped by System Organ Class (SOC) name. Severity, frequency, and relationship of AEs to study drug were presented in preferred terms by SOC grouping. Separate summaries were provided for the four study periods, from after administration of each dose of study drug to the time of the next dose of study drug or discharge. A list of each individual AE was provided, including start date, end date, severity, relatedness, outcome, and duration. Vital signs, ECG, and laboratory parameters were presented as summary statistics.

[0366] Example 2: Study Design This was designed to be an inpatient, open-label, randomized (IN period only), four-period, four-treatment, six-sequence, crossover study involving 14 healthy volunteers. If fewer than 10 subjects completed the study, additional subjects were screened and enrolled until a total of at least 10 subjects completed. Subjects were assigned to one of six sequences, with at least two subjects in each sequence. Each subject received four treatments during the four dosing periods. Regimen A: 3 mg nalmefene IN dose (one 0.1 mL spray of 30 mg / mL WFI in one nostril) Treatment B: 3 mg IN dose of nalmefene and 0.25% Intravail (one 0.1 mL spray of 30 mg / mL WFI + 0.25% in one nostril) Regimen C: 1.5 mg nalmefene IN dose (one 0.1 mL spray of a 15 mg / mL solution in WFI into one nostril) Treatment D: 1.5 mg nalmefene IM dose (1.5 mL of 1.0 mg / mL injectable saline). This treatment was administered in Period 4.

[0367] Subjects stayed in the inpatient facility for 17 days to complete the entire study and were discharged after completing discharge procedures in Period 4. Three to five days after discharge, subjects received a telephone call to inquire about any AEs and concomitant medications since discharge.

[0368] After obtaining informed consent, subjects were screened for eligibility to participate in the study, including a medical history, physical examination, height, weight, BMI, clinical chemistry, coagulation markers, hematology, infectious disease serology, urinalysis, urine toxicology screen, vital signs, and ECG. The day after admission, subjects received study medication in a randomized order with a 4-day washout period between doses until all four treatments were administered (IN only, Periods 1-3). For PK analysis, blood samples were collected pre-dose and at 2.5, 5, 10, 15, 20, 30, 45, and 1, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, and 72 hours after administration of study medication. The IM formulation was administered in Period 4.

[0369] On study drug administration days, 12-lead ECGs were obtained approximately 1 hour before and approximately 1 and 8 hours after dosing. Vital signs were measured predose and approximately 0.5, 1, 2, and 8 hours after dosing. The order of assessments on dosing days was ECG, vital signs, and then PK blood draws when scheduled at the same nominal time. The target time for PK blood draws was considered most critical. If blood draws deviated from the scheduled time by more than ±1 minute during the first 60 minutes of blood draw or by more than ±5 minutes thereafter, this was considered a protocol deviation. ECGs and vital signs were collected within 15 minutes before the nominal time for blood draw. ECGs and vital signs were checked at screening, admission, discharge, and follow-up visits. Vital signs were also checked daily after dosing. Laboratory measurements were repeated after the final PK blood draw before discharge. AEs were assessed by spontaneous reporting by the subjects, by nasal examination, and by measurement of vital signs, ECG, and clinical laboratory parameters.

[0370] Example 3: Subject Selection and Screening Subjects were healthy volunteers who stayed at the clinical site for 17 days and met the following inclusion and exclusion criteria:

[0371] Inclusion Criteria: Subjects were included if they met the following inclusion criteria: Be male and female between the ages of 18 and 55; Written informed consent was obtained; BMI between 18 and 30 kg / m 2 Being; have adequate venous access; No clinically significant concomitant medical conditions were identified by history, physical examination, laboratory tests, vital signs, and 12-lead ECG; Male subjects agreed to use acceptable contraception with their female partners throughout the study and for 90 days after the last dose of study drug, and agreed not to donate sperm. Female subjects of childbearing potential agreed to use acceptable birth control methods throughout the study and for 30 days after the last dose of study drug. Oral contraceptives were prohibited; Agree not to consume alcohol, beverages containing xanthines >500 mg / day (e.g., Coca-Cola®, coffee, tea, etc.), or grapefruit / grapefruit juice, or participate in strenuous exercise from 72 hours prior to admission until the final blood draw in this study.

[0372] Exclusion criteria: Subjects were excluded if they had any of the following criteria: the presence of any IN condition, including abnormal nasal anatomy, nasal symptoms (i.e., nasal congestion and / or runny nose, nasal polyps, etc.), or the product being sprayed into the nasal passages before drug administration, or failure of the smell test; - Received an investigational drug within 30 days prior to Day 1; -Taking any prescription or OTC medications, dietary supplements, herbal products, vitamins, or using opioid analgesics for pain relief within 14 days prior to Day 1; a positive urine drug screen for alcohol, opioids, cocaine, amphetamine, methamphetamine, benzodiazepines, THC, barbiturates, or methadone at screening or admission; Previous or current opioid dependence, alcohol dependence, or other drug dependence (excluding nicotine and caffeine) based on medical history; Subjects had smoked an average of more than 20 cigarettes per day in the month prior to screening or had been unable to quit smoking (or refrain from using nicotine-containing substances) at least 1 hour before and 2 hours after IN dosing; systolic blood pressure (BP) less than 90 mmHg or more than 140 mmHg, diastolic BP less than 55 mmHg or more than 90 mmHg, and respiratory rate less than 8 breaths per minute (rpm) or more than 20 rpm; On a standard 12-lead ECG, a QTcF interval of >440 msec for men and >450 msec for women; Presence of significant acute or chronic medical illness in the investigator's judgment; the likelihood of needing concomitant medications during the trial; -Having donated blood or transfused blood, or undergoing plasma or platelet apheresis within 60 days prior to Day 1; For women, being pregnant, breastfeeding, or planning to become pregnant during the study period or within 30 days after the last drug dose; positive test result for HBsAg, HCVAb, or HIVAb at screening; current or recent (within 7 days prior to screening) upper respiratory tract infection; Abnormal liver function tests (ALT, AST, total bilirubin) >1.5 times the upper limit of normal.

[0373] Example 4: Test Drugs Source and Description of Study Drug: The organizational name for nalmefene is 17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol. NIDA supplied cGMP-grade nalmefene HCl (manufactured by Rusan Pharma, Ltd.) to the clinical site pharmacy. The pharmacy prepared 30 mg / mL strength IN nalmefene HCl solutions with 0.25% Intravail, 30 mg / mL strength IN nalmefene HCl solutions without 0.25% Intravail, and 15 mg / mL strength IN nalmefene HCl solutions using water for injection. The pharmacy also prepared 1.0 mg / mL strength IM nalmefene HCl solution using Sterile Injectable Saline, USP. The IM solutions were tested for sterility, pyrogenicity, and other quality control tests before being released for administration.

[0374] The pharmacy acquired the Aptar multi-dose nasal spray device, which delivers 0.1 mL intranasally.

[0375] An aliquot of each dosing solution was sent to Research Triangle Institute for determination of nalmefene concentration.

[0376] Detailed instructions for prescribing the study medication were provided by the pharmacist in a separate document.

[0377] Study Medication Administration: Subjects were dosed with at least a 5 minute interval between subjects.

[0378] Between 8:00 AM and 10:00 AM, subjects received each of the three IN formulations by administration into one nostril. The volume of each formulation was 0.1 mL. All three formulations were administered to subjects in a reclining position using a dosing device. Subjects remained in a reclining position for approximately 1 hour after dosing. Subjects were instructed to hold their breath while the nasal spray was administered into their nose.

[0379] Each dosing device was weighed before and after dosing to determine the weight of the dose administered to each subject.

[0380] For IM injection, 1.5 mL of a 1.0 mg / mL nalmefene solution was administered in the arm opposite the arm used for blood collection. Subjects received the IM formulation between 08:00 am and 10:00 am.

[0381] Study Drug Accountability: The investigator recorded all study drug administration to subjects throughout the study in a diary. In addition, study medication was inventoried and audited against the administration record. The inhaler device was marked with subject ID and date and kept at the site until the clinical monitor completed the account verification and the sponsor notified the site how to dispose of the device.

[0382] Used / Unused Supplies: Unused study medication was inventoried at the end of the study. If study medication was lost or damaged, its disposal was documented. Unused study medication was stored at the clinical site until directed by NIDA to be destroyed at the end of the study.

[0383] Example 5: Testing Procedure Subject Screening Assessments: Subjects were initially screened for eligibility prior to admission and completed upon admission. Assessments conducted during screening included demographic information, medical history, 12-lead ECG, physical examination, height, weight, BMI, nasal examination, olfaction, and vital signs (heart rate, blood pressure, respiratory rate, and temperature). To ensure eligibility, subjects were asked about their intake of alcohol and caffeine-containing beverages or foods (e.g., coffee, tea, chocolate, cola, and Red Bull®), as well as smoking. Urine was collected for medical urinalysis and urine toxicology screening. Blood was collected for hematology, chemistry, coagulation markers, serum pregnancy tests (for women), and viral serology (HIV Ab, HBsAg, and HCVA Ab). Prior to screening, subjects were asked about their 30-day use of prescription and over-the-counter medications, dietary supplements, herbal products, and vitamins, or recent use of opioid analgesics for pain relief. This information was updated throughout the screening process until admission.

[0384] An eligibility checklist was provided and reviewed upon completion of the outpatient screening assessment, and if subjects were still eligible, they were scheduled for admission and final eligibility assessment.

[0385] Up to 18 subjects (14 enrolled; 4 alternates) were admitted and assessed for final eligibility on Study Day 1. 14 eligible subjects, including at least 6 women, were randomized.

[0386] Admission screening procedures were conducted on Study Day 1. Eligibility was confirmed by an update on medication use since the last visit; an update on medical history (new illnesses or conditions since the last visit); a physical and nasal examination; an olfactory test; a 12-lead ECG; vital signs [seated (5-minute) blood pressure, heart rate, respiratory rate, and temperature] (may be repeated twice); chemistry, coagulation, hematology, serum pregnancy, and urinalysis; urine toxicology screens for drugs and alcohol (both of which must be negative to be eligible); and an eligibility checklist review.

[0387] Subject Randomization: If subjects still met the eligibility criteria, they were randomized to one of three IN doses: (i) 3 mg IN nalmefene (one 0.1 mL spray of a 30 mg / mL formulation into one nostril); (ii) 3 mg IN nalmefene + 0.25% Intravail (one 0.1 mL spray of a 30 mg / mL + 0.25% Intravail formulation into one nostril); (iii) 1.5 mg nalmefene (one 0.1 mL spray of a 15 mg / mL formulation into one nostril).

[0388] After verifying eligibility and completing admission procedures, subjects were randomized to a dosing sequence to receive the IN dose (Periods 1-3). Subjects were assigned to each of six possible dosing sequences to ensure at least two subjects in each group. Periods 1-3 comprise the double-blind portion of the study. The randomization schedule was provided by Technical Resources International, Inc. (Bethesda, MD).

[0389] All subjects received 1.5 mg nalmefene IM (1.5 mL of a 1.0 mg / mL solution) in Period 4. Pharmacists were provided with the randomization schedule to prepare individual doses.

[0390] Study Drug Administration, PK Sample Collection, and Safety Monitoring: Study drug was administered intranasally on Days 1, 5, and 9 as specified in the crossover randomization. All subjects received an IM dose on Day 13. Approximately 1 hour before dosing, ECG, blood pressure, heart rate, olfaction (Periods 1-3), and respiratory rate were measured and times recorded. Approximately 1 hour and 8 hours after dosing, ECGs were repeated and times recorded. Vital signs, including heart rate, blood pressure, and respiratory rate, were measured in the sitting position (5 minutes) before dosing and approximately 0.5 hours (reclined), 1 hour, 2 hours, and 8 hours after each dose.

[0391] Measurements were performed in a reclined position 0.5 hours after dosing, as subjects had to remain in a reclined position for 1 hour after dosing. A physician was present during IN and IM dosing and for at least 5 minutes after dosing. Nasal examinations were performed before dosing and 5, 30, 1, 4, and 24 hours after dosing in Periods 1-3. To assess olfactory function, olfactory tests were performed at screening, Day -1 (baseline); before dosing and 4 hours after dosing during Periods 1-3; and before discharge. A member of clinical staff observed subjects for at least 1 hour after dosing.

[0392] For PK analysis, blood samples were collected into 4-mL sodium heparin tubes at predose and 2.5, 5, 10, 15, 20, 30, and 45 minutes after study drug administration, as well as at 1, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, and 72 hours after administration. The order of assessments on the dosing day was ECG, vital signs, and then PK blood sampling, when scheduled at the same nominal time. The target time for PK blood sampling was considered most critical. If the blood sampling time deviated from the scheduled time by more than ±1 minute during the first 60 minutes of blood sampling or by more than ±5 minutes thereafter, this was considered a protocol deviation. ECG and vital signs were collected within 15 minutes before the nominal time of blood sampling.

[0393] A total of 352 mL of blood was collected in 88 samples for PK analysis. An additional 48 mL (men) to 63 mL (women) of blood was collected for clinical laboratory evaluations during the study. The estimated total volume of blood collected was 400 mL for men and 415 mL for women.

[0394] Dietary and Other Restrictions: Subjects were asked to abstain from nicotine, caffeine, or other xanthine-containing products (e.g., coffee, tea, chocolate, cola, and beverages such as Red Bull®) for at least one hour before and two hours after dosing. Alcohol consumption was not permitted throughout the inpatient study period. Subjects had to abstain from smoking (or use of any nicotine-containing substance) for at least one hour before and two hours after dosing. Subjects fasted from midnight the night before the dosing session until at least one hour after administration of the study drug. Water was provided ad libitum. A common diet was provided for all meals during the inpatient portion of the study. Breakfast was served approximately one hour after dosing, lunch approximately four hours after dosing, dinner approximately 10 hours after dosing, and breakfast approximately 13 hours after dosing.

[0395] Discontinuation of Study Drug: Subjects were closely monitored during hospitalization, before and after drug administration. Vital signs, ECG measurements, and AE reports were used to ensure the safety of nalmefene administration and the appropriateness of administering the next dose. Vital signs were required to be within acceptable limits before nalmefene administration.

[0396] On the four study days when the study drug was administered, vital sign criteria that had to be met before dosing were as follows (subjects were seated at least 5 minutes before measurement): Systolic blood pressure: ≤140 mmHg and ≥90 mmHg. Diastolic blood pressure: ≤90 mmHg and ≥55 mmHg. Heart rate: ≤100 beats per minute (bpm) and ≥40 bpm. Respiratory rate: ≤20 breaths per minute (rpm) and ≥8 rpm. Vital signs could be repeated once. Furthermore, any clinically significant abnormal ECG at any time after admission required discontinuation of the study drug.

[0397] Concomitant Medication Use: Subjects were not permitted to take prescription or over-the-counter medications, oral contraceptives, herbal products, dietary supplements, or vitamins during their hospital stay. However, no medical treatment was denied at the investigator's discretion.

[0398] Discharge: On the day of discharge from the hospital, whether the study was completed or the subject withdrew, assessment of concomitant medications; AEs; chemistry, coagulation markers, hematology, urinalysis, serum pregnancy test; physical and nasal examination; olfactory examination; urine toxicology screen for drugs and alcohol; ECG, and vital signs were performed.

[0399] Once subjects completed all four periods, vital signs collected during discharge procedures after the fourth dose were used in place of those that would have been completed 72 hours after dosing.

[0400] Three to five days after discharge, subjects received a telephone call inquiring about any AEs or medications they had used since discharge. If a clinically significant AE was ongoing at the time of the call, the AE was followed until it resolved or stabilized.

[0401] Clinical trial participant withdrawal: Early termination of the targetThe criteria for terminating a subject's participation in the study were as follows: systolic blood pressure >180 mmHg, diastolic blood pressure >110 mmHg, or a respiratory rate <8 or >24 rpm, confirmed by repeat testing; significant arrhythmias defined as more than six supraventricular tachycardias or three or more ventricular tachycardias; QTcF interval >500 msec; significant reported nausea or abdominal pain; significant reported chest pain or dyspnea; subject confusion, seizures or seizure-like behavior, agitation, or inability to cooperate; or subject's desire to leave the study or reluctance or inability to cooperate in carrying out assigned protocol procedures.

[0402] Once the discontinuation criteria were exceeded, subjects were closely observed and treated as necessary to ensure recovery to normal baseline conditions before discharge from the hospital or transfer to another treatment facility. The study was stopped if more than two subjects showed a similar pattern of excessive cardiovascular or behavioral changes, or a pattern of change from baseline after drug administration that could not be easily explained by other factors.

[0403] Subject Discontinuation for Protocol Violation Subjects were excluded or discharged if their behavior was disruptive, incompatible with study procedures, or otherwise inconsistent with remaining in the hospital.

[0404] Subject withdrawal : All subjects who wished to withdraw from the study voluntarily and for any reason had the right to do so without obligation. The investigator recorded the subject's reason for withdrawing from the study and indicated whether they thought this was related to the study drug. Any procedures / examinations scheduled for the subject at the completion of the study were performed as soon as possible after withdrawal. Subjects were considered lost to follow-up if they did not return two phone calls. Subjects who withdrew for medical reasons continued to be followed by the investigator or other physicians, as appropriate.

[0405] Risks and Discomforts: The majority of safety data regarding the use of nalmefene have been obtained from patients receiving opioid medications. In patients receiving opioid medications, nalmefene may hasten the onset of opioid withdrawal. All subjects were questioned about opioid abuse and dependence and screened for opioid medication use (including methadone) prior to the start of the study to minimize the possibility of withdrawal symptoms occurring during the study. Withdrawal is characterized by nausea, chills, muscle pain, dysphoria, abdominal cramps, and joint pain. Common adverse reactions of nalmefene with an incidence greater than 1% are nausea, vomiting, tachycardia, hypertension, postoperative pain, fever, dizziness, headache, chills, hypotension, and vasodilation. Adverse events of nalmefene with an incidence less than 1% include bradycardia, arrhythmia, diarrhea, dry mouth, somnolence, depression, agitation, irritability, tremor, confusion, withdrawal syndrome, myoclonus, pharyngitis, pruritus, and urinary retention. The incidence of adverse events was highest in patients receiving nalmefene at doses greater than the recommended 1.5 mg IM.

[0406] Example 6: Evaluation Method Adverse events: Reports of AEs were elicited by verbal probes (e.g., "How are you feeling?") administered after admission. Any events spontaneously reported by subjects or observed by study staff were also recorded. AEs were assessed for severity and relationship to study drug according to the following criteria:

[0407] Clinical Chemistry: Clinical chemistry tests included total protein, albumin, blood urea nitrogen, creatinine, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, sodium, potassium, chloride, CO2, calcium, glucose, and total cholesterol. Laboratories that performed these assessments were either directly regulated by CAP or CLIA, or indirectly regulated according to CLIA guidelines. Laboratories were required to provide a copy of their current certification.

[0408] Coagulation Markers: Coagulation markers were performed, including prothrombin time and activated partial thromboplastin time. Laboratories that performed these assessments were either directly regulated by CAP or CLIA, or indirectly regulated according to CLIA guidelines. Laboratories were required to provide a copy of their current certification.

[0409] Demographics: Age, sex, racial / ethnic group, date of birth, and date and time informed consent was signed were collected.

[0410] ECG: A 12-lead ECG was performed according to standard procedures. Subjects were in the supine position for at least 5 minutes before obtaining the ECG. Results were reviewed by the investigator or study physician for interpretation. The investigator could consult a board-certified cardiologist if necessary. The Fridericia formula was used to correct the QT interval (QTcF) (Fridericia LS, Acta Medica Scandinavica. 1920; 53:469-586).

[0411] Eligibility checklist: An eligibility checklist containing inclusion / exclusion criteria was used at the end of outpatient screening and detailed on the day of admission to ensure eligibility to participate in the study.

[0412] Hematology: Complete blood counts including hemoglobin, hematocrit, red blood cells, total white blood cells; and automated white blood cell differential and platelet count were performed. Laboratories that performed these assessments were either directly regulated by CAP or CLIA, or indirectly regulated according to CLIA guidelines. Laboratories were required to provide a copy of their most recent certification.

[0413] Infectious Disease Serology: Serological testing for HIVAb, HBsAg, and HCVAb was performed at screening. Only subjects who tested negative for these viruses were eligible to be enrolled in the study. HIVAB test results were kept by the study site under confidentiality restrictions. Information about these test results never became part of the study database.

[0414] Study Medication Administration Record: Administration of study medication was reported on the Study Medication Administration Record Case Report Form (CRF), which included the date and time of study medication administration. The dose, route, and time of administration were recorded. The nostril used for administration was recorded. Any problems that arose were also recorded.

[0415] Medical History: To ensure medical suitability, all potential study subjects underwent a medical history, including questions about current and past opioid use, abuse, and dependence, and recent smoking history. Women were asked about their birth control method preferences. To ensure eligibility, subjects were asked about recent alcohol intake and consumption of xanthine-containing products.

[0416] Plasma nalmefene levels: Blood was obtained by direct venipuncture or via an IV catheter placed in the forearm during the blood collection period, or longer if possible. Four milliliters of blood were collected at each time point and placed into Vacutainer® tubes containing sodium heparin. Plasma nalmefene concentrations were determined in a bioanalytical laboratory using a sensitive, specific, and validated liquid chromatography-tandem mass spectrometry method.

[0417] Rhinitis Scoring: Rhinitis was assessed by trained observers at screening, baseline, within 2 hours before IN dosing, and at 5, 30, and 60 minutes and 4 and 24 hours after dosing. If the PK sample was consistent with the rhinitis assessment, the nasal assessment was performed within 5 minutes after obtaining the PK sample. Rhinitis Scale 0 - Normal-appearing mucosa. No bleeding. 1 - Inflamed mucous membranes (erythema / edema). No bleeding. 2 - Light bleeding that stops within 1 minute. 3 - Light bleeding that takes 1-5 minutes to stop. 4 - Heavy bleeding lasting 4-60 minutes, not requiring medical intervention. 5 - Ulcerative lesions. Bleeding requiring medical intervention.

[0418] Olfactory Testing: Olfactory testing to assess olfactory function was performed using "Sniffin' Sticks" at screening and admission (day -1); pre-dose and 4 hours post-dose during periods 1-3; and prior to discharge. "Sniffin' Sticks" is a screening test that uses 12 different odors. Identifying 10 or more odors (out of 12 items) constitutes a normal olfactory test. To be eligible to participate in the study, subjects must correctly identify 10 of the 12 odors at screening and admission. Subjects who identified fewer than 10 odors during the study were reported as an adverse event (hyposmia).

[0419] Physical Examination: A physical examination of the oral cavity, head, eyes, ears, nose, neck, and pharynx, heart, lungs, abdomen, liver, extremities, skin, nerves, lymph nodes, and psychiatry (mental status), as well as a general appearance, was performed by a physician during screening. Height and weight were recorded at screening. BMI was calculated to ensure subjects were eligible for the study. Nasal passages were examined by a physician during screening and after each dose for evidence of inflammation (erythema, edema, and erosion). Nasal examination was performed after blood samples were collected when the timing of collection was the same.

[0420] Previous and Concomitant Medications: Prescription and over-the-counter (OTC) medications, herbal products, dietary supplements, and vitamins used in the 30 days prior to screening and up until the day of admission were recorded as previous medications. Additionally, any medications taken by the subject other than study medications from the day of admission through the last day of the study were considered concomitant medications, even if these were prescription or over-the-counter (OTC) medications, herbal products, dietary supplements, and vitamins. Oral contraceptives were not permitted. Concomitant medications were not permitted unless the medication was prescribed by a physician to treat an AE or other intercurrent illness. All medications tried during the period of previous and concomitant medication use were recorded on the Previous and Concomitant Medications CRF.

[0421] Pregnancy Testing: An FDA-cleared qualitative serum pregnancy test assessing human beta-chorionic gonadotropin was performed by a local clinical laboratory to test all female subjects.

[0422] Urinalysis: Medical urine testing for specific gravity, glucose, bilirubin, ketones, blood, pH, protein, nitrite, and leukocyte esterase was performed by a local clinical laboratory.

[0423] Vital signs: Vital signs collected included blood pressure, heart rate, and respiratory rate in a sitting position (for at least 5 minutes) before and after dosing, except for 30 minutes after IN administration, which were collected in a reclined position. At all other times, blood pressure, heart rate, respiratory rate, and temperature were checked in a sitting position (for at least 5 minutes).

[0424] Drug and Alcohol Urine Toxicology Screening: Urine toxicology screening for alcohol, opioids, cocaine, amphetamines, methamphetamines, benzodiazepines, barbiturates, THC, and methadone was performed by a local clinical laboratory.

[0425] Discharge / Final Subject Disposition: The Subject Disposition CRF captured all data regarding the subject's discharge from the hospital: reason for discharge (i.e., completion of the inpatient portion of the study or early termination from the study) and date of discharge.

[0426] Example 7: Regulatory and Reporting Requirements Good Clinical Practice: This study was conducted in accordance with the latest version of the International Conference on Harmonization Guidance Document E6(R1): Good Clinical Practices: Consolidated Guideline. An operations manual was provided to all study sites as a study quality assurance tool.

[0427] FDA Form 1572: The investigator signed a Statement of Investigator (FDA Form 1572) prior to initiating this study. Form 1572 was updated as necessary.

[0428] IRB Approval: Prior to initiating this study, the investigator obtained written approval of the record from the IRB to conduct this study. If changes to the study protocol were necessary, the site's investigator submitted the protocol revision in writing to the local IRB for IRB approval before implementation. Additionally, NIDA and the local IRB approved all advertising materials used to recruit subjects and any educational materials given to subjects. Progress reports were submitted to the local IRB annually, or as frequently as required by the IRB.

[0429] Informed Consent: All potential study subjects were given a current copy of the informed consent form to take home and read. All aspects of the study were explained in plain language. All study subjects were given a signed copy of the informed consent form.

[0430] Drug Accountability: Upon receipt, the investigator or designee was responsible for taking an inventory of the study medication. A record of this inventory was kept and the amount used was documented. All unused or expired study medication was disposed of according to the sponsor's instructions.

[0431] External Monitoring: medical monitor A medical monitor was appointed for this study. The medical monitor could advise the investigator and sponsor on the severity and relevance of any serious adverse event (SAE) to the study intervention and determine whether the SAE should be reported to the FDA in an expedited report within 7 or 15 days or in an annual report. The medical monitor was also responsible for tracking reported AEs and assessing their trends. If the medical monitor and investigator disagreed on an SAE assessment, both opinions were reported to the FDA.

[0432] clinical monitorAll investigators allowed representatives from the sponsor to monitor all case report forms (CRFs) and corresponding source documentation for each subject periodically during and after the study at mutually convenient times. These monitoring visits provided the sponsor with an opportunity to evaluate the progress of the study and to alert the sponsor to potential issues. Monitors affirmed that submitted data were accurate and consistent with source documentation, verified that the investigational product was properly stored and accounted for, confirmed that subject consent to participate in the study was properly obtained and documented, confirmed that research subjects participating in the study met the inclusion and exclusion criteria, and affirmed that all required documentation required by GCP guidelines was properly submitted.

[0433] The monitor conducted a study initiation visit prior to the start of the study, during which the monitor ensured that correct study documentation was present, assisted in training the investigators and other site personnel in study procedures and GCP guidelines, verified receipt of study supplies, and ensured that acceptable facilities and staff were available to conduct the study.

[0434] Regular monitoring visits by NIDA representatives were scheduled at appropriate intervals. During these visits, the monitors ensured that study procedures were being carried out in accordance with protocol guidelines and reviewed AEs, SAEs, and medication records. At the conclusion of the study, the monitors advised on the retention of study records and on the disposal of unused study medication in accordance with sponsor instructions.

[0435] Adverse Event Reporting: In accordance with FDA reporting requirements, the investigator or subinvestigator collected, documented, and reported all AEs that occurred during the clinical trial according to the following procedures: The occurrence of AEs was assessed from the time the subject received the first dose of study drug, daily during the inpatient portion of the study, until discharge, and at the time of the final follow-up telephone contact.

[0436] An AE was defined as any reaction, adverse event, or untoward event that occurred during a clinical trial, whether or not the event was related to the study drug or considered clinically significant. For this study, subject-reported events and clinically significant abnormal findings on physical examination, vital signs, ECG, or laboratory evaluation were recorded on the AE CRF. Any new illness, symptom, sign, or clinically significant laboratory abnormality, or worsening of a pre-existing condition or abnormality, was considered an AE. Stable chronic conditions, such as arthritis, that were present before entry into the clinical trial and did not worsen were not considered AEs.

[0437] All AEs recorded during the inpatient portion of the study, regardless of severity, were followed by the investigator until satisfactory resolution. AEs were required to be reported after discharge until the date of final follow-up. AEs were recorded and tracked at follow-up visits. AEs were tracked until resolution only if they were serious or if the investigator assessed the AE as clinically significant.

[0438] Serious Adverse Events: Each adverse event or reaction was classified by the investigator as serious or non-serious. Appropriate reporting procedures were followed based on the seriousness of the adverse event or reaction. Title 21 of the Code of Federal Regulations, Part 312.32, and the International Council for Harmonisation (ICH) Guideline for Industry: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, ICH-E2A March 1995, implemented by the U.S. Food and Drug Administration, define a serious adverse event (SAE) or serious adverse drug experience as an untoward medical occurrence, at any dose, that (i) causes death, (ii) is life-threatening (Note: The term "life-threatening" in the definition of "serious" refers to an event in which the subject is at risk of death at the time of the event, not an event that could hypothetically cause death even if more severe), (iii) requires hospitalization or an extension of an existing hospitalization, (iv) results in permanent or significant disability / incapacity, or (v) is a congenital anomaly / birth defect.

[0439] Additionally, any significant medical event that may not cause death, may not be life-threatening, or may not require hospitalization was considered a serious adverse drug reaction that, based on sound medical judgment, may endanger the subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definition above.

[0440] An unexpected AE is one whose nature, severity, or frequency is not described in the current product labeling.

[0441] Reporting of AEs and SAEs is discussed below. Ultimately, there were serious consequences for sponsors who failed to comply with FDA regulations governing SAE reporting, including criminal and / or civil penalties. The principal investigators in this study were responsible for promptly reporting all SAEs to the NIDA-appointed medical monitor to enable NIDA to comply with these regulations.

[0442] If a study subject withdrew from the study, or if the investigator decided to discontinue a subject from the study due to an SAE, the subject was required to have appropriate follow-up medical monitoring, including hospitalization as necessary. Monitoring continued until the problem prompting hospitalization was resolved, or stabilized with no further expected changes, or was found to be clearly unrelated to the study drug or to progress to death.

[0443] Example 8: Analytical Plan Study Endpoint: The primary endpoint of this study was the pharmacokinetic parameter C of nalmefene administered as three IN and IM treatment regimens: 3 mg nalmefene IN, 3 mg nalmefene + 0.25% Intravail IN, 1.5 mg nalmefene IN, and 1.5 mg nalmefene IM. max , T max , AUC 0-t , and AUC 0-inf It was.

[0444] Secondary endpoints of the study were to ascertain secondary pharmacokinetic parameters and adverse events (AEs), vital signs (heart rate, sitting blood pressure, and respiratory rate), electrocardiogram (ECG), laboratory changes, and rhinitis (erythema, edema, and erosion) after administration of nalmefene.

[0445] Study population: Safety Group The safety population included all subjects who received at least one dose of study drug.

[0446] PK-evaluable population: The evaluable population included all subjects who completed at least one treatment with sufficient sampling time points to derive meaningful PK parameters.

[0447] Sample Size: This pilot study was designed to obtain information on the PK of IN nalmefene under the conditions of this study. The number of subjects was deemed appropriate for this type of study.

[0448] Descriptive Statistics: Summary demographics (N, age, weight, height, BMI, sex, race, and ethnic group) are shown. Demographics (N, age, weight, height, BMI, race, and ethnic group) for each sex were also calculated.

[0449] PK Data Analysis: Individual plasma concentrations over time were tabulated and summarized. The following summary statistics were presented: N, arithmetic mean, SD of the arithmetic mean, median, minimum, and maximum. Plasma concentration versus time curves (individual and mean) were presented.

[0450] Pharmacokinetic parameters (C max , T max , AUC 0-t , AUC 0-∞ , t 1 / 2 , λz, and apparent clearance (CL / F) (Table 1)) were calculated using noncompartmental methods and a PK software program (Phoenix WinNonlin version 6.3 or higher, Pharsight Corp, Mountain View, CA.) or equivalent.

[0451] Table 1. Pharmacokinetic parameters of nalmefene TIFF0007730443000008.tif150147

[0452] Individual PK parameters were tabulated and summarized. The following summary statistics were provided for PK parameters: N, arithmetic mean, SD of arithmetic mean, geometric mean, SD of geometric mean, median, minimum, and maximum. max are shown as N, median, minimum, and maximum values.

[0453] Statistical analysis of PK parameters: C of nalmefene max , AUC 0-t , and AUC 0-inf The dose-corrected AUC after IN administration was calculated. 0-inf and dose-corrected AUC of the IM formulation 0-inf The relative IN bioavailability of nalmefene after three different IN administrations was determined by comparing

[0454] Within the framework of ANOVA, the PK parameters (C max Comparisons of C (AUC and AUC) were performed using a mixed-effects model in which administration sequence, duration, and treatment were independent factors. To compare the three IN formulations with the IM formulation, max We constructed 90% confidence intervals for the ratio of least-squares geometric means of the and AUC parameters. These 90% confidence intervals were obtained by exponentiating the 90% confidence intervals of the differences between least-squares means on the ln scale.

[0455] Safety Data Analysis: Clinically significant values ​​of systolic and diastolic blood pressure, heart rate, body temperature, and respiratory rate were demonstrated. Clinically significant ECG changes were demonstrated by dosing session.

[0456] Adverse events : AEs were coded using the latest version of the Medical Dictionary for Regulatory Affairs (MedDRA) Preferred Terms and grouped by System Organ Class (SOC) name. Severity, frequency, and relationship of the AE to the study drug were presented in preferred terms by SOC grouping. Separate summaries were provided for the four study periods, from after each dose to the time of the next dose or discharge. A list of each individual AE was provided, including start date, end date, severity, relatedness, outcome, and duration.

[0457] Clinical laboratory parameters : Clinically relevant concentrations of analytes were demonstrated by dosing session for each group.

[0458] Missing Data: Missing data were not imputed. The number of data points reflected in summary statistics was indicated by representing the number of observations.

[0459] Example 9: Data Management and Case Report Forms Data management activities and statistical analysis support were coordinated through the Data Management Center.

[0460] Data Collection: Data were collected at the study site, documented in source documents, and transcribed into Case Report Forms (CRFs) at the site. CRFs were provided by the Data Management Center. CRFs had to be completed continuously throughout the study. Medical records and source documents were the source of data verification. Clinical monitors collected the completed CRFs after monitoring them against the source documents periodically throughout the study. The investigator was responsible for keeping accurate, complete, and up-to-date records for each subject. The investigator was also responsible for keeping all source documents related to the study, including clinical laboratory data, ECG tracings, etc.

[0461] Case Report Form Completion: An electronic CRF (eCRF) was provided to each subject. Subject identifiers and the actual dates (and times, if applicable) of each assessment were entered into the eCRF. The investigator reviewed each subject's final completed eCRF and signed and dated the appropriate CRF page to certify that it was complete and accurate.

[0462] Data Compilation and Management: Data received at the Data Management Center was reviewed, verified, and edited before being entered into the main study database. If incomplete or inaccurate data was discovered, a data clarification request was routed to the clinical site for action. After the site resolved data inconsistencies and errors, the data was returned to the Data Management Center. All corrections and changes to the data were reviewed and entered into the main study database. Data entry into the database utilized a single-data entry procedure with 100% quality control verification of all data entered into the database.

[0463] The investigator agreed to periodic data audits by sponsor-appointed monitors to ensure that the data submitted with appropriate documentation matched the source documentation at the site. The investigator also verified that the investigational product was properly stored and accounted for, subject informed consent for study participation was obtained and documented in the subject's progress notes, all required documentation in accordance with GCP guidelines was in order, and the site was conducting the study in accordance with the study protocol. Any discrepancies were resolved, and any changes to data documentation were made using established data management center procedures.

[0464] Data Processing: A database was constructed from eCRFs capturing each data element from each CRF. Data were verified manually and electronically. The database underwent a 100% quality assurance audit before being locked and unlocked for statistical analysis.

[0465] All AE information from the AE CRF was entered into the main study database. AEs were coded using preferred terms and system organ class names using the most recent version of MedDRA at the time of database closure.

[0466] Study Documentation and Record-Keeping: Study documentation included all eCRFs, data amendments, workbooks, source documents, monitoring records and appointment schedules, sponsor and investigator correspondence and regulatory documents (e.g., signed protocols and amendments, IRB correspondence and approved consent forms and signed informed consent documents, investigator statements, and clinical supply receipts and distribution records).

[0467] Source documents included all original observation records or clinical activity notes and all reports and records necessary for the evaluation and reconstruction of the clinical research study. Thus, source documents included, but were not limited to, laboratory reports, ECG tracings, x-rays, radiologist reports, subject diaries, biopsy reports, ultrasound photographs, subject progress notes, hospital or pharmacy records, and any other similar reports or records of any procedures performed according to the protocol.

[0468] Whenever possible, original observation records were kept as source documents; however, photocopies were acceptable provided they were clear, legible, and accurate reproductions of the original documents.

[0469] Government agency regulations and mandates require investigators to retain all study documentation related to the conduct of a clinical trial, and these documents must be retained for a minimum of two years after discontinuation of an IND or two years after approval of an NDA.

[0470] Confidentiality: Maintaining confidentiality of data Attention has been drawn to regulations promulgated by the U.S. Food and Drug Administration (FDA) under the Freedom of Information Act which provide, in part, that proprietary information provided to investigators and IRBs will be treated as confidential by the FDA only if it is treated as confidential by the investigators and IRBs.

[0471] By signing this protocol, the Investigator assures NIDA that the information provided to the Investigator by NIDA will be kept confidential and that such information will be disclosed to the IRB, expert committees; affiliated agencies; and employees only with an appropriate understanding of confidentiality with such boards or committees; affiliated agencies; and employees.

[0472] Maintaining confidentiality of subject records To maintain subject confidentiality, all laboratory specimens, eCRFs, reports, and other records were identified only by coded study subject numbers and alpha codes. Research and clinical records were stored in locked cabinets. Only study staff, NIDA monitoring contractors, and NIDA program personnel had access to the records. Subject information was not released without written authorization except when monitoring by FDA, NIDA monitoring contractors, or NIDA personnel was required.

[0473] Example 10: Assessment and reporting of adverse events and serious adverse events General Procedure: AEs were recorded after the first dose of study drug was administered. AEs were recorded on the AE CRF. Event severity was reported according to the guidance below. Event relationship to study drug administration was reported according to the guidance below.

[0474] Severity of the event: Mild: Aware of symptoms but easily tolerated. Moderate: Discomfort enough to interfere with daily activities. Severe: Unable to work or carry out daily activities or function normally.

[0475] Relatedness of Event: The investigator was responsible for defining, in the investigator's judgment, the relationship of the AE / SAE to the study drug. The degree of certainty that the AE / SAE was attributable to the study drug or another cause (e.g., natural history of underlying disease, concomitant therapy, etc.) was determined by the extent to which this experience was understood in terms of one or more of the following: Exposure: Is there evidence that the subject was exposed to the study drug? Timing of study drug administration: Did the AE / SAE occur within a reasonable timeline after study drug administration? Consistency with test drug safety profile: known pharmacology and toxicology of the test drug in animals and humans; similar responses have been previously described with the test drug. Other explanations for the adverse event, such as concomitant medications, intercurrent illnesses, ineffective therapies, diagnostic tests, procedures, or other confounding findings. Response to discontinuation of study drug: The terms and definitions used to evaluate the relationship between study drug and AE / SAE were as follows: Unknown: This category had to be used only when the cause of the AE / SAE could not be ascertained. Not at all related: Subject was not given study drug, the timeline of AE / SAE onset to study drug administration was not valid, or there was another obvious cause of the AE / SAE. Unlikely related: There was evidence of exposure to the study drug or there was another more likely cause of the AE / SAE. Possibly relevant: There was evidence of exposure to study drug and the timeline of AE / SAE onset to study drug administration was reasonable, but the AE / SAE may have been due to an equally likely alternative cause. Probably related: There is evidence of exposure to the study drug, the timeline of the onset of the AE / SAE relative to study drug administration is plausible, and the AE / SAE is more likely to be explained by the study drug than any other cause. Certainly relevant: There was evidence of exposure to the study drug, the timeline of AE / SAE onset relative to study drug administration was plausible, the AE / SAE was more likely to be explained by the study drug than any other cause, and the AE / SAE showed a pattern consistent with prior knowledge of the study drug or study drug class.

[0476] Specific Instructions - Laboratory / ECG Adverse Events: A laboratory or ECG AE is any clinically significant worsening of a study variable occurring during the study, whether or not considered related to study drug. For each such change, provide the information requested on the day of the study, severity, likelihood of relationship to study drug, change in study drug dose due to the AE, and any action required.

[0477] All laboratory AEs were specified as an increase or decrease in test result (e.g., "increased glucose," "decreased potassium") or a term indicating the abnormality (e.g., hyperkalemia, azotemia, hypokalemia, or bradycardia). Any abnormal laboratory value that was deemed clinically insignificant was recorded as clinically insignificant on the clinical laboratory report CRF, along with a comment justifying the determination.

[0478] Reporting of serious and unexpected adverse events: 24 hour reporting requirement Any serious adverse event, including death, from any cause, whether related to study drug or not, occurring in any subject from the time of admission until discharge was to be reported by email within 24 hours to the NIDA Medical Monitor and the NIDA Project Officer.

[0479] Follow-up of all adverse events / serious adverse events All medical adverse events were followed until resolution or until all attempts to confirm resolution of the AE / SAE were exhausted, which required an extension of hospital stay or a change in status from outpatient to inpatient. Information about all procedures, outcomes, and whether the subject was referred to a primary care provider for further follow-up was recorded in the original documentation. All serious and unexpected AEs that occurred up until the last safety assessment were reported. All AEs from follow-up days 18 to 20 were recorded and followed until resolution only if the AE was serious or if the investigator assessed the AE as clinically significant.

[0480] Investigators were required to provide the medical monitor and IND sponsor with all relevant follow-up information necessary to facilitate a thorough understanding of the event and a determination regarding its relationship to study drug.

[0481] Reporting to the FDA IND sponsors should report SAEs to: SAEs that are unexpected (or, if expected, unusually severe or rare), life-threatening, or fatal, and at least possibly related to the study drug, must be reported to the FDA within seven days, and within eight days in a written follow-up report; If the SAE is unexpected (or, if expected, is unusually severe or rare) and not immediately life-threatening, it must be reported to the FDA within 15 days; Other cases were required to be reported to the FDA in annual reports.

[0482] Example 11: Summary of PK parameters Table 2 below shows the mean (%CV) plasma concentrations of nalmefene after a single intranasal and intramuscular dose of nalmefene in healthy subjects. The coefficient of variation is expressed as a percent (%CV) and is shown in parentheses.

[0483] Table 2. Mean (%CV) plasma concentrations of nalmefene after single intranasal and intramuscular administration of nalmefene to healthy subjects TIFF0007730443000009.tif144142N=10~14 Lower limit of quantitation (LLOQ)=0.2ng / mL

[0484] Figure 1A and 2A As can be seen from Table 3 below, Intravail® (dodecylmaltoside) is a T max Without Intravail®, the T of 2 hours is shorter, making it much faster than IM injection. maxAlthough IN nalmefene cannot be used as a first-line (rescue) drug for overdose, it still has a long half-life (T 1 / 2 ) is long and would be suitable as a second or follow-up medication. With Intravail® (as seen in row 2), the dose-normalized C max was also significantly increased when compared to IM administration. As can be seen from the data, Intravail® is a true absorption enhancer, speeding up and enhancing absorption, but does not alter the bioavailability (compared to IM) or half-life of IN nalmefene.

[0485] It should be noted that Intravail® did not alter the AUC of IN nalmefene, but results with naltrexone were different. With naltrexone, the AUC increased significantly (data not shown). This important difference could not have been predicted based on the structure of the opioid antagonists or the function of these moieties as opioid antagonists.

[0486] Table 3. Mean pharmacokinetics of nalmefene after single intranasal and intramuscular administration of nalmefene to healthy subjects TIFF0007730443000010.tif87150a:N=14 b: N=13 c: Median (minimum, maximum)

[0487] Intranasal naltrexone formulations The following tables set forth exemplary formulations of nalmefene for intranasal administration for the treatments disclosed herein: Table 4 sets forth simple aqueous solution formulations dispensed in approximately 100 μL increments, such as those used in the experiments described above.

[0488] (Table 4) TIFF0007730443000011.tif96128

[0489] Table 5 describes formulations for intranasal administration dissolved in 100 μL of aqueous solution containing excipients, such as compounds that act as isotonicity agents, stabilizers, and / or preservatives or surfactants. EDTA stands for edetate disodium, and BZK stands for benzalkonium chloride.

[0490] (Table 5) TIFF0007730443000012.tif113146

[0491] Examples 1-31A are also provided which further contain a sufficient amount of hydrochloric acid to achieve a pH of 3.5 to 5.5. The acid must be a pharmaceutically acceptable acid, for example, hydrochloric acid.

[0492] Although the invention has been described in the above examples with reference to specific details of certain aspects of the invention, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention.

Claims

1. A pharmaceutical composition for intranasal use in treating opioid overdose or symptoms thereof in a subject, wherein the subject is a human; a) about 1 mg to about 4 mg of nalmefene, or a salt, hydrate, or solvate thereof; b) about 0.05 mg to about 2.5 mg of dodecyl maltoside; c) water; Including, the pH of the composition is 4.0 to 5.0; The pharmaceutical composition comprises a final volume of about 50 μL to about 250 μL.

2. 10. The composition of claim 1, further comprising about 0.2 mg to about 1.2 mg of an isotonic agent.

3. 3. The composition of claim 2, wherein the isotonic agent is NaCl.

4. 10. The composition of claim 1, further comprising about 0.1 mg to about 0.5 mg of a stabilizer.

5. 5. The composition of claim 4, wherein the stabilizer is edetate disodium.

6. 10. The composition of claim 1, further comprising about 0.005% (w / v) to about 1% (w / v) of a preservative.

7. 7. The composition of claim 6, wherein the preservative is benzalkonium chloride.

8. The composition of claim 1, wherein the pH of the composition is about 5.

9. 9. The composition of claim 8, wherein the composition comprises about 0.25 mg of dodecyl maltoside.

10. 2. The composition of claim 1, wherein the nalmefene is nalmefene hydrochloride.

11. 11. The composition of claim 10, comprising about 3 mg of nalmefene hydrochloride.

12. 10. The composition of claim 1, further comprising an acid.

13. 13. The composition of claim 12, wherein the acid is hydrochloric acid.

14. 10. The composition of claim 1, wherein the symptoms of opioid overdose are selected from respiratory depression, central nervous system depression, altered level of consciousness, miosis, cardiovascular depression, hypoxemia, acute lung injury, aspiration pneumonia, sedation, unresponsiveness to stimuli, unconsciousness, respiratory arrest, irregular or absent pulse, choking or gurgling sounds, blue or purple nails or lips, decreased muscle tone, constricted pupils, vomiting, and hypotension.

15. 10. The composition of claim 1, wherein about 50 μL to about 250 μL of the composition is administered to the subject.

16. 16. The composition of claim 15, wherein administration of the composition results in complete or partial recovery from the symptoms of opioid overdose.

17. T of the composition max 16. The composition of claim 15, wherein the time is less than 30 minutes.

18. T of the composition max 16. The composition of claim 15, wherein the time is less than 25 minutes.

19. T of the composition max 16. The composition of claim 15, wherein the time is less than 20 minutes.

20. 16. The composition of claim 15, wherein the subject is free of respiratory depression for about 3 hours to about 16 hours after administration of the composition.

21. A pharmaceutical composition for intranasal use in treating opioid overdose or symptoms thereof in a subject, wherein the subject is a human; a) about 1 mg to about 4 mg of nalmefene, or a salt, hydrate, or solvate thereof; b) about 0.05 mg to about 2.5 mg of dodecyl maltoside; c) about 0.2 mg to about 1.2 mg sodium chloride; d) about 0.1 to about 0.5 mg of edetate disodium; e) about 0.005% (w / v) to about 1% (w / v) benzalkonium chloride; and f) water; Including, the pH of the composition is 4.0 to 5.0; The pharmaceutical composition comprises a final volume of about 50 μL to about 250 μL.

22. The composition comprises: a) approximately 3 mg of nalmefene hydrochloride; b) about 0.25 mg dodecyl maltoside; c) approximately 0.87 mg of sodium chloride; d) about 0.2 mg of edetate disodium; e) about 0.04% (w / v) benzalkonium chloride; and f) enough water for a total volume of approximately 100 μL; Including, 22. The composition of claim 21, wherein the composition is administered to a subject in a volume of about 100 μL.

Images