KR20210131996A - Compositions, devices and methods for the treatment of overdose and reward-based disorders - Google Patents

Abstract

A medicament suitable for nasal delivery comprising a device filled with a pharmaceutical composition comprising naltrexone is provided. Formulations and methods for treating alcohol use disorders and related conditions with pharmaceuticals are also provided.

Description

Compositions, devices and methods for the treatment of overdose and reward-based disorders

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is entitled to 35 U.S.C. Serial Nos. 62/782,943, filed December 20, 2018, and U.S. Serial Number 16/311,944, filed December 20, 2018. Claims priority under §119(e), the entire disclosure of all of which is hereby incorporated by reference into the disclosure of this application in its entirety. This application also incorporates by reference the disclosures of PCT Publication Nos. WO2017/223566 and WO2018/089709, as set forth herein in their entireties.

technical field

The present invention relates generally to pharmaceutical compositions, and more particularly to intranasal formulations comprising naltrexone and forms thereof, and opioid overdose ( opioid overdose) and its symptoms, and methods of its use in treating disorders such as alcohol use disorders.

Naltrexone was originally developed to treat opioid dependence due to its effect on blocking the euphoric effects of opioids. Naltrexone tablet formulations for oral administration have been used to treat opioid addiction since 1984. To improve compliance, a long-acting depot form of naltrexone administered once or more per month has been developed. Data from clinical trials have demonstrated that depot formulations are effective in reducing relapses to opioid use. Currently, there is an intramuscular sustained release formulation of naltrexone (Vivitrol ^{® ) for monthly administration and one oral formulation approved by the FDA.} These formulations aim to maintain a relatively steady state of naltrexone in an amount sufficient to always prevent naltrexone poisoning.

Opioid overdose is a related but somewhat different problem and a serious public health problem. In 2017, approximately 72,000 people died from drug overdose. Most of these, about 49,000, were opioid-related. More than 19,000 of these deaths were related to prescription opioid analgesics other than non-methadone compounds; Nearly 3,300 were associated with methadone; About 16,000 were related to heroin; Nearly 30,000 of these deaths were attributable to fentanyl and related synthetic opioids, a significant increase compared to the previous year. In addition, the number of deaths from opioid-related overdose in 2016 exceeded both the peak number of HIV and the peak number of gun-related deaths, and has increased dramatically over the past nine years. There remains a need for effective treatments to reverse opioid overdose.

On the other hand, there also remains a need for treatment of "reward-based" disorders, which often involve opioids or other abused substances such as alcohol, but stimulate the brain's centers of pleasure, reward and reinforcement and It is often accompanied by an unhealthy overdose of a substance or other activity that leads to involvement in their behavior.

For example, alcohol can stimulate the brain's reward circuitry, and it can intensify continued drinking of alcohol. Problem drinking, which becomes severe enough, results in a medical diagnosis of alcohol use disorder (AUD). In 2014, approximately 6.8% (16.3 million adults) in the United States over the age of 18 had an AUD. This includes 10.6 million men and 5.7 million women. Also, in 2014, an estimated 679,000 young people aged 12-17 years (2.7% of this age group) had AUD. In 2012, 3.3 million deaths, or 5.9% of deaths worldwide (7.6% of men and 4.0% of women) were attributed to alcohol consumption (WHO global Status Report on alcohol and Health, 2014).

To be diagnosed with AUD in the United States, an individual must meet certain criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM). For example, in the 5th edition of the DSM, an individual who meets 2 of 11 criteria during the same 12-month period is diagnosed with AUD. The severity of AUD (mild, moderate, or severe) is based on the number of criteria met. In Europe, individuals are screened using the Alcohol Use Disorders Identification Test (AUDIT). Individuals with AUD may drink heavily and, as a result, endanger both themselves and others.

Alcohol abuse is a drinking pattern with significant and recurrent adverse effects. Alcohol abusers may be unable to fulfill their primary school, work, or family obligations. Individuals with alcoholism (also known as alcoholism) lose reliable control of their alcohol use and may not be able to stop once they start drinking. Alcohol dependence is characterized by tolerance (the need to drink more to achieve the same "height"), and withdrawal symptoms when drinking is abruptly stopped. Withdrawal symptoms include vomiting, sweating, restlessness, nervousness, tremors, hallucinations and convulsions.

Problematic drinking has multiple causes, and genetic, physiological, psychological and social factors all play a role. Not all individuals are equally affected by each cause. For some with AUD, psychological characteristics such as behavioral behavior, low self-esteem, and the need for approval promote inappropriate drinking. Due to genetic factors, some individuals are particularly vulnerable to alcoholism. AUD can cause physiological changes that increase drinking, which is the only way to avoid discomfort, and individuals with AUD can drink partially to alleviate or avoid withdrawal symptoms.

Individuals with disabilities associated with reward-based behaviors, such as AUD, may request counseling and psychotherapy from a health care professional, such as a physician, dietitian, psychiatrist, psychological or clinical social worker, or by attending a 12-step alcohol anonymous meeting. can However, for a variety of reasons, access to, acceptance and success of these resources may be limited.

Significant resistance to the use of drugs for the treatment of disorders related to reward-based behavior, such as AUD, persists, and current evidence indicates that drugs are not sufficiently used in the treatment of AUD. In Europe, oral nalmefene has been approved and can be taken by patients while drinking. However, as of January 2015, disulfiram, acamprosate and oral or sustained release injectable naltrexone are the only drugs approved by the US Food and Drug Administration, particularly for the treatment of AUD. However, all of these drugs should be taken in patients who are able to abstain from alcohol or who have completed alcohol withdrawal prior to initiation of treatment. Accordingly, there is still a need for medications to treat AUD subjects who are drinking alcohol.

Non-drug reward-based disorders manifest in psychological and behavioral patterns similar to substance use disorders. Specifically, cravings, impaired control of behavior, tolerance, withdrawal, and high rates of relapse can be found in subjects suffering from addictive behaviors that adversely affect an individual's physical, mental, social or economic well-being. [See, eg, Marks, 1990; Lejoyeux et al, 2000; National Institute on Drug Abuse (NIDA) et al, 2002; Potenza, 2006; and Olsen, 2011]. Drug and non-drug rewards also exhibit the same physiological symptoms. For example, human brain function imaging studies have been conducted in gambling [Breiter et al, 2001], shopping [Knutson et al, 2007], orgasm [Komisaruk et al, 2004], playing video games [ See: Koepp et al, 1998; Hoeft et al, 2008] and the sight of appetizing food (Wang et al, 2004) have been found to activate many of the same brain regions (ie, mesocortical limbic system and dilated amygdala) as drugs of abuse.

An intranasal (IN) formulation of naltrexone has the potential to be used to reverse opioid overdose and to treat reward-based disorders without the use of needle or sustained release formulations. Opioid antagonists, such as naltrexone, administered orally or by injection, have been shown to be able to reverse opioid overdose and reduce alcohol consumption and responsive operants, although studies have shown that treating these conditions There remains a real need for a simple, quick and compliant means to do so.

Disclosed herein is an intranasal formulation comprising an aqueous solution comprising naltrexone or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a compensation-based disorder, such as an opioid overdose or alcohol use disorder (AUD), in a subject comprising administering to the subject an IN formulation comprising a therapeutically effective amount of naltrexone or a pharmaceutically acceptable salt thereof. A method of treatment is disclosed.

Also disclosed herein is nasal delivery of a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutical formulation disclosed herein to a subject experiencing an opioid overdose or having a reward-based disorder, such as an alcohol use disorder (AUD). Apparatus suitable for this is disclosed. In certain embodiments, the device is pre-primed. In certain embodiments, the device may be primed prior to use. In certain embodiments, the device is a single-dose device. In certain embodiments, the device is a multi-dose device.

1 shows the mean naltrexone plasma concentration versus time profile following administration of Test Article 1, Test Article 2, Test Article 3 and Reference Article on a linear scale up to 12 hours.
Figure 2 shows the mean naltrexone plasma concentration versus time profile after dosing of Test Article 1, Test Article 2, Test Article 3 and Reference Article on a fly logarithmic scale for up to 12 hours.
3 shows mean 6β-naltrexol (major naltrexone metabolite) plasma concentration versus time (cleavage at 12 hours) following administration of Test Article 1, Test Article 2, Test Article 3 and Reference Article on a linear scale up to 12 hours. ) indicates the profile.
Figure 4 shows mean 6β-naltrexol (major naltrexone metabolite) plasma concentration versus time (at 12 hours) following administration of Test Article 1, Test Article 2, Test Article 3 and Reference Article on a logarithmic scale up to 12 hours. cut) profile.

The following embodiments further illustrate the invention disclosed herein.

Provided herein is an intranasal formulation comprising Embodiment 1 : an aqueous solution comprising from about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof.

Also disclosed herein is Embodiment 2 : an aqueous solution comprising from about 10 mg/mL to about 40 mg/mL (preferably from about 10 mg/mL to about 30 mg/mL) of naltrexone or a pharmaceutically acceptable salt thereof to about 50 to about An intranasal formulation is provided, comprising a volume of 250 μL (preferably about 50 to 150 μL).

The present disclosure also provides the following embodiments.

Embodiment 3 : The method according to embodiment 1 or 2,

isotonicity agents;

preservatives;

stabilizers;

absorption enhancers; and

Sufficient amount of water to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL)

Further comprising a, formulation.

Embodiment 4 : The method according to Embodiment 3,

about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;

about 0.1 mg to about 1.2 mg of an isotonic agent;

about 0.001 mg to about 0.1 mg of a preservative;

about 0.1 mg to about 0.5 mg of a stabilizer;

about 0.05 mg to about 2.5 mg of an absorption enhancer; and

Sufficient amount of water to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL)

A formulation comprising a.

Embodiment 5 : The method according to Embodiment 3,

about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;

from about 0.1% to about 1.2% of an isotonic agent;

from about 0.001% to about 0.1% of a preservative;

from about 0.1% to about 0.5% of a stabilizer;

about 0.05% to about 2.5% absorption enhancer

A formulation comprising a.

Embodiment 6 : according to embodiment 4 or 5,

the isotonicity agent is NaCl;

the preservative is benzalkonium chloride;

the stabilizing agent is disodium edetate;

wherein the absorption enhancer is an alkylsaccharide.

Embodiment 7 : The formulation of embodiment 6, wherein the alkylsaccharide is dodecyl maltoside.

Embodiment 8 : The method according to embodiment 7,

about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;

about 0.1 mg to about 1.2 mg of NaCl;

from about 0.001 mg to about 0.1 mg of benzalkonium chloride;

about 0.15 mg to about 0.5 mg of disodium edetate;

from about 0.05 mg to about 2.5 mg of dodecyl maltoside; and

Sufficient amount of water to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL)

A formulation comprising a.

Embodiment 9 : The formulation of embodiment 8, comprising from about 0.1 mg to about 0.5 mg of dodecyl maltoside.

Embodiment 10 : The formulation of embodiment 9, comprising about 0.25 mg of dodecyl maltoside.

Embodiment 11 : The formulation of embodiment 8, comprising about 0.2 mg to about 0.3 mg of disodium edetate.

Embodiment 12 : The method according to embodiment 9,

about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;

about 0.3 mg to about 0.7 mg of NaCl;

about 0.02 mg of benzalkonium chloride;

about 0.3 mg of disodium edetate;

about 0.25 mg of dodecyl maltoside; and

Sufficient amount of water to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL)

A formulation comprising a.

Embodiment 13 The formulation of embodiment 10, wherein the amount of water is sufficient to achieve a final volume of about 80 to about 120 μL.

Embodiment 14 : The formulation of embodiment 11, wherein the amount of water is sufficient to achieve a final volume of about 100 μL.

Embodiment 15 : The method according to embodiment 7,

about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;

about 0.1% to about 1.2% NaCl;

from about 0.001% to about 0.1% benzalkonium chloride;

about 0.15% to about 0.5% disodium edetate;

from about 0.05% to about 2.5% dodecyl maltoside; and

water

A formulation comprising a.

Embodiment 16 : The formulation of embodiment 15, comprising from about 0.1% to about 0.5% dodecyl maltoside.

Embodiment 17 : The formulation of embodiment 16, comprising about 0.25% dodecyl maltoside.

Embodiment 18 : The formulation of embodiment 15, comprising from about 0.2% to about 0.3% disodium edetate.

Embodiment 19 : The method according to embodiment 17,

about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;

about 0.3% to about 0.7% NaCl;

about 0.02% benzalkonium chloride;

about 0.3% disodium edetate;

about 0.25% dodecyl maltoside; and

water

A formulation comprising a.

Embodiment 20 The formulation of embodiment 19, wherein the amount of water is sufficient to achieve a final volume of about 50 to about 150 μL.

Embodiment 21 The formulation of embodiment 20, wherein the amount of water is sufficient to achieve a final volume of about 100 μL.

Embodiment 22 : The formulation according to any one of embodiments 1-21, wherein the naltrexone is naltrexone hydrochloride.

Embodiment 23 : The formulation of embodiment 22, comprising about 1.2 mg, about 1.6 mg, about 2.0 mg or about 3.0 mg of naltrexone or an equivalent amount of naltrexone hydrochloride.

Also disclosed herein is embodiment 24 : an opioid overdose or compensation basis in a subject comprising administering to the subject an intranasal formulation comprising an aqueous solution comprising about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof. A method of treating a disorder is provided.

Also disclosed herein is Embodiment 25 : administering to a subject a first intranasal formulation comprising an aqueous solution comprising about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof; and a second intranasal formulation comprising an aqueous solution comprising about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof. .

Also disclosed herein is Embodiment 26 : an aqueous solution comprising from about 10 mg/mL to about 40 mg/mL (preferably from about 10 mg/mL to about 30 mg/mL) of naltrexone or a pharmaceutically acceptable salt thereof to about 50 to about A method of treating an opioid overdose or compensation based disorder in a subject is provided comprising administering to the subject an intranasal formulation comprising a volume of 250 μL (preferably about 50 to about 150 μL).

Also disclosed herein is Embodiment 27 : a first intranasal formulation comprising an aqueous solution comprising from about 10 mg/mL to about 40 mg/mL of naltrexone or a pharmaceutically acceptable salt thereof, in a volume of about 50 to about 250 ul, to the subject. and administering a second intranasal formulation comprising an aqueous solution comprising about 10 mg/mL to about 40 mg/mL of naltrexone or a pharmaceutically acceptable salt thereof in a volume of about 50 to about 250 μL, A method of treating an opioid overdose or a reward-based disorder in a subject is provided.

Embodiment 28 : The method of embodiment 25 or 27, wherein the second intranasal formulation is administered between about 1 hour and about 3 hours after administration of the first intranasal formulation.

Embodiment 29 : The intranasal formulation of any one of embodiments 24-28, wherein

isotonic agents;

preservatives;

stabilizers;

absorption enhancers; and

Sufficient amount of water to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL)

Further comprising a, method.

Embodiment 30 : The method of embodiment 29, wherein the intranasal formulation comprises

about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;

about 0.1 mg to about 1.2 mg of an isotonic agent;

about 0.001 mg to about 0.1 mg of a preservative;

about 0.1 mg to about 0.5 mg of a stabilizer;

about 0.05 mg to about 2.5 mg of an absorption enhancer; and

Sufficient amount of water to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL)

A method comprising

Embodiment 31 : The method of embodiment 29, wherein said intranasal formulation comprises

about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;

from about 0.1% to about 1.2% of an isotonic agent;

from about 0.001% to about 0.1% of a preservative;

from about 0.1% to about 0.5% of a stabilizer;

about 0.05% to about 2.5% absorption enhancer

A method comprising

Embodiment 32 : The method according to embodiment 30 or 31,

the isotonicity agent is NaCl;

the preservative is benzalkonium chloride;

the stabilizing agent is disodium edetate;

wherein the absorption enhancer is an alkylsaccharide.

Embodiment 33 : The method of embodiment 32, wherein the alkylsaccharide is dodecyl maltoside.

Embodiment 34 : The intranasal formulation of embodiment 33, wherein

about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;

about 0.1 mg to about 1.2 mg of NaCl;

from about 0.001 mg to about 0.1 mg of benzalkonium chloride;

about 0.15 mg to about 0.5 mg of disodium edetate;

from about 0.05 mg to about 2.5 mg of dodecyl maltoside; and

Sufficient amount of water to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL)

A method comprising

Embodiment 35 : The method of embodiment 34, wherein the intranasal formulation comprises from about 0.1 mg to about 0.5 mg of dodecyl maltoside.

Embodiment 36 The method of embodiment 35, wherein the intranasal formulation comprises about 0.25 mg of dodecyl maltoside.

Embodiment 37 The method of embodiment 34, wherein the intranasal formulation comprises about 0.2 mg to about 0.3 mg of disodium edetate.

Embodiment 38 : The method of embodiment 36, wherein the intranasal formulation comprises

about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;

about 0.3 mg to about 0.7 mg of NaCl;

about 0.02 mg of benzalkonium chloride;

about 0.3 mg of disodium edetate;

about 0.25 mg of dodecyl maltoside; and

Sufficient amount of water to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL)

A method comprising

Embodiment 39 The method of embodiment 38, wherein the amount of water is sufficient to achieve a final volume of about 50 to about 150 μL.

Embodiment 40 : The method of embodiment 39, wherein the amount of water is sufficient to achieve a final volume of about 100 μL.

Embodiment 41 : The method according to embodiment 33,

about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;

about 0.1% to about 1.2% NaCl;

from about 0.001% to about 0.1% benzalkonium chloride;

about 0.1% to about 0.5% disodium edetate;

from about 0.05% to about 2.5% dodecyl maltoside; and

water

A method comprising

Embodiment 42 : The method of embodiment 41, wherein the intranasal formulation comprises from about 0.1% to about 0.5% dodecyl maltoside.

Embodiment 43 The method of embodiment 42, wherein the intranasal formulation comprises about 0.25% dodecyl maltoside.

Embodiment 44 : The method of embodiment 41, wherein the intranasal formulation comprises from about 0.2% to about 0.3% disodium edetate.

Embodiment 45 : The method of embodiment 43, wherein said intranasal formulation comprises

about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;

about 0.3% to about 0.7% NaCl;

about 0.02% benzalkonium chloride;

about 0.3% disodium edetate;

about 0.25% dodecyl maltoside; and

water

A method comprising

Embodiment 46 The method of embodiment 45, wherein the amount of water is sufficient to achieve a final volume of about 50 to about 150 μL.

Embodiment 47 The method of embodiment 46, wherein the amount of water is sufficient to achieve a final volume of about 100 μL.

Embodiment 48 : The method according to any one of embodiments 24-47, wherein the naltrexone is naltrexone hydrochloride.

Embodiment 49 : The method of embodiment 48, wherein the intranasal formulation comprises about 1.2 mg, about 1.6 mg, about 2.0 mg or about 3.0 mg of naltrexone or an equivalent amount of naltrexone hydrochloride.

Embodiment 50 : The method of any one of embodiments 24-49, wherein the method treats an opioid overdose.

Embodiment 51 : The method according to any one of embodiments 24-49, wherein the method treats a reward based disorder.

Embodiment 52 : The method of embodiment 48, wherein the reward-based disorder is a substance use disorder.

Embodiment 53 : The method according to embodiment 48, wherein the substance use disorder is an alcohol use disorder.

Embodiment 54 : The method of embodiment 53, wherein the intranasal formulation comprising naltrexone is administered prior to ingestion of the alcohol.

Embodiment 55 The method of embodiment 54, wherein the intranasal formulation comprising naltrexone is administered about 1-2 hours prior to ingestion of the alcohol.

Embodiment 56 : The method of embodiment 54, wherein the intranasal formulation comprising naltrexone is administered about 0.5 to about 1 hour prior to ingestion of the alcohol.

Embodiment 57 : The method of embodiment 54, wherein the intranasal formulation comprising naltrexone is administered about 10 to about 30 minutes prior to ingestion of the alcohol.

Embodiment 58 : The method of embodiment 54, wherein the intranasal formulation comprising naltrexone is administered about 5 to about 10 minutes prior to ingestion of the alcohol.

Embodiment 59 : The method of embodiment 53, wherein the intranasal formulation comprising naltrexone is administered concurrently with alcohol intake.

Embodiment 57 : The method of embodiment 53, wherein the intranasal formulation comprising naltrexone is administered within 0.5 hours of initiation of alcohol intake.

Embodiment 58 : The method of any one of embodiments 24-57, wherein the intranasal formulation comprising naltrexone is administered to the subject 1-4 times a day.

Embodiment 59 : The method of embodiment 58, wherein the intranasal formulation comprising naltrexone is administered per day at a dose of about 1.2 mg, about 1.6 mg, about 2 mg, or about 3 mg according to the need of the subject.

Embodiment 60 : The method of embodiment 58, wherein the intranasal formulation comprising naltrexone is administered as a first dose of about 1.2 mg, about 1.6 mg, about 2 mg or about 3 mg in the morning, and about 1.2 mg as needed prior to alcohol consumption. mg, about 1.6 mg, about 2 mg or about 3 mg as a subsequent dose.

Also disclosed herein is embodiment 61 : administering a pharmaceutical formulation to a subject experiencing an opioid overdose or having a reward-based disorder comprising a plurality of doses each comprising the intranasal formulation described in any one of embodiments 1 to 23. A multi-dose device suitable for nasal delivery is provided.

Embodiment 62 : The device of embodiment 61, wherein about 0.5 to about 0.2 mL (preferably about 0.05 to about 0.15 mL) of said formulation is delivered to the subject in each dose.

Embodiment 63 The device of embodiment 62, wherein about 0.1 mL of the formulation is delivered to the subject in each dose.

Also disclosed herein is Embodiment 64 : the formulation, method or device described in any one of the preceding embodiments, comprising:

"when it comprises about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof", the included amount is about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;

When the method states "comprising about 10 mg/mL to about 40 mg/mL (preferably about 10 mg/mL to about 30 mg/mL) of naltrexone or a pharmaceutically acceptable salt thereof," the included concentrations are A formulation, method, or device, wherein the formulation, method or device is about 30 mg/mL of naltrexone or a pharmaceutically acceptable salt thereof.

Embodiment 64 Also provided herein is a formulation selected from those described in the Examples disclosed herein.

Also provided are embodiments in which any of the above embodiments can be combined with any one or more of these embodiments, provided that the combinations are not mutually exclusive.

Justice

As used herein, the following terms have the meanings given.

Where numerical ranges are disclosed, unless otherwise specified, such designations are intended to include the numbers themselves and ranges therebetween. This range can be an integer or continuous between end values. For example, a range of “2 to 6 doses” is intended to include 2, 3, 4, 5, and 6 doses, as doses are in integer units. For example, a range “1 to 3 μM (micrometers)”, which is intended to include 1 μM, 3 μM, and everything in between, is compared to any number of significant figures (eg, 1.255 μM, 2.1 μM, 2.9999 μM, etc.) do.

The term “about,” as used herein, is intended to limit the numerical value it modifies, which expresses such value as a variable within a range. Unless a specific range is stated, such as a tolerance or standard deviation for a mean value provided in a chart or table of data, the term "about" means the range encompassing the recited number and, taking into account significant numbers, also that value. It is to be understood that by rounding off or rounding off it is to be understood to mean the greater of the range covered, the range shall include ±20% of the stated value.

As used herein, the term “absorption enhancer” refers to a functional excipient included in a formulation to improve absorption of a pharmacologically active drug. This term usually refers to formulations that function to increase absorption by enhancing membrane permeability, rather than increasing solubility. As such, these agents are sometimes referred to as penetration enhancers. Examples of absorption enhancers include aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoylcarnitine, dodecyl maltoside, EDTA, glycocholine acid, glycodeoxycholic acid, glycofurol, glycosylated sphingosine, glycyrrhetic 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, quiraya saponin, salicylic acid, sodium salt, β-sitosterol- β-D-glucoside, sucrose cocoyl, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid and tetradecyl maltoside. Alkylsaccharides (e.g., nonionic alkylsaccharide surfactants such as alkylglycosides and sucrose esters of fatty acids consisting of aliphatic hydrocarbon chains each linked to a sugar moiety by glycoside or ester bonds), cyclodextrins (hydrophobic molecules) Cyclic oligosaccharides composed of 6 or more monosaccharide units with a central cavity forming a complex with the cyclic oligosaccharides, which have been mainly used to increase the solubility and solubility of drugs and enhance absorption of low-molecular-weight drugs), chitosanthin (desorption of chitin) Linear cationic polysaccharides resulting from acetylation), and bile salts and their derivatives (e.g., sodium glycocholate, sodium taurocholate and sodium taurodihydrofusidate), tend to be the most acceptable absorption enhancers among them. There are [see, eg, Aungst, AAPS Journal 14(1):10-8, 2011; Maggio, J. Excipients and Food Chem. 5(2):100-12, 2014].

As used herein, the term "addiction" refers to a medical condition characterized by compulsory involvement in reward stimuli, despite deleterious consequences. As used herein, the term “addictive behavior” refers to behavior that is both reward and reinforcement.

As used herein, the term “agonist” refers to a moiety that interacts with a receptor and thereby initiates a physiological or pharmacological response characteristic of that receptor. The term “antagonist,” as used herein, refers to competitively binding to a receptor at the same site as an agonist (eg, an endogenous ligand), but does not activate an intracellular response initiated by the active form of the receptor, thereby resulting in an agonist or partial agonist. refers to a moiety capable of inhibiting an intracellular response by Antagonists do not reduce the baseline intracellular response in the absence of an agonist or partial agonist. The term “inverse agonist” refers to an endogenous form of a receptor or constitutively activated form of a receptor, which binds to the baseline intracellular response initiated by the activated form of the agonist receptor, with the activity observed in the absence of the agonist or partial agonist. refers to a moiety that inhibits below the usual baseline level.

The term "alcohol use disorder" refers to the criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders in the United States (DSM, the most recent revision, now DSM-V), or the World Health Organization's ICD (International Standards of Diseases and Related Health Problems) It is defined by the same criteria set out in the corresponding widely accepted criteria of Statistical Classification, the most recent revision, now ICD-10). Related terms and disorders include “alcohol abuse” and “alcohol dependence” (as used in DSM-IV), “adverse alcohol use” and “alcohol dependence syndrome” (as used in ICD-10), and alcoholism.

As used herein, the term “antibacterial preservative” refers to a pharmaceutically acceptable excipient having antibacterial properties that is added to a pharmaceutical composition to maintain microbiological stability. The compound functions as both a preservative and a stabilizer.

As used herein, the term “disease” refers to an abnormal state of the body or part thereof, which all of which impair normal function, and is usually manifested by distinguishing signs and symptoms, and is a measure of the survival period or life of the human body or animal. In the sense of diminishing quality, the terms "disease", "syndrome" and "condition" (such as a medical condition) are intended to be generally synonymous and are used interchangeably.

The term "pharmaceutical composition" is used herein interchangeably with the term "pharmaceutical formulation" or merely "formulation" and is an active pharmaceutical ingredient (i.e., drug substance) in combination with at least one pharmaceutically acceptable excipient or carrier. indicates

The term “equivalent,” as used herein, refers to the weight of the opioid antagonist naltrexone and its pharmaceutically acceptable salts that are equimolar to a specified weight of naltrexone hydrochloride.

As used herein, the term "excipient" includes for the purpose of imparting a therapeutic enhancement to the active ingredient in the final dosage form, such as long-term stabilization, bulking of solid dosage forms, or facilitation of drug absorption, lowering of viscosity or improving solubility. It refers to a natural or synthetic substance that is formulated with the active ingredient of a medicament.

As used herein, the term “therapeutically effective dose” refers to a dose effective to treat a disease, to reduce one or more observable symptoms of a disease, or to delay or alleviate the onset or progression of symptoms of a more serious condition. , which often continues after the condition the patient is currently experiencing. A therapeutically effective dose may, but need not, completely eliminate all symptoms of the disease.

The terms "in need of treatment" and the term "in need of" when referring to treatment are used interchangeably and are caregivers (e.g., doctors, nurses, practicing nurses, ) for reference.

As used herein, two embodiments are "mutually exclusive" when one is defined as different from the other. For example, an embodiment in which the amount of naltrexone hydrochloride is designated as 3 mg is mutually exclusive with an embodiment in which the amount of naltrexone hydrochloride is designated as 2 mg. However, embodiments in which the amount of naltrexone hydrochloride is designated as 4 mg are not mutually exclusive with embodiments in which less than about 10% of the pharmaceutical composition is excreted from the nasal cavity through drainage into the nasopharynx or externally.

As used herein, the term "naloxone" refers to a compound of the structure:

or a pharmaceutically acceptable salt, hydrate or solvate thereof. The CAS registration 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; 4,5a-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one; and (-)-12-allyl-7,7a,8,9-tetrahydro-3,7a-dihydroxy-4aH-8,9c-iminoethanophenanthro[4,5-bcd]furan-5 (6H)-ones. Naloxone hydrochloride can be anhydrous (CAS Registry No. 357-08-4) and also forms dihydrates (CAS Registry No. 51481-60-8). It is sold under various brand names including ^{Narcan ®} , Nalone ^® , Nalossone ^® , Naloxona ^® , Naloxonum ^® , Narcanti ^® and Narcon ^{® .}

As used herein, the term “naltrexone” refers to a compound of the structure:

or a pharmaceutically acceptable salt, hydrate or solvate thereof. The CAS registration 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. The term “naltrexone” includes “naltrexone hydrochloride”. It is sold under the trade names ^{Antaxone ®} , Depade ^® , Nalorex ^® , Revia ^® , Trexan ^® , Vivitrex ^® and Vivitrol ^{® .}

As used herein, the term “methylnaltrexone” refers to the cation (5α)-17-(cyclopropylmethyl)-3,14-dihydroxy-17-methyl-4,5-epoxymorpholin-17-ium-6-one , refers to a pharmaceutically acceptable salt comprising a compound of the structure:

In the above formula, X ⁻ is a pharmaceutically acceptable anion. Methylnaltrexone bromide (CAS registration number 75232-52-7) is marketed under the trade name Relistor ^® .

As used herein, the term “nalmefene” refers to 17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol, a compound of the structure:

refers to Nalmefene hydrochloride (CAS registration number 58895-64-0) is sold under the trade names Nalmetrene ^® , Cervene ^® , Revex ^® , Arthrene ^® and Incystene ^® .

As used herein, the term “nostril” is synonymous with “naris”.

The term “opioid antagonist” includes naloxone, methylnaltrexone and nalmefene and pharmaceutically acceptable salts thereof, in addition to naltrexone and pharmaceutically acceptable salts thereof. In certain embodiments, the opioid antagonist is naltrexone hydrochloride. In certain embodiments, the opioid antagonist is naloxone. In certain embodiments, the opioid antagonist is methylnaltrexone bromide. In certain embodiments, nasal administration is accomplished using a device described herein.

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 the opioid antagonist naltrexone, whereby the composition is a mammalian It is suitable for use for certain efficacious results in (eg, but not limited to, humans).

As used herein, the term “reinforcing stimulus” refers to a stimulus that increases the likelihood of repeating the behavior it is paired with.

As used herein, the term “stimulus” refers to a stimulus that the subject's brain interprets as being benign in nature, or approaching. Compensatory stimulation usually results in the release of dopamine in the subject's brain.

As used herein, a “reward-based disorder” is a disorder associated with reward-based behavior, wherein the user adds and/or engages in involvement in reward stimuli, despite deleterious consequences. Reward-based disorders include substance use disorders such as alcohol use disorders, addictions, and disorders of behavioral involvement such as gambling disorders (compulsive gambling), eating disorders (bulimia, bulimia nervosa), kleptomania, arson.

As used herein, the term "subject" is intended to be synonymous with "patient" and is any mammal (preferably a mammal suffering from a condition that would benefit from treatment with a therapeutically effective amount of the opioid antagonist naltrexone or a salt thereof). person) refers to

The term “substance use disorder” refers to the criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders in the United States (DSM, the latest edition, now DSM-V), or the World Health Organization's International Statistical Classification of Disease and Related Health (ICD). Problems, the most recent revision, now defined by similar criteria set out in the corresponding widely accepted criteria of ICD-10). Related terms and disorders include “substance abuse” and “substance dependence” (as used in DSM-IV). Substance use disorders occur when the repeated use of alcohol and/or drugs causes significant clinical and functional impairment, such as health problems, disabilities, or failure to fulfill major responsibilities at work, school, or home. According to DSM-5, the diagnosis of substance use disorder is based on evidence of impaired control, social impairment, risky use, and pharmacological criteria. Substances that may be the focus of a substance use disorder include opioids, alcohol, tobacco, and other abused substances such as cannabinoids, stimulants such as cocaine and amphetamines, sedatives such as benzodiazepines, hallucinogens, and inhalants. Alcohol use disorder is a substance use disorder. A substance use disorder may be considered a “reward-based disorder.”

As used herein, the term “tonic agent” refers to a compound that modifies the osmotic pressure of a formulation, eg, to render it isotonic. Tonics include dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, and the like.

As used herein, "treat", "treatment", etc., means to reduce or eliminate one or more of its cause, its progression, its severity or its symptoms, or otherwise beneficially alter a subject's disease. to improve the disability.

As used herein, the term “AUC” refers to the area under the drug plasma concentration-time curve. As used herein, the term “AUC _0-t ” refers to the area under the drug plasma concentration-time curve from t=0 to the last measurable concentration. As used herein, the term "AUC _0-∞ " or "AUC _0-inf " refers to the area under the drug plasma concentration-time curve extrapolated to infinity (infinity).

As used herein, the term “bioavailability (F)” refers to the proportion of a dose of a drug that is absorbed from the site of administration and reaches the systemic circulation in an unaltered form. As used herein, the term “absolute bioavailability” is used when the fraction of absorbed drug is related to its IV bioavailability. It can be calculated using the formula:

The term relative bioavailability (F _rel ) is used to compare two different extravascular routes of drug administration and can be calculated using the formula:

As used herein, the term “clearance (CL)” refers to the rate at which a drug is cleared divided by its plasma concentration and provides the volume of plasma at which the drug is completely cleared per unit of time. CL is equal to the clearance rate constant (λ) _{multiplied by the volume of distribution (V d} ), where “V _d ” is the volume of fluid required to contain the amount of drug present in the body at the same concentration as plasma. As used herein, the term “appearance clearance (CL/F)” refers to clearance that does not take into account the bioavailability of a drug. It is the ratio of dose to AUC.

As used herein, the term “C _max ” refers to the maximum observed plasma concentration.

As used herein, the term “t _1/2 ” or “half-life” refers to the amount of time required for half of a drug to be eliminated from the body or for the concentration of a drug to drop by half.

As used herein, the term “coefficient of variation (CV)” refers to the ratio of the standard deviation of a sample to the sample mean. It is often expressed as a percentage.

As used herein, the term “confidence interval” refers to a range of values that includes the true mean value of a parameter at a specified percentage of time.

As used herein, the term “clearance rate constant (λ)” refers to the rate of drug clearance from the body. This rate is constant in the first-order rate equation and is independent of the drug concentration in the body. λ is the slope of the plasma concentration-time line (logarithmic y scale). As used herein, the term “λ _z ” refers to the terminal phase clearance rate constant, and the “end phase” of the drug plasma concentration-time curve is a straight line when plotted as a partial logarithmic graph. Because the main mechanism for lowering drug concentrations during the terminal phase is the removal of the drug from the body, the terminal phase is often referred to as the "clearance phase". A distinguishing feature of the terminal clearance phase is that the relative proportion of drug in the plasma and the peripheral volume of distribution remain constant. Between these “end phases”, the drug returns to the plasma from the volume of rapid and delayed distribution and is permanently removed from the plasma by metabolism or renal excretion.

opioid antagonists

Opioid receptor antagonists are a well-recognized class of chemicals. These are described in detail in the scientific and patent literature. Naltrexone and its active metabolite 6β-naltrexol are opioid antagonists with no agonist properties at the μ-opioid receptor (MOR), κ-opioid receptor (KOR) and δ-opioid receptor (DOR). Naltrexone works by reversibly blocking opioid receptors, thereby attenuating the effects of opioids. Although its mechanism of action in alcoholism is not fully understood, without wishing to be bound by theory, it is unlikely that naltrexone modulates the dopaminergic midlimbic pathway (one of the major centers of risk-reward analysis in the brain, and the tertiary pleasure center). , which is thought to be the main center of reward associated with addiction, where all major drugs of abuse are thought to be activated. The mechanism of action may be antagonism against endogenous opiates such as tetrahydroparaberoline, the production of which is enhanced in the presence of alcohol.

Naltrexone is commercially available as the hydrochloride salt. Naltrexone hydrochloride (17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) is used to prevent the intoxicating effect in the treatment of patients with opioid poisoning. It significantly blocks physical dependence on intravenously administered opioids and can lead to withdrawal from opioid dependence, but patients do not develop tolerance or dependence on naltrexone. Naltrexone is also effective in reducing alcohol cravings in the treatment of alcoholism, especially when combined with psychosocial therapy.

When naltrexone is administered intranasally rather than orally, its bioavailability is significantly improved. When administered orally, naltrexone undergoes rapid and extensive first-pass metabolism to 6-β-naltrexol, despite almost complete absorption from the gastrointestinal tract. As a result, the amount of naltrexone that reaches the systemic circulation is limited. The oral bioavailability of naltrexone has been reported to be as low as 5% (Gonzalez and Brogden, Drugs 35:192-213, 1988). The study presented herein found that the oral bioavailability of naltrexone was similarly low, about 9%.

Provided herein are methods of treatment using nasal delivery of a pharmaceutical composition to a patient comprising a therapeutically effective amount of the opioid antagonist naltrexone. In certain embodiments, the therapeutically effective amount per dose is equivalent to about 1 to about 4 mg of naltrexone hydrochloride. In certain embodiments, a therapeutically effective amount is equivalent to about 1 to about 3 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount per dose is about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, About 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9 , or about 4.0 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount per dose is equivalent to about 1.2 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount per dose is equivalent to about 1.6 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount per dose is equivalent to about 2.0 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount per dose is equivalent to about 3.0 mg of naltrexone hydrochloride. In order to achieve a therapeutic effect, it may be administered several times in succession. In certain embodiments, the opioid antagonist is anhydrous naltrexone hydrochloride.

While many embodiments of the pharmaceutical compositions described herein are described and exemplified as naltrexone, other opioid antagonists may be adapted for nasal delivery based on the teachings herein. Indeed, it will be readily apparent to those skilled in the art from the teachings herein that the devices and pharmaceutical compositions described herein may be suitable for other opioid antagonists. Opioid receptor antagonists described herein include μ-opioid, κ-opioid and δ-opioid receptor antagonists. Examples of useful opioid receptor antagonists include naltrexone, naloxone, methylnaltrexone and nalmefene. Other useful opioid receptor antagonists are known in the art (eg, US Pat. No. 4,987,136).

pharmaceutical composition

Also provided are pharmaceutical compositions comprising the opioid antagonist naltrexone. In certain embodiments, the pharmaceutical composition comprises the opioid antagonist naltrexone and a pharmaceutically acceptable carrier. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. Some embodiments of the present invention include methods of preparing a pharmaceutical composition comprising admixing the opioid antagonist naltrexone and a pharmaceutically acceptable carrier. The pharmaceutical composition is applied directly to the nasal cavity using the device described herein. In the case of a spray, this can be achieved, for example, by means of a metered spray spray pump.

Liquid formulations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. Additional ingredients in the liquid formulation may include: antibacterial preservatives such as benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenyl ethyl alcohol and mixtures thereof; Polysorbate 80 NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monolaurate, polyoxy Ethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoiso Stearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate, etc. and mixtures thereof, etc. of surfactants; tonics such as dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, and the like, and mixtures thereof; and suspending agents such as microcrystalline cellulose, sodium carboxymethylcellulose NF, polyacrylic acid, magnesium aluminum silicate, xanthan gum, and the like and mixtures thereof.

Ideally, for the treatment of AUD, when an opioid antagonist is administered intranasally prior to ingestion of alcohol, the opioid antagonist is absorbed rapidly, i.e. within about 15-30 minutes, and/or at a maximum plasma concentration of about 25 to about 40 minutes ( T _max ). For example, in certain embodiments, the opioid antagonist is absorbed within the first 15 minutes after administration, and _{the time to maximum plasma concentration (T max} ) is 15 minutes or less. Alternatively, the opioid antagonist is absorbed within the first 30 minutes after administration, and the T _max is 40 minutes or less.

The use of absorption enhancers such as alkylsaccharides (also referred to herein as alkylglycosides), cyclodextrins, and chitosan can increase the rate at which naltrexone is absorbed and decrease the _{T max .} These absorption enhancers usually function by influencing the two main mechanisms of nasal absorption: intercellular transport through the openings of tight bonds between cells and transcellular transport or transexocytosis through cells by vesicle carriers. .

In various aspects, the alkylglycosides of the invention include, but are not limited to, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl- alkylglycosides such as , heptadecyl- and octadecyl-α- or β-D-maltoside, -glycoside or -sucroside; alkyl thioglucosides such as heptyl- or octyl 1-thio α- or β-D-glucopyranoside; alkyl thiosucrose; alkyl maltotriosides; long-chain aliphatic carbonic acid amides of sucrose α-amino acids-alkyl ethers; derivatives of palatinose and isomaltamine linked to an alkyl chain by an amide bond; derivatives of isomaltamine linked to the alkyl chain by urea; long-chain aliphatic ureido carbonates of sucrose β-amino-alkyl ethers; and long chain aliphatic carbonic acid amides of sucrose β-amino-alkyl ethers.

Thus, as described above, the hydrophobic alkyl may be selected from any desired size depending on the desired hydrophobicity and hydrophilicity of the saccharide moiety. For example, one preferred range for an alkyl chain is from about 9 to about 24 carbon atoms. Even more preferred ranges are from about 9 to about 16 or about 14 carbon atoms. Similarly, some preferred glycosides have an alkyl chain of 9, 10, 12, 13, 14, 16, 18, 20, 22 or 24 carbon atoms, such as nonyl-, decyl-, dodecyl- and tetra maltose, sucrose and glucose bound by glycosidic bonds to decyl sucrose, glucoside and maltoside, and the like. These compositions are non-toxic because they degrade into alcohols or fatty acids and oligosaccharides and are amphiphilic. Additionally, the linkage between the hydrophobic alkyl group and the hydrophilic saccharide may include, among other possibilities, glycoside, thioglycoside, amide, ureido or ester linkages.

As used herein, "saccharide" includes monosaccharides, oligosaccharides, or polysaccharides in straight or cyclic form, or combinations thereof, to form sugar chains. Oligosaccharides are sugars with two or more monosaccharide residues. Accordingly, examples of saccharides include glucose, maltose, maltotriose, maltotetraose, sucrose and trehalose.

In one embodiment, an exemplary alkylsaccharide is an alkylmaltoside. Alkylmaltosides are glycosides of the disaccharide maltose and alcohol. Typical alkylmaltosides are dodecylmaltoside, tetradecylmaltoside and hexadecylmaltoside, which consist of a straight chain alcohol of 12, 14 and 16 carbons, respectively, and glycosidically linked to maltose. In an exemplary embodiment, the alkylglycoside is tetradecylmaltoside.

For example, one alkyl saccharide is 1-On-dodecyl-β-D-maltopyranoside (or lauryl-β-D-maltopyranoside, dodecyl maltopyranoside, dodecyl malto side, Intravail ^® and DDM; referred to as _{C 24} H ₄₆ Q _{11 ).} Alkylsaccharides are used in commercial food and personal care products and have been designated as Generally Recognized as Safe (GRAS) substances for food applications. They are odorless, tasteless, nontoxic, non-mutagenic and non-irritating enhancers of transmucosal absorption that are sensitized in the Draize test at concentrations up to 25%. Alkylsaccharides increase uptake by increasing intercellular permeability, as indicated by a decrease in transepithelial electrical resistance, and they may also increase transexocytosis. The effect is short-lived. Other alkylsaccharides include tetradecyl maltoside (TDM) and sucrose dodecanoate.

In sugar chemistry, an anomer is either a sugar or one of a pair of cyclic stereoisomers (designated α or β) of a glycoside, only the configuration at the hemiacetal (or hemiketal) carbon, also called the anomeric carbon or reducing carbon. this is different A sugar is an alpha anomer if its structure resembles that of having a hydroxyl group on the anomeric carbon in the axial position of glucose. However, when that hydroxyl is equatorial, the sugar is a beta anomer. For example, the two cyclic forms of glucose, α-D-glucopyranose and β-D-glucopyranose, are anomers. Likewise, alkylglycosides occur as anomers. For example, dodecyl β-D-maltoside and dodecyl α-D-maltoside are two cyclic forms of dodecyl maltoside. Because two different anomers are two different chemical structures, they have different physical and chemical properties. In one aspect of the invention, the alkylglycosides of the invention are β-anomers. In an exemplary aspect, the alkylglycoside is the β anomer of an alkylmaltoside, such as tetradecyl-β-D-maltoside (TDM).

Thus, in one aspect of the invention, the alkylglycoside used is a substantially pure alkylglycoside. As used herein, "substantially pure" alkylglycosides are defined as less than about 2% other anomeric forms, preferably less than about 1.5% other comonomer forms, and more preferably less than about 1% other comonomer forms. Refers to one anomeric form (α or β anomeric form) of an alkylglycoside having an anomeric form. In one aspect, the substantially pure alkylglycoside contains greater than 98% either the α or β anomer. In another aspect, the substantially pure alkylglycoside contains greater than 99% of either the α or β anomer. In another aspect, the substantially pure alkylglycoside contains greater than 99.5% of either the α or β anomer. In another aspect, the substantially pure alkylglycoside contains greater than 99.9% of either the α or β anomer.

In certain embodiments, the intranasal formulation comprises from about 0.001% to about 5.0% by weight dodecyl maltoside. In certain embodiments, the intranasal formulation comprises from about 0.01% to about 2.5% dodecyl maltoside. In certain embodiments, the intranasal formulation comprises from about 0.05% to about 2.5% dodecyl maltoside. In certain embodiments, the intranasal formulation comprises from about 0.1% to about 0.5% dodecyl maltoside by weight. In certain embodiments, the intranasal formulation comprises from about 0.15% to about 0.35% dodecyl maltoside. In certain embodiments, the intranasal formulation comprises from about 0.15% to about 0.2% dodecyl maltoside by weight. In certain embodiments, the intranasal formulation comprises about 0.18% dodecyl maltoside. In certain embodiments, the intranasal formulation comprises from about 0.2% to about 0.3% dodecyl maltoside. In certain embodiments, the intranasal formulation comprises about 0.25% dodecyl maltoside.

When 0.18% dodecyl maltoside was added to the sumatriptan intranasal formulation, the maximal plasma concentration was increased almost 4-fold compared to the Imitrex nasal spray, and the T _max was decreased from 1-2 hours to 8-10 minutes. Total exposure as measured by immunization under the concentration-time curve (AUC) increased by 32%. The naltrexone intranasal formulation has the potential to be used to treat AUD without the use of a needle or sustained release formulation. Inclusion of dodecyl maltoside may improve pharmacokinetic parameters in some applications.

Some absorption enhancing excipients may alter intercellular and/or transcellular pathways, while others may prolong residence time in the nasal cavity or prevent metabolic changes. In the absence of an absorption enhancer, the molecular weight limit for nasal absorption is about 1 kDa, but administration of the drug in combination with an absorption enhancer may enable absorption of molecules of 1 to 30 kDa. However, intranasal administration of most absorption enhancers can cause damage to the nasal mucosa [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, dodecyl maltoside, EDTA, glycocholine Acid, glycidyloxycholic acid, glycofurol, glycosylated sphingosine, glycyrrhetic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroylcarnitine, lauryl sulfate , lysophosphatidylcholine, menthol, poloxamer 407, poloxamer F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol, Quillaja saponin, salicylic acid, β-cytosterol-β -D-glucoside, sucrose cocoate, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid and tetradecyl maltoside.

The opioid antagonist naltrexone described herein can be formulated into a pharmaceutical composition using techniques known in the art. Suitable pharmaceutically acceptable carriers other than those mentioned herein are known in the art.

The opioid antagonist naltrexone 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 acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, such as pharmaceutically acceptable salts listed in Berge et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977); Citric acid, ethenesulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethioic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the like. Acid addition salts can be obtained as direct products of compound synthesis. Alternatively, the salt may be isolated by dissolving the free base in a suitable solvent containing a suitable acid and evaporating the solvent or otherwise separating the salt and solvent. The opioid antagonist naltrexone described herein can form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

Accordingly, provided herein is a pharmaceutical formulation for intranasal administration comprising naltrexone or a salt thereof, such as naltrexone hydrochloride. In certain embodiments, the formulation is an aqueous solution. In certain embodiments, the formulation comprises from about 25 to about 200 μL of an aqueous solution per dose. In certain embodiments, the formulation comprises from about 50 to about 200 μL of an aqueous solution per dose. In certain embodiments, the formulation comprises no more than about 140 μL per dose. In certain embodiments, the formulation comprises no more than about 100 μL per dose.

In certain embodiments, the formulation comprises from about 1% (w/w) to about 4% (w/w) naltrexone hydrochloride. In certain embodiments, the formulation comprises from about 1% (w/w) to about 3% (w/w) naltrexone hydrochloride. In certain embodiments, the dosage form is about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9 or about 4.0% (w/w) naltrexone hydrochloride. In certain embodiments, the formulation comprises about 1.2% (w/w) naltrexone hydrochloride. In certain embodiments, the formulation comprises about 1.6% (w/w) naltrexone hydrochloride. In certain embodiments, the formulation comprises about 2% (w/w) naltrexone hydrochloride. In certain embodiments, the formulation comprises about 3% (w/w) naltrexone hydrochloride.

In certain embodiments, the formulation comprises about 1 mg to about 4 mg of naltrexone hydrochloride. In certain embodiments, the formulation comprises from about 1 mg to about 3 mg of naltrexone hydrochloride. In certain embodiments, the formulation comprises about 2 mg to about 4 mg of naltrexone hydrochloride. In certain embodiments, the dosage form is about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0 mg of naltrexone hydrochloride. In certain embodiments, the formulation comprises about 1.2 mg of naltrexone hydrochloride. In certain embodiments, the formulation comprises about 1.6 mg of naltrexone hydrochloride. In certain embodiments, the formulation comprises about 2 mg of naltrexone hydrochloride. In certain embodiments, the formulation comprises about 3 mg of naltrexone hydrochloride.

Aqueous formulations for intranasal administration disclosed herein are also pharmaceutically acceptable, such as one or more isotonic agents, one or more preservatives, one or more stabilizing agents, one or more absorption enhancers, and one or more agents for adjusting the pH or buffering agent of the solution. It may contain excipients.

In certain embodiments, the intranasal formulation further comprises an isotonic agent, eg, sodium chloride (NaCl).

In certain embodiments, the intranasal formulation further comprises a compound that is a preservative and/or a surfactant.

In certain embodiments, preservatives and/or surfactants include benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenyl ethyl alcohol; Polysorbate 80 NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxy Ethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoiso from stearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate, and the like, and mixtures thereof; is chosen

In certain embodiments, the intranasal formulation further comprises a stabilizing agent.

In certain embodiments, the stabilizing agent is disodium edetate (EDTA).

In certain embodiments, the pharmaceutical composition is in about 100 μL of an aqueous solution.

In certain embodiments, upon nasal delivery of the pharmaceutical composition to the patient, less than about 10% of the pharmaceutical composition is released from the nasal cavity through the nasopharynx or external drainage.

Nasal drug delivery devices and kits

Also provided is a pharmaceutical composition in a device suitable for nasal delivery to a subject suffering from AUD comprising a therapeutically effective amount of the opioid antagonist naltrexone or a pharmaceutically acceptable salt thereof. In certain embodiments, the device is pre-primed. In certain embodiments, the device may be primed prior to use. In certain embodiments, the device can be operated with one hand.

Nasal delivery is considered an attractive route for systemic drug delivery, especially when rapid absorption and effectiveness are desired. In addition, nasal delivery may help to solve problems related to unpleasant taste, poor bioavailability, slow absorption, drug degradation, adverse events in the gastrointestinal tract (AEs), first-pass metabolism and long-term oral naltrexone use. Avoid associated liver toxicity.

Liquid intranasal formulations are primarily aqueous solutions, but suspensions and emulsions may also be delivered.

Some emergency medical services (EMS) programs have developed systems for intranasal administration of the opioid antagonist naloxone, using existing medical devices and existing technology for approved drugs, although not in a manner not approved by the FDA. This is accomplished by using an injectable formulation (1 mg/mL) and administering 1 mL into the nostril via a commercially available nasal nebulizer/nebulizer device. This system combines an FDA-approved naloxone injection product (Luer fitted tip, no needle) with a commercially available medical device called a mucosal spray device (MAD™ Nasal, Wolfe Tory medical, Inc.). This initiative is consistent with the US Needlestick Safety Prevention Act (Public Law 106-430). EMS programs are aware of the limitations of these systems, and one limitation is that they cannot be used immediately without being assembled. This mode of administration appears to be effective in reversing narcissism, but the formulation is not concentrated for intranasal retention. The delivery volume of 1 mL per nostril is more than the amount normally used for intranasal drug administration. Thus, drug is lost from the nasal passages due to drainage into the nasopharynx or drainage out of the nasal passages. The device described herein is a ready-to-use improved product that has been specifically optimized, concentrated, and formulated for nasal delivery.

Metered spray pumps have dominated the nasal drug delivery market since their introduction. Pumps typically deliver 100 μL (or other volumes ranging from 25 to 200 μL or greater) per spray, and they provide high reproducibility of the emitted dose and plume geometry in in vitro tests.

Examples of standard metered spray pumps include those provided by Aptar Pharma, Inc, such as the multi-dose "Classic Technology Platform" nasal spray device. Such devices include a reservoir holding a nasal spray formulation (e.g., 50, 100, 150, 200, 60, or 120 doses), a closure (e.g., screw, crimp or snap-on), and a single dose. To construct, include actuators that deliver between 45 and 1000 μL (eg, 50, 100, 140, 150 or 200 μL) of fluid per actuation. The actuator may be configured to count a dose, deliver a gel formulation, and vice versa.

In conventional spray pump systems, an antimicrobial preservative is usually required to maintain the microbiological stability of the liquid formulation. However, preservative-free systems are also available, such as Advanced Preservative Free (APF) systems from Aptar, which are breathable, contain a filter membrane for airflow that prevents contamination, and , has a metal-free fluid pathway for oxidizing the formulation, and can be used in any orientation. Additional nasal spray devices such as Aptar are optimized with clog-resistant dispenser tips (useful for high-viscosity and high-volatile formulations), actuators that do not require repriming after long periods of inactivity, and the like.

Particle size and plume shape may vary within certain limits and may depend on the nature of the pump, formulation, orifice of the actuator, and applied force. The droplet size distribution of a nasal spray is an important parameter as it significantly affects the in vivo deposition of drugs in the nasal cavity. Droplet size is affected by the operating parameters and formulation of the device. A typical median droplet size should be about 30 to about 100 μm. If the droplets are too large (> about 120 μm), deposition occurs mainly in the anterior part of the nose, and if the droplets are too small (< about 10 μm), they can be inhaled and reach the lungs, which should be avoided for safety reasons. do. In its ability as a surfactant, benzalkonium chloride can affect the surface tension of droplets from a delivered nasal spray plume, and have a narrow droplet size distribution (DSD), plus a spherical or substantially spherical shape with the viscosity of a liquid formulation. create particles.

The plume shape, droplet size and DSD of the delivered plum after nebulization can be determined under specific experimental and instrumental conditions by appropriate and validated and/or calibrated analytical procedures known in the art. These include photography, laser diffraction and impact systems (Cascade Impaction, NGI). The plume shape, droplet size and DSD can influence pharmacokinetic outcomes such as _{C max} , T _{max and linear dose proportionality.}

The droplet size distribution can be controlled in 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 will have a D(v,50) of between 30 and 70 μm and a D(v,90) of less than 100 μm.

In certain embodiments, the percentage of droplets smaller than 10 μm will be less than 10%. In certain embodiments, the percentage of droplets smaller than 10 μm will be less than 5%. In certain embodiments, the percentage of droplets smaller than 10 μm will be less than 2%. In certain embodiments, the percentage of droplets smaller than 10 μm will be less than 1%.

In certain embodiments, the dosage form when dispensed by actuation from the device produces a uniform circular plume with an elliptical ratio approaching one. The elliptical ratio is calculated as the exponent of _{the maximum diameter (D max} ) and the minimum diameter (D _min ) of the spray pattern orthogonal to the spray flow direction (eg, from “top”). In certain embodiments, the elliptical ratio is less than ±2.0. In certain embodiments, the elliptical ratio is less than ±1.5. In certain embodiments, the elliptical ratio is less than ±1.3. In certain embodiments, the elliptical ratio is less than ±1.2. In certain embodiments, the elliptical ratio is less than ±1.1. In certain embodiments, the elliptical ratio is about ±1.0.

The details and mechanical principles of particle generation for different types of nasal aerosol devices have been described (Vidgren and Kublik, Adv. Drug Deliv. Rev. 29:157-77, 1998]. Conventional spray pumps replace the discharged liquid with air, thus requiring a preservative to prevent contamination. However, fueled by studies suggesting the potential for adverse effects of preservatives (eg irritation of the nasal mucosa), pump manufacturers have developed different spray systems that do not require preservatives. These systems use collapsible bags, moving pistons or compressed gas to compensate for the ejected liquid volume (www.aptar.com and www.rexam.com). A solution with a moving piston and a collapsible bag that compensates for the ejected liquid volume provides the added benefit of drawing air into the dip tube and being able to be ejected back without the risk of damaging subsequent sprays. This can be useful for some products where the patient is supine and a head-down application is recommended. Another method used to avoid preservatives is that the air displacing the discharged liquid is filtered through a sterile air filter. Also, some systems have a ball valve on the tip to prevent contamination of the liquid in the applicator tip (www.apota.com). Recently, pumps have been designed as a side operation and have been introduced for the delivery of fluticasone furonate for indications of seasonal and perennial allergic rhinitis. The 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 re-priming, and pumps incorporating a pressure point function to improve dose reproducibility and dose counter and a lock-out mechanism to enhance dose control and safety (www. .rexam.com and www.apota.com).

Conventional simple metered-dose spray pumps require priming and some degree of overdosing to maintain the suitability of the dose for the indicated number of doses. They are well suited for drugs administered daily over an extended period of time, but due to the limited control of the priming procedure and dosing, they are not suitable for drugs with a narrow therapeutic window unless special devices are selected, especially when they are not often used. . For expensive drugs and vaccines intended for single-dose or sporadic use, and where strict control of dosage and formulation is particularly important, single-dose or double-dose nebulizer devices are preferred (www.apota.com). . A simple variant of the single-dose spray device (MAD™) is provided by LMA (LMA, Salt Lake City, UT, USA; www.lmana.com). A nosepiece with a spray tip is mounted on a standard syringe. The liquid drug to be delivered is first aspirated into the syringe and then the spray tip is mounted on the syringe. This device has been used, for example, in academic research and vaccine research to deliver topical steroids in patients with chronic sinusitis. Both adults and children in the US market using pre-filled devices (Accuspray™, Becton Dickinson Technologies, Research Triangle Park, NC, USA; www.bdpharma.com) based on the same principle in 1 or 2 doses Influenza vaccine FluMist™ (www.flumist), approved for Ten years ago, the same device for two doses was marketed from a Swiss company to deliver another influenza vaccine.

Pre-primed single- and double-dose devices are also available and consist of a reservoir, piston and swirl chamber (eg Aptar, formerly see UDS UnitDose and BDS BiDose™ devices from Pfeffer). A mist is formed when the liquid is extruded from the swirl chamber. These devices are held between the second and third fingers with the thumb of the actuator. The pressure point mechanism introduced in some devices ensures the reproducibility of the actuating force and the emitted plume characteristics. Currently, Imitrex ^® (www.gsk.com) and Zomig ^® (www.az.com; pfeiffer/Aptar single-dose device), commercially available influenza vaccine Flu-Mist (www.flumist.com; Becton Dickinson single-dose spray) device), and commercially available nasal migraine medications such as an intranasal formulation of naloxone for opioid overdose rescue, Narcan Nasal ^® (narcan.com; Adapt Pharma) are delivered with this type of device.

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

Historically, intranasal administration of drugs in large quantities, such as syringes equipped with mucosal nebulizer devices, has been fraught with difficulties because portions of the formulation tend to drip from the nostrils or into the lower nasopharynx. Thus, in certain embodiments, upon nasal delivery of the pharmaceutical composition, less than about 20% of the pharmaceutical composition is released from the nasal cavity via drainage into or out of the nasopharynx. In certain embodiments, upon nasal delivery of said pharmaceutical composition to said patient, less than about 10% of said pharmaceutical composition is released from the nasal cavity via drainage into or out of the nasopharynx. In certain embodiments, upon nasal delivery of said pharmaceutical composition to said patient, less than about 5% of said pharmaceutical composition is released from the nasal cavity via drainage into or out of the nasopharynx.

The design of current container closure systems for inhaled nebulized drug products includes both pre-metered and device-metered presentations using mechanical or electrical assistance and/or energy from the patient's suction to create a nebulizing plume. . A pre-metered presentation contains a previously measured dose or dose fraction of some type of unit (eg, single or multiple blisters or other cavities) and is inserted into the device by the patient during manufacture or prior to use. do. A typical device-metered unit has a reservoir containing sufficient formulation for multiple doses delivered as a metered spray by the device itself when activated by the patient.

A novel nasal drug delivery method that can be adapted to any type of dispersion technology for both liquids and powders is the breath-powered Bi-Directional™ technology. This concept provides a delivery method that can take advantage of the natural functional aspects of the upper airway to overcome many of the limitations inherent to conventional nasal devices. The breath-powered Bi-Directional™ device consists of a mouthpiece and sealing nosepiece with an optimized truncated cone shape and a comfortable surface that mechanically expands the first portion of the nasal valve. The user slides the sealing nosepiece into one nostril to form a flexible soft tissue and seal of the nasal opening, at which point mechanically expanding the narrow slit-shaped portion of the nasal triangular valve. The user then ejects through the attached mouthpiece. Upon release into the mouthpiece against the resistance of the device, the soft palate (or velum) rises spontaneously by the static pressure of the middle head, isolating the nasal cavity from the rest of the respiratory system. This mechanism allows liquid or powder particles to be released into an air stream that enters one nostril, passes completely through the periphery of the nasal septum, and exits from the opposite nostril.

In sterile filling, there is no need to use a preservative in the device, but because overfilling is required, a waste fraction similar to metered-dose, multiple-dose sprays is obtained. To release 100 μL, a volume of 125 μL is filled into the device (pfeiffer/Aptar single-dose device) used for the ^{intranasal migraine medications Imitrex ®} (sumatriptan) and Zomig ^{® (zolmitriptan), half of which is double-dose} Charged for (bi-dose) design. Sterile drug products may be produced using aseptic processing or terminal sterilization. Terminal sterilization usually involves filling and sealing product containers under high quality environmental conditions. The product is filled and sealed in this type of environment, which serves to minimize the microbial and particulate content of the product during processing and to ensure the success of the subsequent sterilization process. In most cases, products, containers and closures have low bioburden, but are not sterile. The product in the final container is then subjected to a sterilization process such as heat or irradiation. In the sterilization process, drug products, containers and closures are first subjected to separate sterilization methods as needed, and then fed together. Since there is no process for sterilizing the product in the final container, it is important to fill and seal the container in a very high quality environment. Aseptic processing involves more variables than terminal sterilization. Prior to aseptic assembly into the final product, individual parts of the final product are typically subjected to various sterilization processes. For example, glass containers are further treated with drying heat; Rubber closures are treated with wet heat; Liquid dosage forms are treated by filtration. Each of these manufacturing processes requires verification and control.

treatment method

Provided herein are methods of treating alcohol use disorders and related conditions comprising intranasally administering a therapeutically effective amount of naltrexone or a salt or hydrate thereof.

Sinclair method and variants

The Sinclair method is a treatment for AUD in which pharmacological extinction, i.e., the use of opioid antagonists such as naltrexone, is used to change the custom-forming behavior of drinking into a convention-erasing behavior. This effect returns the craving for alcohol to its pre-intoxication state.

The method consists in taking an oral dose of naltrexone about 1, about 2, about 3 or about 4 hours before the subject ingests the alcohol. This pre-ingestion dose of oral naltrexone disrupts the body's behavioral and reward cycles, thereby causing the individual to want less to drink instead of more. Most importantly, because studies have shown that this methodology is equally effective with and without treatment, subjects can choose whether or not to combine this treatment with other treatments without adversely affecting actual physical outcomes. have. Importantly, unlike other currently approved AUD drug regimens, the Sinclair method requires the use of oral naltrexone while the individual continues their usual drinking behavior. As a result, maintenance of the drug treatment protocol is expected to be much higher than that of abstinence alone.

Using the Sinclair method, the disappearance of the AUD can occur within 6 months. However, the effectiveness of oral naltrexone has a slow onset, very low bioavailability, and prevents elevated levels of the peripheral selective active metabolite 6-β-naltrexol, and injectable form of naltrexone, for example, regularly It presents obvious difficulties associated with needles, including the need for administration by a medical practitioner at scheduled intervals. Thus, intranasal administration of naltrexone in pre-primed, single or multiple-use nasal spray pumps and the use of absorption enhancers should significantly improve outcomes in the treatment of AUD. Timing of administration may also affect effectiveness. The intranasal formulation of naltrexone is rapidly absorbed, providing rapid onset of action and high bioavailability without the use of a needle.

Accordingly, disclosed herein is a method of treating an alcohol use disorder or related condition in a subject comprising administering to the subject an intranasal formulation comprising a therapeutically effective amount of naltrexone or a pharmaceutically acceptable salt thereof.

In certain embodiments, the intranasal formulation comprising naltrexone is administered prior to ingestion of alcohol.

In certain embodiments, the intranasal formulation comprising naltrexone is administered about 1 to about 2 hours prior to ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered about 1 hour prior to ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered about 0.5 to about 1 hour prior to ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered about 10 to about 30 minutes prior to ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered about 5 to about 10 minutes prior to ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered immediately prior to ingestion of alcohol.

In certain embodiments, the intranasal formulation comprising naltrexone is administered concurrently with ingestion of alcohol.

In certain embodiments, the intranasal formulation comprising naltrexone is administered immediately after ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered within one hour of initiation of alcohol intake.

Because intranasal naltrexone is rapidly ingested through the nasal mucosa and appears rapidly into plasma, as evidenced by the study below, intranasal administration provides a subject with naltrexone, long before and even simultaneously with ingestion, in the case of alcohol. Or administered immediately after administration and expected to experience benefits such as extinction and reduced cravings. Absorption enhancers are expected to promote this effect.

In certain embodiments, the alcohol use disorder is alcohol abuse. In certain embodiments, the alcohol use disorder is alcohol dependence. In certain embodiments, the alcohol use disorder is alcoholism.

It is also expected that these methods will be effective in the treatment of other substance use disorders and reward-based disorders.

The methods disclosed herein can be achieved by administration of various embodiments of the formulations disclosed herein, such as the section of "Pharmaceutical Formulations" above, the above embodiments, and the examples below. The formulations can be administered using devices known in the art, such as the devices disclosed herein in the section entitled "Nasal Drug Delivery Devices and Kits".

Also provided herein are embodiments in which any of the embodiments described above may be combined with any one or more embodiment(s), provided that the combinations are not mutually exclusive.

Example

The following examples are included to demonstrate preferred embodiments of the present invention. The following examples are presented by way of illustration only and are intended to assist those skilled in the art in using the present invention. These examples are in no way intended to limit the scope of the present invention in any other way. Those of ordinary skill in the art, in light of the present disclosure, will appreciate that many changes can be made in the specific embodiments disclosed and a like or similar result can be obtained without departing from the spirit and scope of the invention.

Example 1: Intranasal Naltrexone Protocol for Treatment of Alcohol Use Disorder

Individuals with alcohol use disorder (AUD) are treated with intranasal naltrexone and screened for abstinence, reduced consumption of alcohol, and/or reduced consumption of alcohol. Individuals with AUD are believed to release endogenous opioids upon ingestion of alcohol. The binding of these opioids to receptors in the brain may be responsible for the potentiating effect of the amount of alcohol. Drinking while the opioid antagonist naltrexone blocks positive reinforcement from alcohol quenches drinking and cravings.

In one example of the protocol, subjects with AUD (eg, about 10-20) are admitted as inpatients to the study site. The initial visit serves the purpose of screening to confirm the diagnosis and obtain written consent. During hospitalization (eg, 1 week or longer), each subject receives a placebo or intranasal dose of naltrexone, followed by ingestion of one or more alcoholic beverages. Naltrexone is administered at the indicated dose and in the indicated manner, about 0.25 to about 4 hours prior to alcohol intake. One example of a dosing treatment is an intranasal formulation that delivers from about 1 to about 4 mg of naltrexone hydrochloride per dose, delivered by a single or multiple use nebulizer device. Another example of dosing treatment is an intranasal formulation that delivers an initial dose of 3 mg naltrexone hydrochloride in the morning followed by subsequent doses of 3 mg naltrexone hydrochloride per day as needed by the patient. Yet another example of a dosing treatment is an intranasal formulation that delivers up to 12 mg of naltrexone hydrochloride per day. Intranasal formulations of naltrexone may or may not contain absorption enhancers such as ^{Intravail ® .}

Intranasal naltrexone is expected to improve suppression of alcohol intake after treatment. In addition, intranasal naltrexone is expected to reduce cravings for alcohol, and the amount of time required for a subject to exhibit pharmacological cessation of alcohol cravings.

Approximately 1 hour prior to dosing, ECG, blood pressure, heart rate and respiration rate are measured and time recorded. At approximately 1 and 4 hours post-dose, the ECG is repeated and the time recorded. Vital signs including heart rate, blood pressure, and respiratory rate in a sitting state (after 5 minutes) were measured before dosing and about 1 hour and 4 hours after each dose. Adverse events (AEs) are recorded and treatment is terminated as needed. The nasal cavity is examined before administration, at 5 minutes, 30 minutes, 60 minutes, 4 hours and 24 hours after administration, and only after intranasal administration.

At screening, admission and discharge, ECG and vital signs are checked once daily. Vital signs are also checked once on the day of naltrexone administration. AEs are assessed by spontaneous reporting by the subject, examination of the nasal mucosa, measurement of vital signs, ECG, and clinical laboratory parameters.

Example 2: Pharmacokinetic data analysis

Non-compartmental pharmacokinetic (PK) parameters of naltrexone and 6β-naltrexol (C _max , T _max , AUC _0-t , AUC _0-∞ , t _1/2 , λz and apparent clearance (CL/F, naltrexone alone) Compare various AUD treatment protocols (eg, 4 mg intranasal; 50 mg oral tablet) with an intramuscular (IM) dose of naltrexone of 2 mg with or without absorption enhancers such as alkylsaccharides. Calculate the dose-adjusted values of AUC and C _{max.Intranasal} (IN) and oral absorption (PO) relative degree of absorption is estimated from dose-corrected AUC. Within the framework of ANOVA, IN and PO versus IM Comparison of IN-transformed PK parameters of naltrexone treatment is carried out.The 90% confidence interval of the ratio of geometric least squares means (IN/IM and PO/IM) of _{AUC and C max parameters is the comparison of each treatment with IM naltrexone.} These 90% confidence intervals are obtained by exponentialization between 90% confidence intervals for the differences between least squares means based on a logarithmic scale.

AEs are coded using the preferred terminology of the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) and grouped by system, institution, class (SOC) designation. Severity, frequency, and relationship to study drug of AEs are presented by SOC grouping by preferred terminology and the like. Separate summaries are provided for the four study periods: after administration of each dose of study drug until the time of subsequent dose of study drug or discharge from the clinic. A list of individual AEs is provided including start date, end date, severity, relationship, outcome and duration.

Clinically significant changes in vital signs, ECG and clinical laboratory parameters are presented as counts and percentages by dosing session.

Example 3: Dose Selection and Pharmaceutical Compositions Containing Absorption Enhancers

Intranasal naltrexone may optionally be formulated with absorption-enhancing excipients.

One such excipient is the alkylsaccharide Intravail ^® . The concentrations of Intravail ^{® in} the nasal formulations were generally 0.1% and 0.2% by weight. In this study, a concentration of 0.25% by weight of alkylsaccharide was used. The 25% Intravail® concentration was non-irritating in the rabbit eye model. The oral “no observable effect level” was about 20,000 to 30,000 mg/kg body weight. Although there were no comparable intranasal data, the essential lack of oral safety suggests that the amount of alkylsaccharide required for nasal toxicity is much higher than that administered in this study.

In this study, a single dose of naltrexone was administered in four ways: a) 4 mg IN in sterile water for injection; b) 4 mg IN in sterile water for injection with 0.25% Intravail ^®; c) 2 mg as intramuscular injection; and d) 50 mg oral tablet. Intranasal administration is expected to increase absorption compared to oral administration. With ^{the addition of Intravail ®} , the rate of absorption from the nasal cavity is expected to increase further.

Example 4: Pharmacokinetic evaluation of intranasal naltrexone

research purpose . The objectives of this clinical study were two: to ^{determine the pharmacokinetics of naltrexone in two intranasal formulations (4 mg with and without Intravail ®} ) and one oral formulation (50 mg tablets) compared to an intramuscular dose of 2 mg naltrexone. to decide; and to determine the safety of intranasal naltrexone, especially with respect to inflammation of the nasal cavity, such as inflammation (erythema, edema and erosion) and bleeding. To this end, the main endpoint of this study was the pharmacokinetic parameters (C _max , T _max , AUC _0-t and AUC _0-inf ) of IN and oral naltrexone formulations compared to the IM dose of 2 mg naltrexone. Secondary endpoints included adverse events (AE), vital signs (heart rate, sitting blood pressure and respiratory rate), electrocardiogram (ECG), changes in the clinical laboratory, and nasal stimulation using the nasal irritation scale.

study design . Fourteen healthy volunteers were enrolled and completed all study drug administration and blood collection for PK assessment. This was an inpatient, non-blind, crossover study involving approximately 14 healthy volunteers. Each subject received each naltrexone treatment: 4 mg IN (one 0.1 mL spray of 40 mg/mL solution in one nostril), 4 mg + Intravail ^® IN (40 mg/mL containing 0.25% Intravail ^{® in one nostril)} 1 spray of 0.1mL solution), 2mg IM and 50mg oral tablet. Subjects stayed at the inpatient facility for 13 days to complete the entire study, and called subjects 3-5 days after discharge to inquire about post-discharge AEs and concomitant medications. Written consent was obtained from all subjects, and informed consent was given for participation in the study, including medical history, physical examination, clinical chemistry, coagulation markers, hematology, infectious serology, urinalysis, uria drug and alcoholic toxicology screening, vital signs, and ECG. screened.

On the day of screening admission, subjects received study drug with a 3-day washout period between administrations, until all treatments were performed. Analysis before dosing and at about 2.5, 5, 10, 15, 20, 30, 45, 60 minutes and 2, 3, 4, 6, 8, 12, 16, 24, 30, 36 and 48 hours after study drug administration blood was collected for On the day of dosing of study drug, 12-lead ECGs were performed at approximately 1 hour before dosing, and at approximately 1 and 4 hours post dosing. Vital signs were measured pre-dose and at approximately 1 and 4 hours post-dose.

On the day of dosing, the order of evaluation was ECG, vital signs, followed by PK blood collection at the same nominal time as scheduled. The target time for PK blood collection was considered the most important, and if blood collection was more than ±1 min from the scheduled time of the first 60 minutes or more than ±5 min from the scheduled time thereafter, this was considered a protocol deviation. Electrocardiograms and vital signs were collected within 10 minutes prior to the nominal time of blood collection. At screening, admission and discharge, ECG and vital signs were checked once daily. Vital signs were checked once on the day of naltrexone administration. Clinical laboratory measurements were repeated after the last PK blood collection and before discharge. AEs were assessed by spontaneous reporting by the subject, examination of the nasal mucosa, measurement of vital signs, ECG, and clinical laboratory parameters.

Inclusion and Exclusion Criteria : 1. Males and females (inclusive) aged 18 to 55 years were included in this study. Written consent was requested. Subjects are as follows:

having a body mass index (BMI) ranging from 18 to 30 kg/m ^{2 (inclusive);}

having adequate venous access;

not having clinically significant concomitant conditions as determined by medical history, physical examination, clinical examination, vital signs, and 12-lead ECG;

consent to use of an acceptable method of contraception other than oral contraceptives throughout the study and for 90 days (30 days for women) after the last study drug administration; and

Consent not to consume alcohol, beverages containing xanthine in excess of 500 mg/day (e.g. Coca-Cola ^® , tea, coffee, etc.), or grapefruit/grapefruit juice, or hospitalization until the final blood collection of the study Agreeing not to engage in strenuous exercise 72 hours prior.

Exclusion criteria include:

any IN condition including abnormal nasal anatomy, nasal symptoms (ie, nasal congestion and/or runny nose, nasal polyps, etc.);

spraying the product into the nasal cavity prior to screening and drug administration;

- administration of the test drug within 30 days prior to Day 1;

recent use (within 14 days of last use of any of these products) of prescription or over-the-counter medications, nutritional supplements, herbal products, vitamins, or opioid analgesics for analgesia;

positive urine drug test for alcohol, opioid, cocaine, amphetamine, methamphetamine, benzodiazepine, tetrahydrocannabinol (THC), barbiturate or methadone at screening or hospitalization;

Based on medical history, previous or current opioid, alcohol, or other drug dependence (excluding nicotine and caffeine);

inability to abstain from smoking (or nicotine-containing substances) consuming on average more than 20 cigarettes per day in the month prior to screening, or at least 1 hour before and 2 hours after naltrexone administration;

systolic blood pressure less than 90 mmHg or greater than 140 mmHg; diastolic blood pressure less than 55 mmHg or greater than 90 mmHg; respiratory rate of less than 8 breaths per minute or greater than 20 breaths per minute;

On standard 12-lead ECG, QTcF intervals of >440 ms in males and >450 ms in females; serious acute or chronic medical condition (in the investigator's judgment);

Possibility of need for concomitant medicinal treatment during study;

-Giving or receiving blood within 60 days prior to Day -1, or experiencing plasma or platelet apheresis;

women who are pregnant, lactating, or planning to become pregnant during the study period or within 30 days of the last naltrexone administration;

positive test for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCVAb) or human immunodeficiency virus antibody (HIVAb) at screening;

present or recent (within 7 days prior to screening) upper respiratory tract infection; and

Abnormal liver function tests (ALT, AST, total bilirubin) > 1.5 times upper limit of normal.

Study Drugs and Dosing . Naltrexone hydrochloride (HCl) was obtained from Mallinckrodt Pharmaceuticals. The IN (40 mg/mL) formulation was prepared by the staff pharmacist of Vince &Associates; The vehicle for the IN formulation was sterile water for injection. The IM formulation (2 mg/mL) was prepared by the staff pharmacist of Vince &Associates; The vehicle was sterile saline for injection. IN naltrexone was administered using the Aptar multiple-dose device with the subject in a supine position (approximately 45 degrees). Subjects were instructed not to breathe from the nasal cavity when the IN dose of naltrexone was administered. Naltrexone HCl for IM injection was administered with a 23 g needle as a 1 mL single injection into the great muscle. Naltrexone HCl for oral administration (50 mg tablets) was supplied from a commercial supplier and was administered with 240 mL water.

Naltrexone was administered on days 1, 4, 7 and 10 in the following order: 4 mg naltrexone IN, 4 mg naltrexone + Intravail ^® IN, 2 mg IM, and 50 mg oral administration. Subjects stayed in the inpatient facility for 13 days to complete the entire study and were discharged 2 days after the 4th dose.

PK evaluation . Blood (4 mL) was administered prior to administration and at 2.5, 5, 10, 15, 20, 30, 45, 60 minutes and 2, 3, 4, 6, 8, 12, 16, 24, 30, 36 of study drug administration initiation. and 48 hours later into a tube containing sodium heparin for PK analysis. Plasma was isolated from whole blood and cryopreserved at 20° C. or lower until assayed. Naltrexone and 6β-naltrexol plasma concentrations were determined by liquid chromatography using tandem mass spectrometry at XenoBiotic laboratories, Inc. (Plainsboro, New Jersey).

safety assessment . Heart rate, blood pressure and respiratory rate were recorded approximately 1 hour before and approximately 1 hour and 4 hours after administration of naltrexone. 12-lead ECGs were obtained approximately 1 hour before and 1 hour and 4 hours after each naltrexone administration. ECG and vital signs were performed within 10 minutes prior to the nominal time of post-dose blood collection. AEs were recorded from initiation of study drug administration to clinic discharge. In an attempt to establish a relationship between the AE and the type of naltrexone dose administered, AEs were recorded for each dosing session. Nasal examinations were performed on Day -1 and prior to dosing, at 5, 30, 60, 4 and 24 hours of IN naltrexone administration, to establish eligibility, Evaluated the evidence.

analysis . Determination of non-compartmental PK parameters of naltrexone and 6β-naltrexol, including T _max , AUC _0-t and AUC _0-inf , t _1/2 , λ _{z and apparent clearance (CL/F, naltrexone alone)} did. The pharmacokinetic parameters (C _max , T _max and AUC) of IN and PO naltrexone were compared with those of IM naltrexone. Dose-adjusted values of AUC and C _{max were calculated.} The relative extent of IN and PO absorption (IN and PO versus IM) is estimated from the dose-corrected AUC. Within the ANOVA framework, comparisons of In- _{converted PK parameters (C max} and AUC ) of IN and PO versus IM naltrexone treatments were performed. For comparison of each treatment with IM naltrexone, a 90% confidence interval of the ratio of geometric least squares means (IN/IM and PO/IM) of the _{AUC and C max parameters was constructed.} These 90% CIs were obtained by indexing the 90% CIs to the difference between least squares means based on the ln scale.

result . The results are presented in Tables 1 to 5 below.

Mean (SD) concentration of naltrexone after single IN, IM or oral administration to healthy subjects hour cure 4 mg IN 4 mg IN + 0.25% Intravail ^® 2 mg IN 50 mg oral 0 0 0 0 0 0 0 0 0 0.042 0.117 (0.17) 1.15 (0.919) 0.678 (1.69) 0 0 0.083 1.51 (1.62) 11.9 (9.69) 1.04 (1.26) 0.109 (0.232) 0.17 3.4 (3.86) 12.1 (6.36) 2.97 (2) 0.851 (1.5) 0.25 4.36 (3.71) 10.4 (3.93) 3.45 (1.58) 2.5 (3.54) 0.33 4.46 (3.62) 9.81 (2.41) 3.58 (1.46) 4.75 (4.71) 0.5 4.08 (1.99) 7.19 (2.08) 3.43 (1.06) 7.16 (4.69) 0.75 3.39 (1.46) 5.46 (1.48) 3.02 (0.749) 6.9 (3.54) One 3.19 (1.51) 4.55 (1.78) 2.73 (0.676) 6.34 (2.78) 2 2.33 (0.832) 3.07 (1.27) 2.35 (0.698) 5.22 (1.73) 3 1.5 (0.633) 2 (0.885) 1.79 (0.491) 3.66 (1.76) 4 1.02 (0.369) 1.25 (0.465) 1.3 (0.341) 2.39 (1.16) 6 0.418 (0.193) 0.536 (0.188) 0.584 (0.185) 1.13 (0.462) 8 0.22 (0.0941) 0.267 (0.105) 0.242 (0.0803) 0.596 (0.426) 12 0.0641 (0.021) 0.0726 (0.028) 0.0626 (0.0269) 0.3 (0.183) 16 0.0214 (0.0131) 0.0226 (0.0165) 0.0101 (0.0132) 0.141 (0.104) 24 0.00462 (0.0117) 0 0 0 0 0.0657 (0.0528) 30 0.00187 (0.00674) 0 0 0 0 0.0345 (0.0224) 36 0 0 0 0 0 0 0.0207 (0.0255) 48 0.0018 (0.0065) 0 0 0 0 0 0

Mean CV% PK parameters of naltrexone after administration to healthy subjects PK parameters 4 mg IN ^a 4 mg IN + 0.25% Intravail ^{® b} 2 mg IM ^c 50 mg oral ^c C _max (ng/mL) 5.35 (66.8) 15.7 (52.0) 4.10 (34.0) 9.34 (31.8) C _max /dose (ng/mL/mg) 1.48 (66.8) 4.35 (52.0) 2.27 (34.0) 0.206 (31.8) T _max (h) ^d 0.50 (0.17, 2.00) 0.17 (0.083, 0.33) 0.33 (0.17, 1.00) 0.50 (0.33, 3.00) AUC _0-t (h ng/mL) 11.9 (34.1) 18.3 (31.2) 12.1 (25.5) 26.5 (32.3) AUC _0-t /dose (h ng/mL/mg) 3.28 (34.1) 5.07 (31.2) 6.71 (25.5) 0.587 (32.3) AUC _0-inf (h ng/mL) 12.0 (33.7) 18.5 (31.0) 12.3 (25.6) 26.9 (31.8) AUC _0-inf /dose (h ng/mL/mg) 3.32 (33.7) 5.10 (31.0) 6.78 (25.6) 0.594 (31.8) AUC _extrap (%) 1.09 (57.0) 0.707 (44.0) 1.01 (71.7) 1.38 (70.1) CL/F (L/h) 330 (28.9) 214 (33.6 154 (19.0) 1890 (41.4) λ _z (1/h) 0.281 (15.1) 0.317 (15.1) 0.361 (16.8) 0.122 (38.0) t _½ (h) 2.52 (14.9) 2.23 (14.9) 1.97 (15.5) 6.41 (36.6) F _rel 0.481 (36.1)c 0.783 (17.7) ^c NA 0.0903 (37.0) NA = Not applicable; Frel = bioavailability to IM dose, calculated as the ratio of AUCinf/dose of IN or PO pathway to IM pathway,
a: N=13; b: N=12; c: N=10; d: median (min, max)

After IN administration of 4 mg naltrexone, the mean concentration at 2.5 minutes after administration was 0.117 ng/mL. When 0.25% Intravail® was added to the formulation, the average concentration increased 10-fold (1.15 ng/mL) at 2.5 minutes. At 5 minutes after administration, the mean concentrations of naltrexone with and without Intravail® were 11.9 ng/mL and 1.51 ng/mL, respectively, and there was an 8-fold difference. The addition of 0.25% Intravail® to the IN formulation _{decreased the median T max} from 30 to 10 min and increased the C _max nearly 3-fold (15.7 vs. 5.35 ng/mL). Overall exposure as measured by AUC _{0-inf increased by 54%.} This indicates that the main effect of Intravail® is to increase absorption to some extent or more.

Mean plasma concentrations of naltrexone at 2.5 and 5 minutes after administration of 2 mg naltrexone IN were 0.678 ng/mL and 1.04 ng/mL, respectively. _{The mean C max} value of 4.10 ng/mL after 20 minutes of administration of 2 mg IM was reduced by 23% compared to after administration of 4 mg IN and by 74% compared to when Intravail® was part of the IN formulation.

The mean C _max value after oral administration was 9.34 ng/mL, which was less than the value observed after IN administration with Intravail® compared to only 4 mg IN, even when 50 mg was administered orally.

The mean terminal half-life (t _1/2 ) of naltrexone was 1.97 to 2.52 hours after IM and IN administration. t _1/2 was 6.41 hours after oral administration.

When AUC _0-inf values were adjusted for dose, the relative bioavailability of naltrexone after IN administration with and without 0.25% Intravail® was 78% and 48%, respectively, compared to IM administration. The relative bioavailability of oral administration is only 9%, indicating extensive first-pass metabolism by the gastrointestinal tract and liver.

Statistical analysis of dose-adjusted PK parameters suggested that nebulization of the IN dose was approximately 48% or 60% of the IM dose per mg with respect to geometric least squares mean (GM) dose-adjusted AUC and C _{max , respectively.} do. IN administration of naltrexone with 0.25% Intravail® was _{higher than the IM route with respect to C max} (geometric least squares mean inter-treatment ratio [GMR] 188%) and lower dose-adjusted for AUC (76% GMR). caused exposure. For the oral route, the GMR of dose-adjusted naltrexone exposure was approximately 9% of the IM dose.

Mixed effects ANOVA results of naltrexone pharmacokinetic parameters following intranasal or oral administration versus intramuscular administration in healthy subjects PK parameters Comparison (see 2 mg IM) GMR (%) 90% CI of GMR (%) lower limit maximum Cmax (ng/mL) 4 mg IN vs. 2 mg IM 121 91.1 160 4 mg IN + Intravail® vs. 2 mg IM 377 321 442 50 mg PO vs. 2 mg IM 231 190 282 AUC _0-t (h ng/mL) 4 mg IN vs. 2 mg IM 96.4 82.6 112 4 mg IN + Intravail® vs. 2 mg IM 152 136 169 50 mg PO vs. 2 mg IM 221 182 268 AUC _0-inf (h ng/mL) 4 mg IN vs. 2 mg IM 96.4 82.7 112 4 mg IN vs. Intravail® vs. 2 mg IM 151 136 168 50 mg PO vs. 2 mg IM 221 183 268 Cmax/dose (ng/mL/mg) 4 mg IN vs. 2 mg IM 60.4 45.5 80.2 4 mg IN + Intravail® vs. 2 mg IM 188 161 221 50 mg PO vs. 2 mg IM 9.3 7.6 11.3 AUC _0-t /dose (h ng/mL/mg) 4 mg IN vs. 2 mg IM 48.2 41.3 56.2 4 mg IN + Intravail® vs. 2 mg IM 75.9 68.1 84.6 50 mg PO vs. 2 mg IM 8.8 7.3 10.7 AUC _0-inf /dose (h ng/mL/mg) 4 mg IN vs. 2 mg IM 48.2 41.4 56.2 4 mg IN + Intravail® vs. 2 mg IM 75.7 68 84.2 50 mg PO vs. 2 mg IM 8.9 7.3 10.7

GMR = geometric least squares mean ratio between treatments (expressed as percentage of reference)

The mean C _max values of 6β-naltrexol were 1.5 ng/mL after IM administration and about 3 ng/mL after IN administration; The Cmax after oral administration of 50 mg was 90.7 ng/mL (Table 2-3). When the administered dose was adjusted, the Cmax values were the same with the IN and IM doses (0.833 and 0.838 ng/ml/mg), but increased about 2-fold (2.0 ng/mL/mg) after oral administration.

The values of AUC _0-inf also increased significantly after oral administration (675 h·ng/mL and 44.0 to 27.1 h·ng/mL, respectively), compared with the IN and IM doses. The extent of first-pass metabolism of naltrexone was demonstrated in the ratio _{of AUC 0-inf of 6β-naltrexol compared to naltrexone;} The ratio after IN and IM administration was about 2.2 to 3.7, but 25 after oral administration.

The average t _1/2 of metabolites was 12.4 to 13.9 hours, independent of the route of administration.

Mean (SD) concentration of 6β-naltrexol following single IN, IM or oral administration to healthy subjects hour cure 4 mg IN 4 mg IN + 0.25% Intravail ^® 2 mg IN 50 mg oral 0 0 0 0.0682 (0.0257) 0.0661 (0.0256) 0.0454 (0.0141) 0.042 0 0 0.082 (0.0378) 0.0627 (0.0248) 0.0448 (0.0202) 0.083 0.0321 (0.0432) 0.238 (0.146) 0.12 (0.117) 1.4 (3.49) 0.17 0.196 (0.196) 0.994 (0.558) 0.283 (0.281) 14.2 (31) 0.25 0.45 (0.448) 1.86 (0.763) 0.454 (0.293) 31.6 (47.3) 0.33 0.693 (0.624) 2.55 (0.918) 0.677 (0.385) 45.5 (43.7) 0.5 1.11 (0.559) 2.84 (0.748) 0.852 (0.328) 68.7 (41.3) 0.75 1.82 (1.16) 2.93 (0.757) 1.08 (0.452) 60.8 (28.2) One 1.83 (0.815) 2.73 (0.481) 1.1 (0.404) 58.6 (18.2) 2 2.68 (0.842) 2.9 (0.767) 1.39 (0.462) 54 (16.3) 3 2.61 (0.793) 2.61 (0.708) 1.48 (0.402) 45.8 (15.2) 4 2.37 (0.669) 2.45 (0.598) 1.46 (0.388) 38 (12.2) 6 1.97 (0.554) 2.03 (0.399) 1.3 (0.252) 28.5 (7.52) 8 1.62 (0.418) 1.67 (0.27) 1.08 (0.165) 22.2 (5.51) 12 1.26 (0.299) 1.25 (0.176) 0.81 (0.131) 15.4 (2.85) 16 0.919 (0.229) 0.923 (0.155) 0.595 (0.115) 11.4 (1.78) 24 0.602 (0.194) 0.618 (0.145) 0.365 (0.0808) 8.14 (2.09) 30 0.418 (0.114) 0.457 (0.116) 0.255 (0.0666) 5.93 (1.85) 36 0.292 (0.0868) 0.312 (0.0862) 0.18 (0.0478) 4.35 (1.54) 48 0.184 (0.0645) 0.175 (0.0623) 0.106 (0.0329) 2.43 (0.882)

Mean (CV%) PK parameters of 6β-naltrexol following administration to healthy subjects PK parameters 4 mg IN ^a 4 mg IN + 0.25% Intravail ^{® b} 2 mg IM ^c 50 mg oral ^c C _max (ng/mL) 3.01 (33.2) 3.29 (23.7) 1.52 (26.8) 90.7 (30.3) C _max /dose (ng/mL/mg) 0.833 (33.2) 0.908 (23.7) 0.838 (26.8) 2.00 (30.3) T _max (h) ^d 2.00 (0.75, 6.0) 0.75 (0.25, 4.00) 3.00 (0.75, 4.00) 0.63 (0.25, 3.00) AUC _0-t (h ng/mL) 40.3 (23.3) 43.0 (17.4) 25.1 (18.3) 614 (19.5) AUC _0-t /dose (h ng/mL/mg) 11.1 (23.3) 11.9 (17.4) 13.9 (18.3) 13.6 (19.5) AUC _0-inf (h ng/mL) 44.0 (23.1) 46.3 (18.3) 27.1 (19.0) 675 (19.9) AUC _0-inf /dose (h ng/mL/mg) 12.2 (23.1) 12.8 (18.3) 15.0 (19.0) 14.9 (19.9) AUC _extrap (%) 8.57 (46.1) 7.02 (37.3) 7.02 (29.4) 8.79 (57.3) λ _z (1/h) 0.0530 (21.8) 0.0553 (15.1) 0.0570 (14.8) 0.0510 (15.8) t _½ (h) 13.7 (22.7) 12.8 (14.6) 12.4 (13.2) 13.9 (15.9) *Median (minimum, maximum) statistics presented for Tmax. All other values are expressed as: M mean (percent coefficient of variation); a: N=13; b: N=12; c: N=10; d: median (min, max)

Clinically between sexes for the PK parameters of either naltrexone or 6β-naltrexol after IN, IM, or PO administration, except for _{a mean C max} of naltrexone after 4 mg IN administration that was approximately 2-fold higher in women compared to men. There was no significant difference.

safety . In total, 10 of 14 subjects (71%) in the safety population experienced at least one AE (during any dosing, relationship to any drug). The most frequent AE was the neurological disorder SOC (7 subjects, 50%), with none being the most frequent AE regardless of severity and attribution (5 subjects, 36%). No severe AEs were observed and only 1 moderate AE was observed, which is a case of vertigo after the first dose (4 mg IN) thought to be related to the treatment agent. 3 subjects experienced an unexpected AE (UAE, defined as an AE not described with respect to nature, severity or frequency in the current product package insert); Two UAEs were considered one treatment-related UAE, independent of study medication, of mild syncope following administration of the dose on Day 1 (4 mg IN). Three subjects discontinued the study due to AEs (hypertension, syncope and out-of-range vital signs prior to dosing).

Example 5: Formulation of intranasal naltrexone

The table below shows examples of naltrexone formulations for intranasal administration for the treatment of disorders. Table 6 shows the formulation of a simple aqueous solution, dispensed in increments of about 100 μL, as used in the above experiments.

Yes Naltrexone HCl, dose
(mg) absorption enhancer μL per dose Concentration, mg/mL One 1.2 Intravail 0.25% 50 24 2 1.2 Intravail 0.25% 100 12 3 1.2 Intravail 0.25% 150 8 4 1.6 Intravail 0.25% 50 32 5 1.6 Intravail 0.25% 100 16 6 1.6 Intravail 0.25% 150 10.7 7 2 Intravail 0.25% 50 40 8 2 Intravail 0.25% 100 20 9 2 Intravail 0.25% 150 13.3 10 3 Intravail 0.25% 100 30 11 3 Intravail 0.25% 150 20 12 4 Intravail 0.25% 100 40 13 4 Intravail 0.25% 150 26.7

Table 7 shows formulations for intranasal administration in 100 μL aqueous solution containing excipients such as isotonic, stabilizer and/or compounds acting as preservatives or surfactants.

Yes Naltrexone HCl absorption enhancer isotonic stabilizator Preservatives/surfactants 14 1.2 mg Intravail 0.25% NaCl 0.74% EDTA 0.3% BZK 0.02% 15 1.2 mg Intravail 0.25% NaCl 0.74% EDTA 0.3% BZK 0.01% 16 1.2 mg Intravail 0.25% NaCl 0.74% EDTA 0.2% BZK 0.02% 17 1.2 mg Intravail 0.25% NaCl 0.74% EDTA 0.2% BZK 0.01% 18 1.6 mg Intravail 0.25% NaCl 0.74% EDTA 0.3% BZK 0.02% 19 1.6 mg Intravail 0.25% NaCl 0.74% EDTA 0.3% BZK 0.01% 20 1.6 mg Intravail 0.25% NaCl 0.74% EDTA 0.2% BZK 0.02% 21 1.6 mg Intravail 0.25% NaCl 0.74% EDTA 0.2% BZK 0.01% 22 2 mg Intravail 0.25% NaCl 0.74% EDTA 0.3% BZK 0.02% 23 2 mg Intravail 0.25% NaCl 0.74% EDTA 0.3% BZK 0.01% 24 2 mg Intravail 0.25% NaCl 0.74% EDTA 0.2% BZK 0.02% 25 2 mg Intravail 0.25% NaCl 0.74% EDTA 0.2% BZK 0.01% 26 3 mg Intravail 0.25% NaCl 0.74% EDTA 0.3% BZK 0.02% 27 3 mg Intravail 0.25% NaCl 0.74% EDTA 0.3% BZK 0.01% 28 3 mg Intravail 0.25% NaCl 0.74% EDTA 0.2% BZK 0.02% 29 3 mg Intravail 0.25% NaCl 0.74% EDTA 0.2% BZK 0.01% 30 1.2 mg Intravail 0.18% NaCl 0.74% EDTA 0.3% BZK 0.02% 31 1.2 mg Intravail 0.18% NaCl 0.74% EDTA 0.3% BZK 0.01% 32 1.2 mg Intravail 0.18% NaCl 0.74% EDTA 0.2% BZK 0.02% 33 1.2 mg Intravail 0.18% NaCl 0.74% EDTA 0.2% BZK 0.01% 34 1.6 mg Intravail 0.18% NaCl 0.74% EDTA 0.3% BZK 0.02% 35 1.6 mg Intravail 0.18% NaCl 0.74% EDTA 0.3% BZK 0.01% 36 1.6 mg Intravail 0.18% NaCl 0.74% EDTA 0.2% BZK 0.02% 37 1.6 mg Intravail 0.18% NaCl 0.74% EDTA 0.2% BZK 0.01% 38 2 mg Intravail 0.18% NaCl 0.74% EDTA 0.3% BZK 0.02% 39 2 mg Intravail 0.18% NaCl 0.74% EDTA 0.3% BZK 0.01% 40 2 mg Intravail 0.18% NaCl 0.74% EDTA 0.2% BZK 0.02% 41 2 mg Intravail 0.18% NaCl 0.74% EDTA 0.2% BZK 0.01% 42 3 mg Intravail 0.18% NaCl 0.74% EDTA 0.3% BZK 0.02% 43 3 mg Intravail 0.18% NaCl 0.74% EDTA 0.3% BZK 0.01% 44 3 mg Intravail 0.18% NaCl 0.74% EDTA 0.2% BZK 0.02% 45 3 mg Intravail 0.18% NaCl 0.74% EDTA 0.2% BZK 0.01%

Also provided is Examples 1A-45A, further comprising hydrochloric acid in an amount sufficient to achieve a pH of 3.5-5.5. The acid should be pharmaceutically acceptable, for example hydrochloric acid.

Example 6: Intranasal Naltrexone Formulation Experiment

As disclosed herein, a series of experiments were conducted to identify a formulation of naltrexone that could produce a pharmaceutically appropriate intranasal product. The formulation is designed to have at least some, and in certain embodiments, all of the following properties:

containing an effective amount of naltrexone;

Naltrexone is rapidly absorbed after administration, providing _{good C max} and relatively short T _{max ;}

forming a solution at room temperature and returning to solution when in solution at refrigeration conditions or upon removal from refrigeration;

free from microbial contamination;

storage stable, not forming or acquiring undesirable impurities, and/or not discoloring over time; and

Non-irritating to nasal membrane tissue.

Using the following observations, various formulations were tested. A 50 mg/mL formulation of naltrexone HCl was turbid at room temperature, indicating incomplete dissolution; The solubility limit of naltrexone hydrochloride in solution at ambient temperature was determined to be about 40 mg/mL. Thereafter, several preparations are run at 30 mg/mL, which additionally have fixed amounts (dodecyl maltoside 0.25%) and NaCl (about 0.74%), and different amounts of preservatives (benzalkonium chloride, 0-0.02%). and a stabilizer (EDTA, 0-0.3%). Crystallization behavior and discoloration were monitored visually. All of these formulations developed crystals when stored under refrigerated conditions. Naltrexone solutions tend to turn yellow with time, between 0-3 months; Formulations containing 0.2% or 0.3% EDTA did not form a yellow solution, whereas formulations containing 0% or 0.1% EDTA started to turn yellow. The 0.3% EDTA formulation was shown to resist yellowing for the longest period of time. Various co-solvents were then evaluated for their potential to reduce crystallization of the drug from solution. Polyethylene glycol (PEG), propylene glycol and benzyl alcohol were tested. The PEG-containing formulation did not prevent crystallization; The formulation containing propylene glycol prevented crystallization, but resulted in high osmotic pressure, which was expected to cause irritation of the nasal membrane tissue; Formulations containing benzyl alcohol prevented crystallization at low concentrations. Total solids content was observed to be related to crystallization, and the amount of naltrexone hydrochloride was reduced to adjust the osmotic pressure to help keep the formulation in solution when stored under refrigerated conditions, resulting in lower concentrations and higher amounts of NaCl. Four formulations of naltrexone suitable for intranasal administration are provided in the Examples below.

Example 7: Additional formulation of intranasal naltrexone

Below are additional examples of batch formulations of naltrexone, each 2000 liquid grams of a given formulation for intranasal administration for the treatment of disorders including, for example, alcohol use disorders, which may be dispensed in increments of about 100 μL, for example. to manufacture

The following examples were prepared as follows. To a weighed 4 L batch vessel equipped with a stir bar, 1800.0 grams of Water for Injection (WFI) was added and mixing was initiated. 24.0 g, 32.0 g, 40.0 g or 60.0 g naltrexone hydrochloride (NH) was added and the NH vessel was rinsed with 4 5 mL WFI rinses and mixed until the NH dissolved visually. While mixing, add 5.0 g DDM and mix until visually dissolved; The same procedure was then performed using 6.0 g of EDTA. Then add an initial dose of 12.6 g, 11.7 g, 10.5 g or 7.9 g of NaCl, depending on the formulation concentration; NaCl was added intermittently and mixed between additions until visually dissolved. Then, while mixing, 40.0 g of BZK 1% stock solution was added, the BZK 1% stock solution vessel was rinsed with 10 mL of rinse and mixed until the BZK was visually dissolved. Finally, the pH of the solution was measured using a calibrated pH meter, and when it exceeded 5.5, it was adjusted until it became 3.5 to 5.5 using 10% HCl, and the target pH was set to 5.0. This is done by dropwise addition and mixing for 3 to 5 minutes between the droplets, followed by adding water to the Q.S. Add up to about 2000.0 g and stir for 5 minutes.

The formulation can be tested according to the above procedures of Examples A to E and according to methods known in the art; Some of these formulations were tested in Example 8 below. The pharmacokinetic properties of these formulations are consistent with the properties of effective drugs for the treatment of opioid overdose, and use "as needed" to treat multiple substance use disorders exemplified by alcohol use disorders and other reward-based disorders. it is expected to do These properties include rapid onset (short T _max ), high plasma concentrations and short half-life compared to oral administration achievable with their formulation.

Example 8: Evaluation of the pharmacokinetics of intranasal naltrexone

A single facility, non-blind, randomized, 4-sequence, 4-treatment, 4-period crossover pilot study was completed in healthy male and non-pregnant female subjects. Twenty healthy subjects were enrolled. Twenty subjects completed the study and had evaluable data across all study durations.

endpoint . The main study endpoints were compared to oral administration of 50 mg naltrexone hydrochloride (reference product, also referred to herein as R), naltrexone hydrochloride nasal spray (test products 1, 2, and 3, respectively, T1, T2 and T3 herein). Determine the pharmacokinetics of three different doses (1.2 mg, 1.6 mg, and 3 mg) of the test article and identify the intranasal dose of the test product that can achieve systemic exposure of naltrexone comparable to an orally administered dose of 50 mg. will do The endpoint of the secondary study is to evaluate the safety and tolerability of the test product, particularly nasal irritation (erythema, edema and erosion).

Inclusion and exclusion criteria . The inclusion criteria for this study were: written consent; At time of consent, male and female subjects 18 to 55 years of age; weight greater than or equal to 48 kg, body mass index (BMI) of 18.0 to 30.0 kg/m ² (inclusive); systolic blood pressure 90 to 140 mmHg at rest, diastolic blood pressure 65 to 90 mmHg (inclusive); resting heart rate from 40 to 100 bpm (inclusive); resting respiratory rate of 8 to 20 (inclusive); adequate venous access; No clinically significant abnormalities on physical examination; no clinically significant abnormalities on the 12-lead ECG, recorded after at least 3 minutes in the supine position; No clinically significant abnormalities in hematology, biochemistry, coagulation and urinalysis parameters; negative test results for anti-HIV-1Ab and anti-HIV-2Ab antibodies, hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus antibody (anti-HCVAb); non-smokers or original smokers (ie, those who have stopped using tobacco or nicotine-containing products within the past 3 months); (Temporary use of tobacco or nicotine-containing products is permitted if there is no nicotine addiction and the subject has consented to quit smoking during the study period); Willingness to accept and adhere to study restrictions (eg, alcohol intake, methylxanthine, diet, exercise, contraception, and medication); and for women, infertility, postmenopausal, or of childbearing potential, use effective non-hormonal contraceptives or hormonal contraceptives at least 4 weeks prior to admission to Period 1 to ensure stable plasma hormone levels throughout the study period. , agree to continue on a stable continuum regimen until the end of the study.

Exclusion criteria at screening were as follows: known hypersensitivity/allergic reaction to study drug substance or any excipient; known severe hypersensitivity reactions to other drugs; Abnormal nasal anatomy, nasal symptoms (i.e., stuffy nose and/or runny nose, nasal polyps, etc.), rhinitis, and other conditions known to affect nasal absorption, or spraying the product into the nasal cavity prior to drug administration any nasal condition, including Based on medical history, previous or current dependence on opioids, alcohol, or other drugs thereof (excluding nicotine and caffeine); intercurrent disease considered by the investigator to be clinically important in the context of the study; the need for concomitant medications during the study; Any condition (such as stomach, kidney or liver, including peptic ulcer, inflammatory bowel disease, or pancreatitis) or surgical condition (cholecystectomy, gastrectomy, etc.); present or recent (within 7 days prior to screening) upper respiratory tract infection; QTc intervals greater than 450 msec in men and greater than 470 msec in women; positive result on urine drug abuse test or ethanol breath test; Depot injections or use of implants of any drug (all but contraceptives) within the past 3 months; average alcohol consumption over the past 6 months of >14 units (12 grams per unit) for men and >7 units for women; Methylxanthine-containing beverage equivalent to >500 mg methylxanthine (100 mg methylxanthine is equivalent to approximately 150 mL coffee, 300 mL tea, 75 mL hot chocolate, 800 mL cola, 300 mL energy drink or 25 g chocolate bar) or food (eg, coffee, tea, cola, soda, chocolate); Participation in a clinical trial within the past 2 months, or participation in two or more clinical trials within the past 12 months; Blood donation or significant blood loss (≥450 mL) for any reason, or plasma exchange was performed within the past 2 months; Difficulty fasting or any dietary restriction that is likely to interfere with the diet provided during the study, such as lactose intolerance, vegan, low fat, low sodium; Difficulty donating blood to one arm; Difficulty swallowing capsules or tablets; women, pregnant or lactating; and any other conditions in which the investigator considers the subject unsuitable for study.

Exclusion criteria for admission were as follows: systolic blood pressure at rest 90 to 140 mmgHg (inclusive); and diastolic blood pressure 65 to 90 (inclusive); resting heart rate from 40 to 100 bpm (inclusive); resting respiratory rate of 8 to 20 (inclusive); QTcF interval >500msec; Serious arrhythmias defined as 6 or more supraventricular tachycardias or 3 or more ventricular tachycardias; a recent disease or condition or treatment that, according to the investigator, may occur at a time that may place the subject at undue risk or interfere with the pharmacokinetics of the study drug due to study participation; In the investigator's opinion, medications should be taken within the past 14 days, as long as they do not interfere with the pharmacokinetics of the study drug or compromise subject safety (use of topical products without systemic absorption, or recommended contraceptives are acceptable), vitamins, nutritional supplements. use of prescription or over-the-counter medications, including food and herbal supplements (including St John's Wort); consumption of alcoholic products within the past 72 hours; positive result on urine drug abuse test or ethanol breath test; positive results on a urine beta-hCG pregnancy test in women of childbearing potential; and any other conditions in which the investigator considers the subject ineligible for the study period.

clinical procedure . Subjects were detained in a clinical research facility for the duration of the study, between 15 and 15 nights. Each subject experienced 4 treatment periods during the study. Each subject received 1 of 4 treatments in each of the 4 treatment periods.

Reference (R) One 50 mg film-coated tablet of naltrexone hydrochloride (NTX) as a single dose Test Product 1 (T1) 1.2 mg naltrexone hydrochloride (NTX) intranasal dose (two 0.1 mL sprays of 12 mg/mL solution) administered twice 2 hours apart. T1 was prepared as described in Formulation Example 49 above. Test Product 2 (T2) 1.6 mg naltrexone hydrochloride (NTX) intranasal dose (two 0.1 mL sprays of 16 mg/mL solution) administered twice 2 hours apart. T2 was prepared as described in Formulation Example 50. Test Product 3 (T3) 3 mg naltrexone hydrochloride (NTX) intranasal dose (two 0.1 mL sprays of 30 mg/mL solution) in two doses 2 hours apart. T3 was prepared as described in Formulation Example 52 above.

According to the randomization scheme, subjects were assigned to one of several treatment sequences in which the investigated products T1, T2, T3 and R were administered in various sequences. The investigational product was administered in the morning after an overnight fast of at least 10 hours. The reference product was administered orally as a single dose with 240 mL of water (swallowed). Each test article was administered once: the first dose was performed in one nostril and the second dose was performed in the other nostril with the subject upright after 2 hours. Subjects were instructed to stop breathing during administration of a nasal spray to a scheduled nostril. Test articles were primed prior to use. After priming, the dosing device was weighed before and after each administration and the weight of the administered dose was determined. The doses of each investigational product were separated by 3-day washout intervals.

In each study period, subjects remained fasted overnight until morning, with meals occurring approximately 3 hours after the reference product dose and 1 hour after the second dose of the test product dose. From 1 hour prior to dosing until 3 hours post-dose (a time point defined with respect to the first dose of the test product or administration of the reference product), no liquids were allowed. Water was provided ad libitum at all other times. The same standardized meals and snacks were provided in all periods. Lunch was served approximately 3 hours after breakfast, and all other meals were scheduled at appropriate times by the clinical site.

Sample collection and analysis . At each study period, 24 venous blood samples (4 mL volume each) were collected to determine plasma concentrations of naltrexone and 6β-naltrexol at the following time points: pre-dose, and at the reference product dose and first of the test product. After dose 0:02, 0:05, 0:10, 0:15, 0:20, 0:30, 0:45, 1:00, 2:00, 2:05, 2:10, 2:15, at 2:20, 2:30, 2:45, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 24:00 and 48:00 hours:minutes.

Plasma concentrations of naltrexone and 6β-naltrexol were determined using previously validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) analytical methods.

The pharmacokinetic parameters of naltrexone and 6β-naltrexol were estimated using a non-compartmental approach assuming a non-linear terminal phase, with Phoenix® WinNonlin® version 8.1 or higher (Cetara USA Inc. Princeton, NJ) or higher. The actual time of blood sampling was used to estimate pharmacokinetic parameters.

The following pharmacokinetic parameters were estimated: maximum observed plasma concentration (C _max ); time of occurrence of C _{max (T max} ); area under the plasma concentration versus time curve (AUC) from pre-dose (time 0) to quantifiable concentration (AUC _{0-t ) to the last sampling time;} AUC from time 0 to infinity (AUC _0-∞ ); apparent end removal rate constant (λ _z ); Appearance terminal clearance half-life (t _1/2 ; note that each value is given here for each of the two-dose administrations) and apparent total clearance of drug from plasma (CL/F). _{C max} , t _max , AUC _0-t and AUC _0-∞ of naltrexone and 6β-naltrexol were the main endpoints.

Using the mixed effects model, analysis of variance (ANOVA) was performed and the In transformed C _max , AUC _0-t and AUC _0-∞ were compared. Sequence, duration, and treatment were included in the ANOVA model as independent factors. Test-to-reference geometric least squares mean ratios (GMRs) and corresponding 90% confidence intervals (CIs) were calculated for _{C max} , AUC _0-t and AUC _{0-∞ .} The relative extent of intranasal absorption (Frel) (test versus reference) was estimated from the _{dose-corrected AUC 0-t.} T _max were compared using a non-parametric test. The secondary endpoints were λ _z , t _1/2 and CL/F.

safety . Safety was assessed through evaluation of adverse events, 12-lead ECG, vital signs, nasal examination, weighing, olfactory testing, and clinical trials (see flow-charts). Adverse events were monitored throughout the study.

result . The results are provided below and in the accompanying drawings.

Table 9 shows the mean and respective summary statistics of the naltrexone primary pharmacokinetic parameters of 20 subjects following administration of Test Article 1, Test Article 2, Test Article 3 and Reference Product.

C _max (ng/mL) t _max (h) AUC _0-t (ng.h/mL) AUC _0-∞ (ng.h/mL) test product 1
(1.2mg NTX) n 20 20 20 20 G _mean 8.10 0.58 12.42 12.60 A _average 8.90 1.18 13.35 13.54 SD 3.86 1.05 4.75 4.81 CV(%) 43.3 88.9 35.6 35.5 test product 2
(1.6mg NTX) n 20 20 20 20 G _mean 9.22 0.60 15.19 15.46 A _average 9.68 1.18 16.07 16.35 SD 3.03 1.03 5.03 5.09 CV(%) 31.3 88.1 31.3 31.2 test product 3
(3.0mg NTX) n 20 20 20 20 G _mean 19.88 0.80 31.33 31.94 A _average 21.01 1.39 32.57 33.13 SD 7.23 1.01 9.02 8.91 CV(%) 34.4 72.5 27.7 26.9 reference product n 20 20 20 19 G _mean 9.31 0.85 23.15 23.81 A _average 11.14 0.98 26.14 27.09 SD 6.92 0.65 13.65 14.53 CV(%) 62.1 66.3 52.2 53.6

Table 10 shows the mean and respective summary statistics of naltrexone secondary pharmacokinetic parameters of 20 subjects after administration of Test Article 1, Test Article 2, Test Article 3 and Reference Product.

pAUC _0-0.033
(ng.h/mL) pAUC _0-0.083
(ng.h/mL) pAUC _0-0.167
(ng.h/mL) pAUC _0-0.250
(ng.h/mL) pAUC _0-0.333
(ng.h/mL) pAUC _0-0.500
(ng.h/mL) λ _z (1/h) t _1/2 (h) CL/F
(L/h) Test Product 1 (1.2mg NTX) n 20 20 20 20 20 20 20 20 20 G _mean
0.11 0.56 1.08 1.50 2.09 0.295 2.35 190.45 A _average 0.02 0.16 0.66 1.22 1.67 2.28 0.324 2.64 207.51 SD 0.04 0.10 0.34 0.56 0.70 0.88 0.129 1.43 95.66 CV(%) 169.5 66.0 50.9 45.7 42.0 38.6 39.9 54.2 46.1 Test Product 2 (1.6mg NTX) n 19 20 20 20 20 20 20 20 20 G _mean
0.08 0.50 1.03 1.47 2.11 0.219 3.16 206.97 0.08 A _average 0.01 0.10 0.58 1.18 1.66 2.36 0.267 3.86 222.73 SD 0.01 0.06 0.29 0.56 0.78 1.04 0.158 2.31 105.01 CV(%) 105.1 60.1 49.2 48.0 46.8 44.1 59.3 59.8 47.1 test product 3
(3.0mg NTX) n 20 20 20 20 20 20 20 20 20 G _mean
0.01 0.21 1.09 2.10 2.93 4.14 0.130 5.34 187.87 A _average 0.02 0.27 1.26 2.41 3.35 4.69 0.137 6.06 195.47 SD 0.02 0.17 0.67 1.21 1.61 2.12 0.036 4.93 58.78 CV(%) 83.8 63.2 52.9 50.3 48.0 45.2 25.9 81.4 30.1 reference product n 19 20 20 20 20 20 19 19 19 G _mean
0.127 5.45 2099.84 A _average 0.00 0.00 0.00 0.04 0.16 0.79 0.130 5.57 2364.41 SD 0.00 0.00 0.01 0.08 0.27 0.95 0.029 1.21 1121.61 CV(%) 235.8 208.1 165.6 120.2 22.5 21.8 47.4

Table 11 presents the mean naltrexone pharmacokinetic parameters and respective summary statistics of 20 subjects after the first and second doses of Trial 1 Product, Trial 2 Product, Trial 3 Product and Reference Product.

1st dose Second dose C _max (ng/mL) t _max (h) pAUC _0-2
(ng.h/mL) C _max (ng/mL) t _max (h) pAUC _2-t
(ng.h/mL) C _max (ng/mL) Trial 1 product (1.2mg NTX) n 20 20 20 20 20 20 G _mean 6.98 0.17 4.34 5.64 2.19 7.69 A _average 7.87 0.18 4.64 6.87 2.19 8.67 SD 3.61 0.06 1.57 3.97 0.06 3.73 CV(%) 45.9 34.9 33.9 57.8 2.7 43.1 Trial 2 product (1.6mg NTX) n 20 20 20 20 20 20 G _mean 7.25 0.18 4.69 7.72 2.19 10.11 A _average 8.12 0.18 5.11 8.47 2.19 10.92 SD 3.74 0.03 1.95 2.87 0.05 3.66 CV(%) 46.1 18.6 38.3 33.9 2.2 33.5 Trial 3 product (3.0mg NTX) n 20 20 20 20 20 20 G _mean 13.98 0.16 8.89 15.15 2.21 21.36 A _average 16.07 0.18 9.99 17.13 2.21 22.50 SD 8.15 0.08 4.14 8.21 0.06 7.08 CV(%) 50.7 43.4 41.4 47.9 2.6 31.4 reference product n 19 20 20 20 20 20 G _mean 0.127 5.45 2099.84 A _average 0.00 0.00 0.00 0.04 0.16 0.79 SD 0.00 0.00 0.01 0.08 0.27 0.95 CV(%) 235.8 208.1 165.6 120.2 22.5

Table 12 presents the mean and respective summary statistics of 6β-naltrexol primary pharmacokinetic parameters of 20 subjects following administration of Trial 1 product, Trial 2 product, Trial 3 product and Reference product.

C _max
(ng/mL) t _max (h) AUC _0-t
(ng.h/mL) AUC _0-∞
(ng.h/mL) Trial 1 product
(1.2mg NTX) n 20 20 20 20 G _mean 2977.69 2.43 39661.64 44752.81 A _average 4726.08 3.00 43010.42 49049.12 SD 8815.95 1.65 18372.27 22391.88 CV(%) 186.5 55.0 42.7 45.7 Trial 2 product
(1.6mg NTX) n 20 20 20 20 G _mean 3460.35 2.93 45308.65 51158.30 A _average 5772.44 3.10 49901.89 57840.89 SD 11486.17 0.88 24055.17 34255.04 CV(%) 199.0 28.4 48.2 59.2 Trial 3 product
(3.0mg NTX) n 20 20 20 20 G _mean 5423.19 3.03 77062.89 86359.93 A _average 5742.45 3.09 80141.96 89628.51 SD 1885.91 0.64 22003.15 24149.84 CV(%) 32.8 20.8 27.5 26.9 reference product n 20 20 20 20 G _mean 1113.795 0.97 727323.16 795385.17 A _average 117199.63 1.13 739175.55 809654.98 SD 37154.79 0.71 129584.07 150316.07 CV(%) 31.7 62.7 17.5 18.6

Table 13 shows the mean and respective summary statistics of secondary pharmacokinetic parameters of 6β-naltrexol in 20 subjects following administration of Trial 1 Product, Trial 2 Product, Trial 3 Product and Reference Product.

pAUC _0-0.033
(ng.h/mL) pAUC _0-0.083
(ng.h/mL) pAUC _0-0.167
(ng.h/mL) pAUC _0-0.250
(ng.h/mL) pAUC _0-0.333
(ng.h/mL) pAUC _0-0.500
(ng.h/mL) λ _z
(1/h) t _1/2
(h) CL/F
(L/h) Test Product 1 (1.2mg NTX) n 20 20 20 20 20 20 20 20 20 G _mean
52.32 121.46 218.83 450.19 0.045 15.43 53.63 A _average 17.83 39.49 94.17 174.39 282.58 531.05 0.046 15.75 58.42 SD 26.38 55.90 111.62 170.14 233.62 352.46 0.009 3.41 24.11 CV(%) 147.9 141.5 118.5 97.6 82.7 66.4 19.4 21.6 41.3 Test Product 2 (1.6mg NTX) n 19 20 20 20 20 20 20 20 20 G _mean
49.63 116.10 208.74 434.59 0.047 14.85 62.55 A _average 14.45 35.67 87.27 166.76 273.69 530.56 0.048 15.28 70.05 SD 20.65 50.66 102.20 159.50 225.54 368.09 0.010 4.17 36.83 CV(%) 143.0 142.0 117.1 95.6 82.4 69.4 20.9 27.3 52.6 Test Product 3 (3.0mg NTX) n 20 20 20 20 20 20 20 20 20 G _mean
58.40 153.54 294.84 647.77 0.047 14.59 69.48 A _average 9.93 27.32 82.31 191.08 353.70 750.71 0.048 14.93 72.36 SD 13.68 33.68 69.66 127.72 212.93 392.87 0.009 3.57 22.31 CV(%) 137.8 123.3 84.6 66.8 60.2 52.3 19.0 23.9 30.8 reference product n 19 20 20 20 20 20 20 20 20 G _mean
273.59 2489.10 0.048 14.39 62.86 A _average 2.11 5.70 49.31 427.56 1769.35 8799.34 0.049 14.67 64.10 SD 2.90 7.39 75.91 713.22 2729.39 9755.51 0.010 2.97 13.57 CV(%) 137.7 129.6 153.9 166.8 154.3 110.9 19.5 20.2 21.2

According to the protocol, using a mixed effects model, analysis of variance (ANOVA) was performed and naltrexone In-transformed C _max , AUC _0-t and AUC _0-∞ were compared. Test-to-reference geometric least squares mean ratios (GMRs) and corresponding 90% confidence intervals (CIs) were calculated. The results of comparing the three different Test Articles (Test Article 1, Test Article 2 and Test Article 3) to the reference are summarized in Table 14.

Mixed Effect ANOYA Results of Pharmacokinetic Parameters of Naltrexone geometric LS mean ^One PK parameters exam 1 Reference exam 1-to-refer
GMR (%) 90% CI C _max 8.10 9.31 86.93 65.69 - 115.04 AUC _0-t 12.42 23.15 53.63 41.69 - 69.00 AUC _0-∞ 12.59 23.80 52.92 41.15 - 68.05 PK parameters test 2 Reference Test 2-versus-reference
GMR (%) 90% CI C _max 9.22 9.31 99.00 74.54 - 131.49 AUC _0-t 15.19 23.15 65.63 50.98 - 84.49 AUC _0-∞ 15.42 23.80 64.78 50.34 - 83.37 PK parameters exam 3 Reference Exam 3-vs-see
GMR (%) 90% CI C _max 19.88 9.31 213.41 162.41 - 280.42 AUC _0-t 31.33 23.15 135.34 107.88 - 169.80 AUC _0-∞ 31.85 23.80 133.83 106.74 - 167.80

¹ LS mean values are _{given in ng/mL for C max} and ng.h/mL for AUC.

According to the protocol, using a mixed effects model, analysis of variance (ANOVA) was performed and the 6β-naltrexol In-transformation C _max , AUC _0-t and AUC _0-∞ were compared. Test-to-reference geometric least squares mean ratios (GMRs) and corresponding 90% confidence intervals (CIs) were calculated. The results of comparing the three different products (Test 1, Test 2 and Trial 3) to the reference are summarized in Table 15.

Mixed Effects ANOVA Results of Naltrexone Pharmacokinetic Parameters geometric LS mean PK parameters exam 1 Reference Exam 1-to-refer
GMR (%) 90% CI C _max 2977.69 1113.795 2.67 2.01 - 3.56 AUC _0-t 39661.64 727323.16 5.45 4.75 - 6.26 AUC _0-∞ 44752.81 795385.17 5.63 4.91 - 6.44 PK parameters test 2 Reference Test 2-versus-reference
GMR (%) 90% CI C _max 3460.35 1113.795 3.11 2.34 - 4.12 AUC _0-t 45308.65 727323.16 6.23 5.38 - 7.21 AUC _0-∞ 51158.30 795385.17 6.43 5.51 - 7.51 PK parameters exam 3 Reference Exam 3-vs-see
GMR (%) 90% CI C _max 5423.19 1113.795 4.87 4.06 - 5.83 AUC _0-t 77062.89 727323.16 10.60 9.39 - 11.95 AUC _0-∞ 86359.93 795385.17 10.86 9.67 - 12.20

¹ LS mean values are _{given in ng/mL for C max} and ng.h/mL for AUC.

According to the protocol, the relative extent (F _rel ) of intranasal absorption (test versus reference) of naltrexone was estimated from the dose-corrected AUC _0-t (AUC _{0-t /D) of the drug.} Table 16 shows the arithmetic mean and coefficient of variation (CV%) of the estimated parameters.

Relative degree of naltrexone-intranasal absorption PK parameters
(unit) Test 1 (n = 20) Test 2 (n = 20) Trial 3 (n = 20) Reference (n = 20) AUC _0-t
(ng.h/mL) 13.35 (35.6%) 16.07 (31.3%) 32.57 (27.7%) 26.14 (52.2%) AUC _0-t /D
(ng.h/mL/mg) 5.56 (35.6%) 5.02 (31.3%) 5.43 (27.7%) 0.52 (52.2%) Frel (%) 1328.78 (61.7%) 1238.87 (65.8%) 1306.38 (61.9%)

n - number of objects

AUC _0-t /D - dose normalized AUC _0-t . For each test article, D corresponds to the total administered dose of the article.

F _rel - relative degree of intranasal absorption (test/reference)

According to the protocol, the tmax obtained for each formulation was compared using the non-parametric test presented in Table 17.

Naltrexone: t _max non-parametric analysis treatment difference median 90% CI Test 1 - Reference 0.29 -0.54 - 0.54 Test 2 - Reference 0.29 -0.46 - 0.64 Test 3 - Reference 0.46 0.17 - 1.17

another embodiment

The detailed description set forth herein is provided to assist those skilled in the art in practicing the present disclosure. However, the disclosure described and claimed herein is not to be limited in scope by the specific embodiments disclosed herein, as these embodiments are intended to be illustrative of some aspects of the disclosure. 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 and scope of the findings of the present invention. Such modifications are intended to be within the scope of the appended claims.

All U.S. or foreign references, patents or applications cited herein are hereby incorporated by reference as if set forth herein in their entirety. In case of inconsistency, the material disclosed herein as written shall control.

While the present invention has been described with reference to the above embodiments, it will be understood that modifications and variations are included within the spirit and scope of the present invention. Accordingly, the present invention is limited only by the following claims.

Claims (66)

An intranasal formulation comprising an aqueous solution comprising about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof. An intranasal formulation comprising an aqueous solution comprising about 10 mg/mL to about 40 mg/mL of naltrexone or a pharmaceutically acceptable salt thereof in a volume of about 50 to about 150 μL. 3. The method of claim 1 or 2,
isotonicity agents;
preservatives;
stabilizers;
absorption enhancers; and
Sufficient amount of water to achieve a final volume of about 50 to about 150 μL
Further comprising a, formulation. 4. The method of claim 3,
about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;
about 0.1 mg to about 1.2 mg of an isotonic agent;
about 0.001 mg to about 0.1 mg of a preservative;
about 0.1 mg to about 0.5 mg of a stabilizer;
about 0.05 mg to about 2.5 mg of an absorption enhancer; and
Sufficient amount of water to achieve a final volume of about 50 to about 150 μL
A formulation comprising a. 4. The method of claim 3,
about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;
from about 0.1% to about 1.2% of an isotonic agent;
from about 0.001% to about 0.1% of a preservative;
from about 0.1% to about 0.5% of a stabilizer;
about 0.05% to about 2.5% absorption enhancer
A formulation comprising a. 6. The method according to claim 4 or 5,
the isotonicity agent is NaCl;
the preservative is benzalkonium chloride;
the stabilizing agent is disodium edetate;
wherein the absorption enhancer is an alkylsaccharide. 7. The formulation of claim 6, wherein the alkylsaccharide is dodecyl maltoside. 8. The method of claim 7,
about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;
about 0.1 mg to about 1.2 mg of NaCl;
from about 0.001 mg to about 0.1 mg of benzalkonium chloride;
about 0.15 mg to about 0.5 mg of disodium edetate;
from about 0.05 mg to about 2.5 mg of dodecyl maltoside; and
Sufficient amount of water to achieve a final volume of about 50 to about 150 μL
A formulation comprising a. 9. The formulation of claim 8 comprising from about 0.1 mg to about 0.5 mg of dodecyl maltoside. 10. The formulation of claim 9 comprising about 0.25 mg of dodecyl maltoside. 9. The formulation of claim 8 comprising from about 0.2 mg to about 0.3 mg of disodium edetate. 10. The method of claim 9,
about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;
about 0.3 mg to about 0.7 mg of NaCl;
about 0.02 mg of benzalkonium chloride;
about 0.3 mg of disodium edetate;
about 0.25 mg of dodecyl maltoside; and
Sufficient amount of water to achieve a final volume of about 50 to about 150 μL
A formulation comprising a. The formulation of claim 10 , wherein the amount of water is sufficient to achieve a final volume of about 80 to about 120 μL. The formulation of claim 11 , wherein the amount of water is sufficient to achieve a final volume of about 100 μL. 8. The method of claim 7,
about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;
about 0.1% to about 1.2% NaCl;
from about 0.001% to about 0.1% benzalkonium chloride;
about 0.15% to about 0.5% disodium edetate;
from about 0.05% to about 2.5% dodecyl maltoside; and
water
A formulation comprising a. 16. The formulation of claim 15 comprising from about 0.1% to about 0.5% dodecyl maltoside. The formulation of claim 16 comprising about 0.25% dodecyl maltoside. 16. The formulation of claim 15 comprising from about 0.2% to about 0.3% disodium edetate. 18. The method of claim 17,
about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;
about 0.3% to about 0.7% NaCl;
about 0.02% benzalkonium chloride;
about 0.3% disodium edetate;
about 0.25% dodecyl maltoside; and
water
A formulation comprising a. The formulation of claim 19 , wherein the amount of water is sufficient to achieve a final volume of about 50 to about 150 μL. The formulation of claim 20 , wherein the amount of water is sufficient to achieve a final volume of about 100 μL. 22. The formulation according to any one of the preceding claims, wherein the naltrexone is naltrexone hydrochloride. 23. The formulation of claim 22 comprising about 1.2 mg, about 1.6 mg, about 2.0 mg or about 3.0 mg of naltrexone or an equivalent amount of naltrexone hydrochloride. An opioid overdose or reward-based disorder in a subject comprising administering to the subject an intranasal formulation comprising an aqueous solution comprising about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof. based disorder). administering to the subject a first intranasal formulation comprising an aqueous solution comprising about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof; and a second intranasal formulation comprising an aqueous solution comprising about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof. An opioid excess in a subject, comprising administering to the subject an intranasal formulation comprising an aqueous solution comprising about 10 mg/mL to about 30 mg/mL of naltrexone or a pharmaceutically acceptable salt thereof in a volume of about 50 to about 150 μL. Methods of treatment of dosing or reward-based disorders. A first intranasal formulation comprising an aqueous solution comprising about 10 mg/mL to about 40 mg/mL of naltrexone or a pharmaceutically acceptable salt thereof in a volume of about 50 to about 250 ul is administered to the subject, and from about 10 mg/mL to An opioid overdose or reward-based disorder in a subject comprising administering a second intranasal formulation comprising an aqueous solution comprising about 40 mg/mL of naltrexone or a pharmaceutically acceptable salt thereof in a volume of about 50 to about 250 μL. treatment methods. 28. The method of claim 25 or 27, wherein the second intranasal formulation is administered between about 1 hour and about 3 hours after administration of the first intranasal formulation. 29. The method of any one of claims 24-28, wherein the intranasal formulation is
isotonic agents;
preservatives;
stabilizers;
absorption enhancers; and
Sufficient amount of water to achieve a final volume of about 50 to about 150 μL
Further comprising a, method. 30. The method of claim 29, wherein said intranasal formulation is
about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;
about 0.1 mg to about 1.2 mg of an isotonic agent;
about 0.001 mg to about 0.1 mg of a preservative;
about 0.1 mg to about 0.5 mg of a stabilizer;
about 0.05 mg to about 2.5 mg of an absorption enhancer; and
Sufficient amount of water to achieve a final volume of about 50 to about 150 μL
A method comprising 30. The method of claim 29, wherein said intranasal formulation is
about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;
from about 0.1% to about 1.2% of an isotonic agent;
from about 0.001% to about 0.1% of a preservative;
from about 0.1% to about 0.5% of a stabilizer;
about 0.05% to about 2.5% absorption enhancer
A method comprising 32. The method of claim 30 or 31,
the isotonicity agent is NaCl;
the preservative is benzalkonium chloride;
the stabilizing agent is disodium edetate;
wherein the absorption enhancer is an alkylsaccharide. 33. The method of claim 32, wherein the alkylsaccharide is dodecyl maltoside. 34. The method of claim 33, wherein said intranasal formulation is
about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;
about 0.1 mg to about 1.2 mg of NaCl;
from about 0.001 mg to about 0.1 mg of benzalkonium chloride;
about 0.15 mg to about 0.5 mg of disodium edetate;
from about 0.05 mg to about 2.5 mg of dodecyl maltoside; and
Sufficient amount of water to achieve a final volume of about 50 to about 150 μL
A method comprising 35. The method of claim 34, wherein the intranasal formulation comprises from about 0.1 mg to about 0.5 mg of dodecyl maltoside. 36. The method of claim 35, wherein the intranasal formulation comprises about 0.25 mg of dodecyl maltoside. 35. The method of claim 34, wherein the intranasal formulation comprises from about 0.2 mg to about 0.3 mg of disodium edetate. 37. The method of claim 36, wherein said intranasal formulation is
about 1 mg to about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof;
about 0.3 mg to about 0.7 mg of NaCl;
about 0.02 mg of benzalkonium chloride;
about 0.3 mg of disodium edetate;
about 0.25 mg of dodecyl maltoside; and
Sufficient amount of water to achieve a final volume of about 50 to about 150 μL
A method comprising The method of claim 38 , wherein the amount of water is sufficient to achieve a final volume of about 50 to about 150 μL. 40. The method of claim 39, wherein the amount of water is sufficient to achieve a final volume of about 100 μL. 34. The method of claim 33,
about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;
about 0.1% to about 1.2% NaCl;
from about 0.001% to about 0.1% benzalkonium chloride;
about 0.1% to about 0.5% disodium edetate;
from about 0.05% to about 2.5% dodecyl maltoside; and
water
A method comprising 42. The method of claim 41, wherein the intranasal formulation comprises from about 0.1% to about 0.5% dodecyl maltoside. 43. The method of claim 42, wherein the intranasal formulation comprises about 0.25% dodecyl maltoside. 42. The method of claim 41, wherein the intranasal formulation comprises from about 0.2% to about 0.3% disodium edetate. 44. The method of claim 43, wherein said intranasal formulation is
about 1% to about 3% of naltrexone or a pharmaceutically acceptable salt thereof;
about 0.3% to about 0.7% NaCl;
about 0.02% benzalkonium chloride;
about 0.3% disodium edetate;
about 0.25% dodecyl maltoside; and
water
A method comprising 46. The method of claim 45, wherein the amount of water is sufficient to achieve a final volume of about 50 to about 150 μL. 47. The method of claim 46, wherein the amount of water is sufficient to achieve a final volume of about 100 μL. 48. The method of any one of claims 24-47, wherein the naltrexone is naltrexone hydrochloride. 49. The method of claim 48, wherein the intranasal formulation comprises about 1.2 mg, about 1.6 mg, about 2.0 mg, or about 3.0 mg of naltrexone or an equivalent amount of naltrexone hydrochloride. 50. The method of any one of claims 24-49, wherein the method treats an opioid overdose. 50. The method of any one of claims 24-49, wherein the method treats a reward based disorder. 49. The method of claim 48, wherein the reward-based disorder is a substance use disorder. 49. The method of claim 48, wherein the substance use disorder is an alcohol use disorder. 54. The method of claim 53, wherein the intranasal formulation comprising naltrexone is administered prior to ingestion of the alcohol. 55. The method of claim 54, wherein the intranasal formulation comprising naltrexone is administered about 1-2 hours prior to ingestion of the alcohol. 55. The method of claim 54, wherein the intranasal formulation comprising naltrexone is administered about 0.5 to about 1 hour prior to ingestion of alcohol. 55. The method of claim 54, wherein the intranasal formulation comprising naltrexone is administered about 10 to about 30 minutes prior to ingestion of the alcohol. 55. The method of claim 54, wherein the intranasal formulation comprising naltrexone is administered about 5 to about 10 minutes prior to ingestion of the alcohol. 54. The method of claim 53, wherein the intranasal formulation comprising naltrexone is administered concurrently with alcohol intake. 54. The method of claim 53, wherein the intranasal formulation comprising naltrexone is administered within 0.5 hours of initiation of alcohol intake. 61. The method of any one of claims 24 to 60, wherein the intranasal formulation comprising naltrexone is administered to the subject 1 to 4 times per day. 62. The method of claim 61, wherein the intranasal formulation comprising naltrexone is administered per day at a dose of about 1.2 mg, about 1.6 mg, about 2 mg, or about 3 mg, depending on the needs of the subject. 36. The method of claim 35, wherein the intranasal formulation comprising naltrexone is administered as a first dose of about 1.2 mg, about 1.6 mg, about 2 mg or about 3 mg in the morning, and about 1.2 mg, about 1.6 as needed prior to alcohol consumption. mg, as a subsequent dose of about 2 mg or about 3 mg. 24. Suitable for nasal delivery of a pharmaceutical formulation to a subject experiencing an opioid overdose or having a compensation-based disorder comprising a plurality of doses each comprising the intranasal formulation of any one of claims 1-23. A multi-dose device. 65. The device of any one of claims 59-64, wherein about 0.05 to about 0.15 mL of the formulation is delivered to the subject in each dose. 66. The device of claim 65, wherein about 0.1 mL of the formulation is delivered to the subject in each dose.

Images