JP2022514340A - Compositions, Devices, and Methods for Treating Overdose and Reward-Based Disorders - Google Patents

Abstract

Drug products adapted for nasal delivery are provided, including devices filled with pharmaceutical compositions containing naltrexone. Formulations and methods for treating alcohol use disorders and related conditions using the drug products are also provided. TIFF2022514340000027.tif100134

Description

Cross-reference to related applications This application is based on 35U.SC 119 (e), US Patent Application No. 62 / 782,943 filed December 20, 2018 and US Patent filed December 20, 2018. Claim the benefit of priority for application 16/311,944. The entire disclosure of both applications is considered part of the disclosure of this application, which is incorporated by reference in the disclosure of this application in its entirety. The present application also incorporates the disclosures of PCT Publication Nos. WO2017 / 223566 and WO2018 / 089709 by reference in their entirety as described herein.

INDUSTRIAL APPLICABILITY The present invention relates generally to pharmaceutical compositions, and more particularly to nasal preparations containing naltrexone and its forms, as well as conditions and symptoms thereof such as opioid overdose and disorders such as alcohol use disorders. With respect to a method of using an intranasal formulation comprising naltrexone and its forms, the method comprises administering an intranasal formulation of the opioid antagonist naltrexone.

Background Information Naltrexone was initially developed to treat opioid dependence because it has the effect of blocking the euphoric effects of opioids. Since 1984, naltrexone tablet preparation for oral administration has been used to treat opioid addiction. To improve compliance, long-acting depot-type naltrexone was developed, which is administered at one-time intervals for one month or longer. Data from clinical trials have demonstrated that depot preparations are effective in reducing the return to opioid-using conditions. Currently, there is one intramuscular sustained-release preparation and one oral preparation of naltrexone (Vivitrol®) for monthly administration approved by the FDA. These formulations are intended to maintain a relatively steady state of naltrexone levels sufficient to prevent naltrexone poisoning at all times.

A related but slightly different issue, opioid overdose, is a serious public health problem. In 2017, about 72,000 people died from drug overdose. Most of these, about 49,000, involved opioids. More than 19,000 of these deaths involved prescription opioid analgesics other than non-methadone synthetics, nearly 3,300 involved methadone, and about 16,000 involved heroin. Nearly 30,000 of these deaths are due to fentanyl and related synthetic opioids, which have increased significantly over the years. In summary, in 2016, the number of opioid-related overdose deaths far exceeded the peak numbers of HIV-related deaths and firearm-related deaths, and surged over the last nine years. There is still a need for effective treatments to reverse opioid overdose.

On the other hand, other abusive substances such as opioids or alcohol are often involved, but other activities that stimulate the brain's pleasant, rewarding, and strengthening centers are also involved, and unhealthy excesses of these substances. There is still a need for treatments for "reward-based" disorders that lead to consumption or immersion in these behaviors.

For example, alcohol can stimulate the reward circuit of the brain and enhance uninterrupted drinking. Severe and problematic drinking is medically diagnosed with alcohol use disorders (AUD). In 2014, about 6.8 percent (16.3 million adults) over the age of 18 had AUD in the United States. This includes 10.6 million men and 5.7 million women. In addition, in 2014, an estimated 679,000 adolescents aged 12 to 17 years (2.7% of this age group) had AUD. In 2012, 3.3 million deaths, or 5.9 percent of global deaths (7.6% for men and 4.0% for females), were due to alcohol consumption (WHO Global Status Report on Alcohol and Health, 2014).

In order to be diagnosed with AUD in the United States, certain criteria must be met as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM). For example, in the 5th edition of DSM, all individuals who meet two of the 11 criteria during the same 12-month period will be diagnosed with AUD. The severity of the 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). People with AUD can drink too much and, as a result, threaten themselves and others.

Alcohol abuse is a drinking pattern that has serious and repetitive adverse consequences. Alcoholics may neglect to fulfill their important school, work, or family obligations. People with alcoholism (also known as alcoholism) have lost solid control over their use of alcohol and often cannot stop drinking once they start drinking. Alcohol dependence is characterized by tolerance (you need to drink more to reach the same "high") and withdrawal symptoms when you stop drinking suddenly. Withdrawal symptoms may include nausea, sweating, restlessness, irritation, tremor, hallucinations, and convulsions.

Problem Drinking has multiple causes, all of which are genetic, physiological, psychological, and social factors. Not all individuals are equally affected by their respective causes. In some people with AUD, psychological traits such as impulsivity, low self-esteem, and a desire for approval stimulate inappropriate drinking. Genetic factors make some people particularly vulnerable to alcohol dependence. AUD can cause physiological changes that make heavy drinking the only way to avoid nasty things, and individuals with AUD may drink alcohol to partially reduce or avoid withdrawal symptoms.

Persons with disabilities related to reward-based behavior, such as AUD, can be from medical professionals, including doctors, nutritionists, psychologists, psychologists, medical social workers, or 12 Counseling and psychological therapy can be sought by attending the 12-step Alcoholic Anonymous meeting. However, access to such sources and their acceptance and success may be limited for a variety of reasons.

Great tolerance to the use of medications to treat reward-based behavioral disorders such as AUD remains long, and the latest evidence shows that medications are less commonly used in AUD treatment. Oral nalmefene is approved in Europe and patients can take it while drinking alcohol. 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 exclusively for the treatment of AUD in the United States. However, all of these medications can be abstinent before the start of treatment or must be taken by inpatients who have completed alcohol withdrawal symptoms. Therefore, there is still a need for medicines to treat AUD subjects who continue to drink.

Disorders based on non-drug rewards manifest themselves in psychological and behavioral patterns similar to substance use disorders. Thirsty, behavioral dysregulation, tolerance, withdrawal symptoms, and high recurrence, especially in subjects suffering from addictive behaviors that have negative consequences for human physical, mental, social, or financial well-being. Rates are found (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 show similar physiological expression. For example, from human brain function imaging studies, gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), video game entertainment (Koepp et al, 1998; Hoeft). et al, 2008), and seeing delicious food (Wang et al, 2004) are the same brain regions as the abusive drug (ie, the mesocorticolimbic system and the extended amygdala). It has been shown to activate much of the disease (Volkow et al, 2004).

Naltrexone intranasal (IN) formulations have the potential to be used to reverse opioid overdose and treat reward-based disorders without the use of needles or sustained-release formulations. Studies have shown that opioid antagonists such as naltrexone, given orally or injectably, can reverse opioid overdose and reduce alcohol consumption and its operant response. There is still a great need for quick and adaptable means.

Summary An intranasal formulation containing an aqueous solution containing naltrexone or a pharmaceutically acceptable salt thereof is disclosed herein.

A method of treating opioid overdose or reward-based disorders, such as alcohol use disorders (AUD), in a subject administered to an IN formulation containing a therapeutically effective amount of naltrexone or a pharmaceutically acceptable salt thereof. Methods are also disclosed herein, including the steps to do so.

A pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutical formulation disclosed herein for a subject experiencing opioid overdose or having a reward-based disorder, such as an alcohol use disorder (AUD). Devices adapted for nasal delivery of objects are also disclosed herein. In certain embodiments, the device is preprimed. In certain embodiments, the device can be primed prior to use. In certain embodiments, the device is a single dose device. In certain embodiments, the device is a multidose device.

Shown is the mean naltrexone plasma concentration-to-time profile after administration of test product 1, test product 2, test product 3, and reference product up to 12 hours on a uniform scale. Shown is the mean naltrexone plasma concentration-to-time profile after administration of test product 1, test product 2, test product 3, and reference product up to 12 hours on a semi-log scale. Average 6β-Naltrexol (major naltrexone metabolite) plasma concentration-to-time profile after administration of Test Product 1, Test Product 2, Test Product 3, and Reference Product on a uniform scale up to 12 hours Is rounded down in 12 hours). Average 6β-Naltrexol (major naltrexone metabolite) plasma concentration-to-time profile (end) after administration of test product 1, test product 2, test product 3, and reference product up to 12 hours on a semi-log scale. Is rounded down in 12 hours).

Detailed Description The following aspects further describe the invention disclosed herein.

The following are provided herein:
Aspect 1:
An intranasal preparation containing an aqueous solution containing about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof.

The following are also provided herein:
Aspect 2:
An aqueous solution containing 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, about 50 to about 250 μL (preferably about 50 to about 50 to about). An intranasal formulation contained in a volume of 150 μL).

The present disclosure further provides the following aspects:
Aspect 3:
Less than:
Isotonic;
Preservative;
Stabilizer;
The formulation according to embodiment 1 or 2, further comprising an absorption enhancer; and an amount of water sufficient to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL).

Aspect 4:
Less than:
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.1 mg to about 1.2 mg isotonic;
About 0.001 mg to about 0.1 mg of preservatives;
About 0.1 mg to about 0.5 mg of stabilizer;
The formulation according to embodiment 3, comprising an absorption promoter of about 0.05 mg to about 2.5 mg; and an amount of water sufficient to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL).

Aspect 5:
Less than:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.1% to about 1.2% isotonic;
About 0.001% to about 0.1% preservatives;
About 0.1% to about 0.5% stabilizer;
The preparation according to embodiment 3, which comprises an absorption promoter of about 0.05% mg to about 2.5%.

Aspect 6:
The isotonic agent is NaCl,
The preservative is benzalkonium chloride,
The stabilizer is disodium edetate,
The absorption enhancer is alkyl saccharides,
The preparation according to Aspect 4 or Aspect 5.

Aspect 7:
The preparation according to embodiment 6, wherein the alkyl saccharide is dodecyl maltoside.

Aspect 8:
Less than:
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.1 mg to about 1.2 mg of NaCl;
About 0.001 mg to about 0.1 mg of benzalkonium chloride;
About 0.15 mg to about 0.5 mg of disodium edetate;
The formulation according to embodiment 7, comprising about 0.05 mg to about 2.5 mg of dodecyl maltoside; and an amount of water sufficient to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL).

Aspect 9:
The preparation according to aspect 8, which comprises about 0.1 mg to about 0.5 mg of dodecyl maltoside.

Aspect 10:
The preparation according to aspect 9, which comprises about 0.25 mg of dodecyl maltoside.

Aspect 11:
The preparation according to aspect 8, which comprises about 0.2 mg and about 0.3 mg of disodium edetate.

Aspect 12:
Less than:
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.3 mg to about 0.7 mg of NaCl;
Approximately 0.02 mg of benzalkonium chloride;
About 0.3 mg disodium edetate;
28. The formulation according to embodiment 9, comprising about 0.25 mg of dodecyl maltoside; and an amount of water sufficient to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL).

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

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

Aspect 15:
Less than:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.1% to about 1.2% NaCl;
About 0.001% to about 0.1% benzalkonium chloride;
About 0.15% to about 0.5% disodium edetate;
The formulation according to embodiment 7, comprising about 0.05% to about 2.5% dodecyl maltoside; and water.

Aspect 16:
The preparation according to embodiment 15, which comprises about 0.1% to about 0.5% dodecyl maltoside.

Aspect 17:
16. The formulation according to embodiment 16, comprising about 0.25% dodecyl maltoside.

Aspect 18:
13. The formulation according to embodiment 15, comprising about 0.2% and about 0.3% disodium edetate.

Aspect 19:
Less than:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.3% to about 0.7% NaCl;
Approximately 0.02% benzalkonium chloride;
Approximately 0.3% disodium edetate;
13. The formulation according to embodiment 17, comprising about 0.25% dodecyl maltoside; and water.

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

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

Aspect 22:
The preparation according to any one of aspects 1 to 21, wherein the naltrexone is naltrexone hydrochloride.

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

The following are also provided herein:
Aspect 24:
A method of treating opioid overdose or reward-based disorders in a subject.
A method comprising administering to a subject an intranasal preparation containing an aqueous solution containing about 1 mg to about 3 mg naltrexone or a pharmaceutically acceptable salt thereof.

The following are also provided herein:
Aspect 25:
A method of treating opioid overdose or reward-based disorders in a subject.
The stage of administering to the subject a first intranasal preparation containing an aqueous solution containing about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof, and about 1 mg to about 4 mg of naltrexone or pharmaceutically acceptable thereof. A method comprising administering a second intranasal formulation comprising an aqueous solution containing a salt.

The following are also provided herein:
Aspect 26:
A method of treating opioid overdose or reward-based disorders in a subject.
An aqueous solution containing 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, about 50 to about 250 μL (preferably about 50 to about 50 to about). A method comprising administering to a subject an intranasal formulation, contained in a volume of 150 μL).

The following are also provided herein:
Aspect 27:
A method of treating opioid overdose or reward-based disorders in a subject.
The stage of administering to a first intranasal preparation, which comprises an aqueous solution containing about 10 mg / mL to about 40 mg / mL naltrexone or a pharmaceutically acceptable salt thereof in a volume of about 50 to about 250 ul. And a second intranasal preparation containing an aqueous solution containing about 10 mg / mL to about 40 mg / mL naltrexone or a pharmaceutically acceptable salt thereof in a volume, that is, in about 50 to about 250 μL. Including the method.

Aspect 28:
25. The method according to aspect 27, wherein the second intranasal preparation is administered about 1 hour to about 3 hours after the administration of the first intranasal preparation.

Aspect 29:
The intranasal preparation is as follows:
Isotonic;
Preservative;
Stabilizer;
The method according to any of aspects 24-28, further comprising an absorption enhancer; and an amount of water sufficient to achieve a final volume of about 50-about 250 μL (preferably about 50-about 150 μL).

Aspect 30:
Intranasal preparation,
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.1 mg to about 1.2 mg isotonic;
About 0.001 mg to about 0.1 mg of preservatives;
About 0.1 mg to about 0.5 mg of stabilizer;
29. The method of embodiment 29, comprising an absorption enhancer of about 0.05 mg to about 2.5 mg; and an amount of water sufficient to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL).

Aspect 31:
The intranasal preparation is as follows:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.1% to about 1.2% isotonic;
About 0.001% to about 0.1% preservatives;
About 0.1% to about 0.5% stabilizer;
29. The method of embodiment 29, comprising about 0.05% mg to about 2.5% absorption enhancer.

Aspect 32:
The isotonic agent is NaCl,
The preservative is benzalkonium chloride,
The stabilizer is disodium edetate,
The absorption enhancer is alkyl saccharides,
The method according to aspect 30 or aspect 28.

Aspect 33:
32. The method of aspect 32, wherein the alkyl saccharide is dodecyl maltoside.

Aspect 34:
The intranasal preparation is as follows:
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.1 mg to about 1.2 mg of NaCl;
About 0.001 mg to about 0.1 mg of benzalkonium chloride;
About 0.15 mg to about 0.5 mg of disodium edetate;
13. The method of embodiment 33, comprising about 0.05 mg to about 2.5 mg of dodecyl maltoside; and an amount of water sufficient to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL).

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

Aspect 36:
35. The method of aspect 35, wherein the intranasal formulation comprises about 0.25 mg of dodecyl maltoside.

Aspect 37:
34. The method of aspect 34, wherein the intranasal formulation comprises from about 0.2 mg to about 0.3 mg disodium edetate.

Aspect 38:
Intranasal preparation,
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.3 mg to about 0.7 mg of NaCl;
Approximately 0.02 mg of benzalkonium chloride;
About 0.3 mg disodium edetate;
13. The method of embodiment 36, comprising about 0.25 mg of dodecyl maltoside; and an amount of water sufficient to achieve a final volume of about 50 to about 250 μL (preferably about 50 to about 150 μL).

Aspect 39:
38. The method of aspect 38, wherein the amount of water is sufficient to achieve a final volume of about 50-about 150 μL.

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

Aspect 41:
Less than:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.1% to about 1.2% NaCl;
About 0.001% to about 0.1% benzalkonium chloride;
About 0.1% to about 0.5% disodium edetate;
33. The method of aspect 33, comprising about 0.05% to about 2.5% dodecyl maltoside; and water.

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

Aspect 43:
42. The method of aspect 42, wherein the intranasal formulation comprises about 0.25% dodecyl maltoside.

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

Aspect 45:
The intranasal preparation is as follows:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.3% to about 0.7% NaCl;
Approximately 0.02% benzalkonium chloride;
Approximately 0.3% disodium edetate;
43. The method of embodiment 43, comprising about 0.25% dodecyl maltoside; and water.

Aspect 46:
The method of aspect 45, wherein the amount of water is sufficient to achieve a final volume of about 50-about 150 μL.

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

Aspect 48:
The method according to any of aspects 24-47, wherein the naltrexone is naltrexone hydrochloride.

Aspect 49:
28. 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 naltrexone or an equivalent amount of naltrexone hydrochloride.

Aspect 50:
The method according to any of aspects 24-49, for treating opioid overdose.

Aspect 51:
The method according to any of aspects 24-49, for treating a reward-based disorder.

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

Aspect 53:
The method of aspect 48, wherein the substance use disorder is an alcohol use disorder.

Aspect 54:
53. The method of aspect 53, wherein the intranasal formulation containing naltrexone is administered prior to alcohol consumption.

Aspect 55:
54. The method of embodiment 54, wherein the intranasal formulation containing naltrexone is administered approximately 1-2 hours before alcohol ingestion.

Aspect 56:
54. The method of embodiment 54, wherein the intranasal formulation containing naltrexone is administered approximately 0.5 to approximately 1 hour before alcohol ingestion.

Aspect 57:
The method of embodiment 54, wherein the intranasal formulation containing naltrexone is administered approximately 10 to approximately 30 minutes prior to alcohol ingestion.

Aspect 58:
54. The method of embodiment 54, wherein the intranasal formulation containing naltrexone is administered approximately 5 to approximately 10 minutes prior to alcohol ingestion.

Aspect 59:
53. The method of aspect 53, wherein the intranasal formulation containing naltrexone is administered at the same time as alcohol ingestion.

Aspect 57:
53. The method of aspect 53, wherein the intranasal formulation containing naltrexone is administered within 0.5 hours after the start of alcohol intake.

Aspect 58:
The method according to any of aspects 24-57, wherein the intranasal formulation containing naltrexone is administered to the subject once to four times daily.

Aspect 59:
28. The method of embodiment 58, wherein the intranasal formulation containing naltrexone is administered at a dose of about 1.2 mg, about 1.6 mg, about 2 mg, or about 3 mg throughout the day as needed by the subject.

Aspect 60:
An intranasal formulation containing naltrexone is given in the morning as a first dose of about 1.2 mg, about 1.6 mg, about 2 mg, or about 3 mg, and as needed before alcohol consumption, about 1.2 mg, about 1.6 mg. 58. The method of embodiment 58, which is administered as a later dose of about 2 mg, or about 3 mg.

The following are also provided herein:
Aspect 61:
Includes multiple doses, each dose comprising the intranasal formulation according to any of aspects 1-23.
A multidose device adapted for nasal delivery of pharmaceutical formulations to subjects experiencing opioid overdose or having a reward-based disability.

Aspect 62:
16. The device according to embodiment 61, wherein a formulation of about 0.05 to about 0.2 mL (preferably about 0.05 to about 0.15 mL) is delivered to the subject at each dose.

Aspect 63:
62. The device of aspect 62, wherein about 0.1 mL of the formulation is delivered to the subject at each dose.

The following are also provided herein:
Aspect 64:
In the case of "containing about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof", the amount contained is about 3 mg of naltrexone or a pharmaceutically acceptable salt thereof; or the method is "about 10 mg". Contains / 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 concentration of which is about 30 mg / mL mg. Naltrexone or a pharmaceutically acceptable salt thereof,
The formulation, method, or device according to any one of the above embodiments.

Aspect 64:
Also provided are formulations selected from the formulations described in the examples disclosed herein.

Also provided are embodiments described above and aspects in which they can be combined, provided that any one or more combinations of these embodiments are not mutually exclusive.

Definitions When the following terms are used herein, they have the indicated meanings.

Unless otherwise specified, the range of values is intended to include the number itself and the range between the numbers. This range may be an integer or contiguous between the values at both ends and including the values at both ends. As an example, doses are expressed in integer units, so the range "2-6 doses" is intended to include 2, 3, 4, 5, and 6 doses. As an example, the range "1-3 μM (micromolar concentration)" is intended to include 1 μM, 3 μM, and any number of significant digits in between (eg, 1.255 μM, 2.1 μM, 2.9999 μM, etc.). Compare with what is done.

As used herein, the term "about" is intended to qualify such values by indicating that the numerical value that "about" modifies is a variable within a range. If a specific range, such as the error range shown in the graph or table of data or the standard deviation to the mean, is not described, the term "about" will take into account the range containing the described values, significant digits. It must be understood that it means the range included by rounding up or down the number, and the range containing the stated value ± 20%, whichever is greater.

As used herein, the term "absorption-promoting agent" refers to a functional excipient contained in a pharmaceutical product to improve the absorption of a pharmacologically active drug. The term usually refers to drugs that have the ability to increase absorption by enhancing membrane penetration rather than increasing solubility. Therefore, such agents are sometimes referred to as permeation enhancers. Examples of absorption enhancers include aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoyl carnitine, dodecyl maltoside, EDTA, glycocholic acid, Glycodeoxycholic acid, glycoflor, glycosylated sphingosine, glycyrrhetinic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroyl carnitine, sodium lauryl sulfate, lysophosphatidylcholine, menthol, poroxamar 407 or F68, poly -L-arginine, polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol, kiraya saponin, salicylic acid, sodium salt, β-citosterol-β-D-glucoside, coconut fatty acid sucrose cocoate, taurocholic acid, tauro Includes deoxycholic acid, taurodihydrofushidic acid, and tetradecyl maltoside. Alkyl saccharides (eg, nonionic alkyl saccharide surfactants, such as alkyl glycosides attached to sugar moieties by glycosidic bonds, and sucrose esters of fatty acids consisting of aliphatic hydrocarbon chains attached to sugar moieties by ester bonds). Cyclodextrin, a cyclic oligosaccharide consisting of 6 or more monosaccharide units that forms an encapsulate with hydrophobic molecules, has a central cavity, primarily for increasing drug solubility and solubility, and for low molecular weight drug absorption. (Has been used to enhance), chitosan (a linear cationic polysaccharide produced from the deacetylation of chitin), and bile salts and their derivatives (eg, sodium glycocholate, sodium taurocorate, and tauro). Sodium dihydrofusidate) tends to be among the most acceptable absorption enhancers. See, for example, 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 obsessive-compulsive devotion to reward stimuli despite adverse consequences. As used herein, the term "addictive behavior" refers to behavior that provides both reward and enhancement.

As used herein, the term "agonist" refers to a portion that interacts with a receptor, activates it, thereby initiating a physiological or pharmacological response specific to that receptor. The term "antagonist" as used herein competitively binds to the same site of an agonist as an agonist (eg, an endogenous ligand), but activates an intracellular response initiated by an activated receptor. However, it refers to a portion that can thereby inhibit an intracellular response by an agonist or partial agonist. Antagonists do not diminish the baseline intracellular response in the absence of agonists or partial agonists. The term "inverse agonist" refers to an agonist or partial agonist of a baseline intracellular response that binds to an endogenous or constitutively activated receptor and is initiated by the activated receptor. Refers to the part that inhibits below the normal basal activity level observed in the absence of.

The term "alcohol use disorder" is a widely accepted standard in the US according to or corresponding to the criteria set forth in the Diagnostic and Statistical Manual of Mental Illness (DSM, latest revision, now DSM-V), eg. , Defined by similar criteria set forth in the World Health Organization's ICD (International Statistical Classification of Diseases and Related Health Problems, latest revision, now ICD-10). Related terms and disorders include "alcohol abuse" and "alcohol dependence" (used in DSM-IV), "alcohol harmful use" and "alcohol dependence syndrome" (used in ICD-10). ), As well as alcoholism.

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

As used herein, the term "disease" and "disorder", "syndrome", and "condition" (such as medical conditions) all impair normal functioning of the human or animal body. It is intended to be largely synonymous as it reflects one abnormal condition of, or part of it, and typically manifests itself in highly characteristic signs and symptoms, reducing the lifespan or quality of life of humans or animals. , And used without distinction.

The term "pharmaceutical composition" is used herein indistinguishable from the term "pharmaceutical formulation" or simply "formulation" and is used herein with an active pharmaceutical ingredient (ie, drug substance) and at least one pharmacy. The combinations of excipients or carriers that are acceptable are shown.

As used herein, the term "equivalent" refers to the weight of the opioid antagonist naltrexone and its pharmaceutically acceptable salt, equimolar to the specified weight of naltrexone hydrochloride.

As used herein, the term "excipient" is formulated with the active ingredient of a drug therapy to provide long-term stabilization, increase the dose of a solid formulation, or therapeutically enhance the active ingredient in the final dosage form. For example, it refers to a natural or synthetic substance included for the purpose of promoting drug absorption, reducing viscosity, or imparting improvement in solubility.

As used herein, the term "therapeutically effective dose" is used to treat a disease, reduce one or more observable symptoms of the disease, or after the condition the patient is currently experiencing. A dose that is effective in delaying the onset or progression of a more serious condition that often follows, or in relieving its symptoms. Therapeutically effective doses may eliminate all symptoms of the disease, but not necessarily all symptoms of the disease.

The term "needs treatment" and the term "needs" when referring to a treatment are used interchangeably and the caregiver (eg, a doctor, etc.) that the subject benefits from the treatment. Refers to the decisions made by a nurse (nurse practitioner).

As used herein, the 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 specified as 3 mg is mutually exclusive with the embodiment in which the amount of naltrexone hydrochloride is specified as 2 mg. However, the embodiment in which the amount of naltrexone hydrochloride is specified as 4 mg is not mutually exclusive with the embodiment in which less than about 10% of the pharmaceutical composition is excreted from the nasal cavity through drainage to the nasopharynx or to the outside.

の化合物、またはその薬学的に許容される塩、水和物、もしくは溶媒和化合物を指す。ナロキソンのCAS登録番号は465-65-6である。ナロキソンの他の名称には、17-アリル-4,5a-エポキシ-3,14-ジヒドロキシモルフィナン-6-オン;(-)-17-アリル-4,5α-エポキシ-3,14-ジヒドロキシモルフィナン-6-オン;4,5a-エポキシ-3,14-ジヒドロキシ-17-(2-プロペニル)モルフィナン-6-オン;および(-)-12-アリル-7,7a,8,9-テトラヒドロ-3,7a-ジヒドロキシ-4aH-8,9c-イミノエタノフェナントロ[4,5-bcd]フラン-5(6H)-オンが含まれる。塩酸ナロキソンは無水(CAS登録番号357-08-4)でもよく、二水和物(CAS番号51481-60-8)も形成する。これは、Narcan(登録商標)、Nalone(登録商標)、Nalossone(登録商標)、Naloxona(登録商標)、Naloxonum(登録商標)、Narcanti(登録商標)、およびNarcon(登録商標)を含む様々な商品名で販売されている。 The term "naloxone" as used herein has the following structure:

Refers to a compound of, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. The CAS Registry Number for Naloxone is 465-65-6. Other names for naloxone include 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one; (-)-17-allyl-4,5α-epoxy-3,14-dihydroxymol. Finan-6-one; 4,5a-epoxy-3,14-dihydroxy-17- (2-propenyl) morphinan-6-one; and (-)-12-allyl-7,7a,8,9-tetrahydro- Includes 3,7a-dihydroxy-4aH-8,9c-iminoethanophenantro [4,5-bcd] furan-5 (6H) -one. Naloxone hydrochloride may be anhydrous (CAS Registry Number 357-08-4) and also forms dihydrate (CAS Registry Number 51481-60-8). It is a variety of products including Narcan®, Nalone®, Nalossone®, Naloxona®, Naloxonum®, Narcanti®, and Narcon®. It is sold by name.

の化合物、またはその薬学的に許容される塩、水和物、もしくは溶媒和化合物を指す。ナルトレキソンのCAS登録番号は16590-41-3である。ナルトレキソンの他の名称には、17-(シクロプロピルメチル)-4,5α-エポキシ-3,14-ジヒドロキシモルフィナン-6-オン;(5α)-17-(シクロプロピルメチル)-3,14-ジヒドロキシ-4,5-エポキシモルフィナン-6-オン;および(1S,5R,13R,17S)-4-(シクロプロピルメチル)-10,17-ジヒドロキシ-12-オキサ-4-アザペンタシクロ[9.6.1.01,13.05,17.07,18]オクタデカ-7(18),8,10-トリエン-14-オンが含まれる。「ナルトレキソン」という用語は「塩酸ナルトレキソン」を含む。塩酸ナルトレキソン(CAS登録番号16676-29-2)は、商品名Antaxone(登録商標)、Depade(登録商標)、Nalorex(登録商標)、Revia(登録商標)、Trexan(登録商標)、Vivitrex(登録商標)、およびVivitrol(登録商標)で販売されている。 The term "naltrexone" as used herein has the following structure:

Refers to a compound of, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. The CAS Registry Number for Naltrexone is 16590-41-3. Other names for naltrexone include 17- (cyclopropylmethyl) -4,5α-epoxy-3,14-dihydroxymorphinan-6-one; (5α) -17- (cyclopropylmethyl) -3,14- Dihydroxy-4,5-epoxymorphinan-6-one; and (1S, 5R, 13R, 17S) -4- (cyclopropylmethyl) -10,17-dihydroxy-12-oxa-4-azapentacyclo [9.6] .1.01,13.05,17.07,18] Octadeca-7 (18), 8,10-Triene-14-On is included. The term "naltrexone" includes "naltrexone hydrochloride". Naltrexone hydrochloride (CAS registration number 16676-29-2) is a trade name of Antaxone®, Depade®, Nalorex®, Revia®, Trexan®, Vivitrex®. ), And Vivitrol®.

の化合物であるカチオン(5α)-17-(シクロプロピルメチル)-3,14-ジヒドロキシ-17-メチル-4,5-エポキシモルフィナニウム-17-イウム-6-オンを含む薬学的に許容される塩を指す。式中、X^-は、薬学的に許容されるアニオンである。臭化メチルナルトレキソン(CAS登録番号75232-52-7)は商品名レリストール(登録商標)で販売されている。 The term "methylnaltrexone" as used herein has the following structure:

Compounds of the cation (5α) -17- (cyclopropylmethyl) -3,14-dihydroxy-17-methyl-4,5-epoxymorphinanium-17-ium-6-one containing pharmaceutically acceptable Refers to salt. In the formula, X ^- is a pharmaceutically acceptable anion. Methyl naltrexone bromide (CAS Registry Number 75232-52-7) is marketed under the trade name Relistol®.

の化合物である17-シクロプロピルメチル-4,5α-エポキシ-6-メチレンモルフィナン-3,14-ジオールを指す。塩酸ナルメフェン(CAS登録番号58895-64-0)は商品名Nalmetrene(登録商標)、Cervene(登録商標)、Revex(登録商標)、Arthrene(登録商標)、およびIncystene(登録商標)で販売されている。 The term "nalmefene" as used herein has the following structure:

Refers to 17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol, which is a compound of. Nalmefene Hydrochloride (CAS Registry Number 58895-64-0) is sold under the trade names Nalmetrene®, Cervene®, Revex®, Arthrene®, and Incystene®. ..

The term "nostril" as used herein is synonymous with "nostril".

The term "opioid antagonist" includes naltrexone and its pharmaceutically acceptable salts, as well as naloxone, methylnaltrexone, and nalmefene, and their pharmaceutically acceptable salts. 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, intranasal administration is accomplished using the devices described herein.

As used herein, the term "pharmaceutical composition" refers to a composition comprising, but not limited to, a salt of the opioid antagonist naltrexone, a solvate compound, and a hydrate. .. This makes the composition subject to use in mammals (eg, non-limitingly human) to obtain the specified effective outcomes.

As used herein, the term "reinforcement stimulus" refers to a stimulus that increases the likelihood of repeating these paired actions.

As used herein, the term "reward stimulus" refers to a stimulus that the subject's brain interprets as being or should be addressed in nature. Typically, reward stimuli release dopamine into the subject's brain.

As used herein, "reward-based disability" is a disability associated with reward-based behavior, in which the user remains immersed in the reward stimulus despite adverse consequences and / or is drowned in the reward stimulus. Reward-based disorders include substance use disorders such as alcoholism and addiction, as well as activity engagement disorders such as gambling disorders (obsessive-compulsive gambling) and eating disorders (bulimia nervosa, bulimia nervosa). Includes bulimia nervosa), kleptomania, and pyromania.

The term "subject" as used herein is intended to be synonymous with "patient" and is likely to benefit from treatment with a therapeutically effective amount of the opioid antagonist naltrexone or a salt thereof. , Refers to any mammal (preferably human).

The term "substance use disorder" is a widely accepted standard in the US according to or corresponding to the criteria set forth in the Diagnostic and Statistical Manual of Mental Illness (DSM, latest revision, now DSM-V), eg. , Defined by similar criteria set forth in the World Health Organization's ICD (International Statistical Classification of Diseases and Related Health Issues, Latest Revised Edition, now ICD-10). Related terms and disorders include "substance abuse" and "substance dependence" (used in DSM-IV). When repeated use of alcohol and / or drugs causes significant clinical or functional dysfunction, such as health problems, disability, and failure to meet significant work, school, or home obligations. , Substance use disorder has occurred. According to DSM-5, the diagnosis of substance use disorder is based on evidence of poor control, social dysfunction, risky use, and pharmacological criteria. Substances that can be the focus of substance use disorders include abuse substances such as opioids, alcohol, tobacco, cannabinoids, stimulants such as cocaine and amphetamines, inhibitors such as benzodiazepines, hallucinogens, inhalants and the like. .. Alcohol use disorder is a substance use disorder. Substance use disorders may be considered "reward-based disorders."

As used herein, the term "tonic agent" refers to a compound that alters the osmolal concentration of a pharmaceutical product, eg, isotonic. Tonic agents 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 the causes, progression, severity, or symptoms of a disorder in a subject, or to separate the disease. It means relieving the disorder so that it can be beneficially changed in this way.

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).

を用いて計算され得る。 As used herein, the term "bioavailability (F)" refers to a fraction of a drug dose that is absorbed from the site of administration and reaches the systemic circulation in unchanged form. The term "absolute bioavailability" as used herein is used when the absorbed drug fraction is associated with its IV bioavailability. This is the following formula:

Can be calculated using.

を用いて計算され得る。 The term relative bioavailability (F _rel ) is used to compare two different extravasational routes of drug administration, using the formula:

Can be calculated using.

As used herein, the term "clearance (CL)" refers to the rate at which a drug is excreted divided by the plasma concentration of the drug, the volume of plasma in which the drug is completely removed per unit time. Represents. CL is equal to the discharge rate constant (λ) multiplied by the volume of distribution (V _d ). "V _d " is the volume of liquid required to contain the amount of drug present in the body at the same concentration as in plasma. As used herein, the term "apparent clearance (CL / F)" refers to clearance that does not take into account the bioavailability of the drug. This is a dose ratio above AUC.

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

As used herein, the term "t _1/2 " or "half-life" refers to the time required for half of a drug to be excreted from the body, or the time required for a drug concentration to drop in half. Point to.

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

As used herein, the term "confidence interval" refers to a range of values that include the true mean of a parameter with a specified percentage of probability.

As used herein, the term "excretion rate constant (λ)" refers to the rate at which a drug is removed from the body, expressed in fractions. This rate is constant at the primary rate and does not depend on the drug concentration in the body. λ is the slope of the plasma concentration-timeline (on the y-log scale). As used herein, the term "λ _z " refers to the terminal phase emission rate constant. The "terminal phase" of the drug plasma concentration-time curve is a straight line plotted on a semi-log graph. The terminal phase is often referred to as the "excretion phase" because the main mechanism for reducing drug levels during the terminal phase is drug excretion from the body. The characteristic of the terminal discharge phase is that the relative ratio of the drug in plasma to the drug in the peripheral volume of distribution remains constant. During this "terminal phase", the drug returns to plasma from a rapid and slow volume of 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. Opioid receptor antagonists are detailed in the scientific and patent literature. Naltrexone and its active metabolite 6β-naltrexone are opioid antagonists at the μ-opioid receptor (MOR), κ-opioid receptor (KOR), and δ-opioid receptor (DOR) and have no agonistic properties. Naltrexone works by reversibly blocking opioid receptors, thereby weakening the effects of opioids. Although its mechanism of action in alcohol dependence is not fully understood, but not limited by theory, it is considered to be a major addiction-related reward center that is believed to activate all major substance abuses. Naltrexone is likely to regulate the dopaminergic central nervous system pathways (one of the primary centers of risk-reward analysis in the brain, and the tertiary pleasant center). Its mechanism of action may be an antagonistic effect on an endogenous opiate, eg, tetrahydropapavellin, whose production increases in the presence of alcohol.

Naltrexone is commercially available as a hydrochloride salt. Naltrexone hydrochloride (17- (cyclopropylmethyl) -4,5α-epoxy-3,14-dihydroxymorphinan-6-one) is used to block euphoric effects in the treatment of opioid addicts. It significantly blocks physical dependence on intravenously administered opioids and stimulates withdrawal symptoms from opioid dependence, but patients do not develop tolerance or dependence on naltrexone. Naltrexone is also effective in treating alcoholism, especially when combined with psychosocial therapies, to reduce alcohol cravings.

Bioavailability is fairly high when naltrexone is given intranasally rather than orally. Naltrexone undergoes rapid, large-scale first-pass metabolism to 6-β-naltrexone, even though it is almost completely absorbed from the gastrointestinal tract when orally administered. As a result, the amount of naltrexone that reaches the systemic circulation is limited. Naltrexone's oral bioavailability has been reported to be as low as 5%. Gonzalez and Brogden, Drugs 35: 192-213, 1988. From the studies presented herein, it was found that the oral bioavailability of naltrexone was similarly low, at about 9%.

Provided herein is a method 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 corresponds to about 1 to about 4 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount corresponds to about 1-3 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective doses per dose are 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, Equivalent to about 3.8, about 3.9, or about 4.0 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount per dose corresponds to approximately 1.2 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount per dose corresponds to approximately 1.6 mg naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount per dose corresponds to approximately 2.0 mg naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount per dose corresponds to approximately 3.0 mg naltrexone hydrochloride. Multiple doses may be taken consecutively to achieve therapeutic efficacy. In certain embodiments, the opioid antagonist is anhydrous naltrexone hydrochloride.

Although many of the aspects of the pharmaceutical compositions described herein are described and exemplified using naltrexone, other opioid antagonists can be adapted for nasal delivery based on the disclosure herein. Indeed, from the disclosure herein, it should be readily apparent to those of skill in the art that the devices and pharmaceutical compositions described herein may be suitable for other opioid antagonists. Opioid receptor antagonists described herein include μ-opioids, kappa-opioids, 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 Formulations Pharmaceutical compositions containing the opioid antagonist naltrexone are also provided. In certain embodiments, the pharmaceutical composition comprises an opioid antagonist naltrexone and a pharmaceutically acceptable carrier. The carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and must not be excessively harmful to its recipient. Some aspects of the invention include a method of producing a pharmaceutical composition comprising mixing the opioid antagonist naltrexone with a pharmaceutically acceptable carrier. The pharmaceutical composition is applied directly to the nasal cavity using the devices described herein. For sprays, this can be accomplished, for example, with a measuring atomizing spray pump.

Liquid preparations include solutions, suspensions, and emulsions, such as water or water-propylene glycol solutions. Additional components in the liquid preparation include antibacterial preservatives such as benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenylethyl alcohol and mixtures thereof; surfactants such as polysorbate 80NF, poly. Oxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxy Ethethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate , Solbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate, etc., and mixtures thereof; tonic agents such as dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, Includes trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine and the like and mixtures thereof; and suspending agents such as crystalline cellulose, sodium carboxymethyl cellulose NF, polyacrylic acid, magnesium aluminum silicate, xanthan gum and the like, and mixtures thereof. May occur.

Ideally, if an opioid antagonist is administered intranasally prior to alcohol intake to treat AUD, the opioid antagonist is absorbed quickly, ie within about 15 to about 30 minutes, and / or about 25. Produces time (T _max ) to maximum plasma concentration of ~ 40 minutes. For example, in certain embodiments, the opioid antagonist is absorbed within the first 15 minutes after administration and the time to maximal plasma concentration (T _max ) is 25 minutes or less. Alternatively, the opioid antagonist is absorbed within the first 30 minutes after administration and has a T _max of 40 minutes or less.

Absorption enhancers, such as alkyl saccharides (also referred to herein as alkyl glycosides), cyclodextrins, and chitosan, may increase the rate at which naltrexone is absorbed and shorten T _max . Such absorption enhancers typically include paracellular transport through the openings of tight junctions between cells, the two main nasal absorption mechanisms, and transcellular passage through cells via vesicle carriers. It works by affecting transport or transcytosis.

In various aspects, the alkyl glycosides of the invention are alkyl glycosides such as octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl-. α-or β-D-maltoside, -glucoside or-scroside; alkylthiomaltosides such as heptyl, octyl, dodecyl-, tridecyl-, and tetradecyl-β-D-thiomaltoside; alkylthioglucosides such as heptyl- or octyl 1 -Thio α- or β-D-glucopyranoside; alkylthiosucrose; alkyl maltotrioside; long-chain aliphatic carbonate amides of sucrose β-amino-alkyl ethers; palatinose and isomaltamine bonded to the alkyl chains by amide bonds Derivatives; Derivatives of isomatalamine bound to an alkyl chain by urea; Long-chain aliphatic carbonate ureides of sucrose β-amino-alkyl ethers; and may contain long-chain aliphatic carbonate amides of sucrose β-amino-alkyl ethers. , Not limited to this.

Therefore, as mentioned above, the hydrophobic alkyl must be selected from any desired size depending on the desired hydrophobicity and the hydrophilicity of the saccharide moiety. For example, one of the preferred ranges of alkyl chains is about 9 to about 24 carbon atoms. An even more preferred range is about 9 to about 16 or about 14 carbon atoms. Similarly, among the preferred glycosides are 9, 10, 12, 13, 14, 16, 18, 18, 20, 22, or 24 alkyl chains of carbon atoms, such as nonyl. -, Decyl-, dodecyl-, and maltose, sucrose, and glucose bound by glycosidic bonds to tetradecylscroside, glucoside, and maltside, etc. are also included. These compositions are nontoxic and amphipathic as they are degraded to alcohols or fatty acids and oligosaccharides. Furthermore, the bond between the hydrophobic alkyl group and the hydrophilic saccharide may include, among other things, a glycosidic bond, a thioglycosidic bond, an amide bond, a ureido bond, or an ester bond.

As used herein, "sugar" includes straight-line or ring-shaped monosaccharides, oligosaccharides, or polysaccharides, or combinations thereof for forming sugar chains. Oligosaccharides are saccharides having two or more monosaccharide residues. Thus, examples of sugars include glucose, maltose, maltotriose, maltotetrarose, sucrose, and trehalose.

In one embodiment, the exemplary alkyl saccharide is an alkyl maltoside. Alkyl maltside is a glycoside of disaccharide maltose and alcohol. Typical alkyl malt acids are dodecyl malt acid, tetradecyl malt acid, and hexadecyl malt acid, which consist of 12, 14, and 16 carbon linear alcohols glycosidic bonded to maltose, respectively. In an exemplary embodiment, the alkyl glycoside is a tetradecylmaltoside.

For example, one of the alkyl saccharides is 1-On-dodecyl-β-D-maltopyranoside (instead, lauryl-β-D-maltopyranoside, dodecylmaltopyranoside, dodecylmaltoside, Intravail®, and DDM; C ₂₄ H ₄₆ Q ₁₁ ). Alkyl saccharides are used in over-the-counter food and personal care products and are designated as Generally Recognized as Safe (GRAS) substances for food applications. These are odorless, tasteless, non-toxic, non-mutagenic, and non-sensitizing, non-sensitizing, transmucosal absorption enhancers up to 25% concentrations in the Draize test. Alkyl saccharides increase absorption by increasing paracellular permeability as indicated by a decrease in transepithelial electrical resistance. Alkyl saccharides can also increase transcytosis. This effect does not last long. Other alkyl saccharides include tetradecylmaltoside (TDM) and sucrose decanoate.

In glycochemistry, anomers are either a pair of cyclic stereoisomers of sugars or glycosides that differ only in their configuration in the hemiacetal (or hemicetal) carbon, also called anomer carbon or reducing carbon. There is (called α or β). If this structure is similar to that of glucose with a hydroxyl group on the anomeric carbon at the axial position, then the sugar is an α-anomer. However, if this hydroxyl is at the equatorial position, the sugar is a β-anomer. For example, two types of cyclic glucose, α-D-glucopyranose and β-D-glucopyranose, are anomers. Similarly, alkyl glycosides also occur as anomers. For example, dodecyl β-D-maltoside and dodecyl α-D-maltoside are two cyclic types of dodecyl maltoside. Two different anomers are two distinct chemical structures and therefore have different physical and chemical properties. In one aspect of the invention, the alkyl glycosides of the invention are β-anomers. In an exemplary aspect, the alkyl glycoside is a β-anomer of an alkyl maltoside, such as tetradecyl-β-D-maltoside (TDM).

Therefore, in one aspect of the invention, the alkyl glycoside used is substantially pure alkyl glycoside. As used herein, "substantially pure" alkyl glycosides are other anomer types of less than about 2%, preferably less than about 1.5%, more preferably less than about 1%. Refers to one type of alkyl glycoside anomer type (either α-anomer type or β-anomer type), including anomer type. In one aspect, substantially pure alkylgycoside contains more than 98% α-anomer or β-anomer. In another aspect, substantially pure alkyl glycosides contain greater than 99% α-anomers or β-anomers. In another aspect, substantially pure alkyl glycosides contain greater than 99.5% α-anomers or β-anomers. In another aspect, substantially pure alkyl glycosides contain greater than 99.9% α-anomers or β-anomers.

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. 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. In certain embodiments, the intranasal formulation comprises approximately 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 approximately 0.25% dodecyl maltoside.

When 0.18% dodecylmaltoside was added to the intranasal formulation of sumatriptan, the maximum plasma concentration increased almost 4-fold compared to the Imitrex nasal atomizer, and T _max decreased from 1 to 2 hours to 8 to 10 minutes. did. Total exposure increased by 32% when measured in the area under the concentration-time curve (AUC). Naltrexone intranasal formulations have the potential to be used in the treatment of AUD without the use of needles or sustained-release formulations. The inclusion of dodecyl maltoside may improve pharmacokinetic parameters in some applications.

Some absorption-promoting excipients can alter paracellular and / or transcellular pathways, while others can prolong nasal retention or block metabolic changes. Without an absorption enhancer, the molecular weight limit for nasal absorption is about 1 kDa, whereas when the drug is administered with an absorption enhancer, it is possible to absorb 1-30 kDa molecules. However, intranasal administration of most absorption enhancers can cause nasal mucosal damage. Maggio, J. Excipients and Food Chem. 5 (2): 100-12, 2014.

Examples of absorption enhancers include aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoylcarnitine, dodecylmaltoside, EDTA, glycocholic acid, Glycodeoxycholic acid, glycoflor, glycosylated spingosine, glycyrrhetinic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroylcarnitine, lauryl sulfate, lysophosphatidylcholine, menthol, poroxamar 407, poroxamar F68, Poly-L-arginine, polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol, kiraya saponin, salicylic acid, β-citosterol-β-D-glucoside, coconut fatty acid sculose, taurocholic acid, taurodeoxycholic acid, taurodihydro Includes fushidic acid, and tetradecylmaltoside.

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

The opioid antagonist naltrexone described herein is pharmaceutically acceptable, optionally comprising a pharmaceutically acceptable acid addition salt prepared from a pharmaceutically acceptable nontoxic acid, including inorganic and organic acids. It may exist as a salt to be added. Typical acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, horse uric acid, hydrogen bromide. Acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitrate, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p -Includes, but is not limited to, pharmaceutically acceptable salts as described in, for example, Berge et al., Journal of Pharmaceutical Sciences, 66: 1-19 (1977), such as toluenesulfonic acid. Acid-added salts may be obtained as a direct product of compound synthesis. Alternatively, the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt may be isolated by evaporating the solvent or by separating the salt and solvent in another way. The opioid antagonist naltrexone described herein may form solvate compounds with standard low molecular weight solvents using methods known to those of skill in the art.

Accordingly, pharmaceutical formulations for intranasal administration containing naltrexone or salts thereof, such as naltrexone hydrochloride, are provided herein. In certain embodiments, the formulation is an aqueous solution. In certain embodiments, the pharmaceutical product comprises from about 25 to about 200 μL of aqueous solution per dose. In certain embodiments, the pharmaceutical product comprises from about 50 to about 200 μL of aqueous solution per dose. In certain embodiments, the pharmaceutical product comprises about 140 μL or less per dose. In certain embodiments, the pharmaceutical product comprises about 100 μL or less per dose.

In certain embodiments, the formulation comprises from about 1% (w / w) to about 4% (w / w) naltrexone hydrochloride. In certain embodiments, the pharmaceutical product comprises from about 1% (w / w) to about 3% (w / w) naltrexone hydrochloride. In certain embodiments, the formulations are 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 it contains 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 pharmaceutical product comprises from about 1 mg to about 4 mg naltrexone hydrochloride. In certain embodiments, the pharmaceutical product comprises from about 1 mg to about 3 mg naltrexone hydrochloride. In certain embodiments, the pharmaceutical product comprises from about 2 mg to about 4 mg naltrexone hydrochloride. In certain embodiments, the formulations are 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 it contains about 4.0 mg of naltrexone hydrochloride. In certain embodiments, the formulation comprises approximately 1.2 mg naltrexone hydrochloride. In certain embodiments, the formulation comprises approximately 1.6 mg naltrexone hydrochloride. In certain embodiments, the formulation comprises approximately 2 mg naltrexone hydrochloride. In certain embodiments, the formulation comprises about 3 mg naltrexone hydrochloride.

Aqueous formulations for intranasal administration disclosed herein also include pharmaceutically acceptable excipients such as one or more isotonic agents, one or more preservatives, one type. Alternatively, it may also contain a plurality of stabilizers, one or more absorption enhancers, and one or more agents that regulate the pH or buffer the solution.

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

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

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

In certain embodiments, the intranasal formulation further comprises a stabilizer.

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

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

In certain embodiments, when the pharmaceutical composition is delivered nasally to the patient, less than about 10% of the pharmaceutical composition is expelled from the nasal cavity through drainage to the nasopharynx or to the outside.

Nasal Drug Delivery Device and Kit Pharmaceutical composition within a device adapted for nasal delivery to subjects suffering from AUD, including a therapeutically effective amount of the opioid antagonist naltrexone or a pharmaceutically acceptable salt thereof. Things are also provided. In certain embodiments, the device is preprimed. In certain embodiments, the device can be primed prior to use. In certain embodiments, the device can be moved with one hand.

Nasal delivery is considered an attractive route for systemic drug delivery, especially if rapid absorption and efficacy are desired. In addition, nasal delivery may help address problems associated with nasty taste, inadequate bioavailability, slow absorption, drug degradation, and adverse events (AEs) in the gastrointestinal tract, with first-pass metabolism. Avoid liver toxicity associated with long-term oral naltrexone use.

Liquid nasal formulations are predominantly aqueous solutions, but suspensions and emulsions can also be delivered.

Several emergency medical (EMS) programs have developed systems for intranasal administration of the opioid antagonist naloxone using existing technology and existing medical equipment for approved drugs, albeit in a manner not approved by the FDA. rice field. This has been accomplished by using an injectable formulation (1 mg / mL) and administering 1 mL per external nostril via a commercially available nasal atomizer / nebulizer device. The system includes an FDA-approved naloxone injection product (without a needle, with a luer-fit tip) and a commercial medical device called the Mucosal Atomization Device (MAD ™ Nasal, Wolfe Tory Medical, Inc.). Combined. This creativity is in line with the U.S. Needlestick Safety and Prevention Act (Public Law 106-430). The EMS program recognizes the limitations of this system, one of which is that the system is not assembled and cannot be used immediately. Although this method of administration appears to be effective in reversing Narcosis, the formulation does not collect in one place so that it is retained in the nasal cavity. The delivery volume of 1 mL per nostril is higher than the delivery volume commonly used for intranasal drug administration. Therefore, the drug is lost from the nasal cavity by being excreted into the nasal pharynx or out of the nasal cavity. The devices described herein are improved, ready-to-use products that are optimized for nasal delivery, are centralized, and are formulated.

Since the introduction of metered spray pumps, it has dominated the nasal drug delivery market. This pump typically delivers 100 μL (or 25-200 μL, and other volumes above) per spray, demonstrating high reproducibility of released dose and plume shape in in vitro studies.

Examples of standard metering spray pumps include metering spray pumps supplied by Aptar Pharma, Inc., such as the Multidose "classic technology platform" nasal sprayer device. Such devices can hold reservoirs, closures (eg, screws, crimps, or snap-ons) that hold multiple doses (eg, 50 doses, 100 doses, 150 doses, 200 doses, 60 doses, or 120 doses). ), And an actuator that delivers 45-1000 μL (eg, 50 μL, 100 μL, 140 μL, 150 μL, or 200 μL) of fluid per operation to include a single dose. Actuators may be configured to count doses, deliver gel formulations, deliver in upside down arrangements, and the like.

Traditional spray pump systems typically require antibacterial preservatives to maintain the microbiological stability of the liquid formulation. However, preservative-free systems, such as Aptar's Advanced Preservative Free (APF) system, are also available. Aptar's Advanced Preservative Free (APF) system is perforated, has an air diversion filter membrane to prevent contamination, has a metal-free fluid path to oxidize the formulation, and is oriented in any direction. Can be used. Additional nasal atomizer devices such as Aptar are optimized with a dispenser tip to prevent clogging (useful for highly viscous and volatile formulations), actuators that do not require repriming after long-term use, etc. Has been done.

The particle size and plume shape may vary within certain limits and depend on the characteristics of the pump, the formulation, the orifice of the actuator, and the force applied. The droplet size distribution of the nasal nebulizer is an important parameter as it has a significant effect on the in vivo adhesion of the drug in the nasal cavity. Droplet size is affected by the operating parameters of the device and the formulation. A typical median droplet size should be about 30 to about 100 μm. If the droplets are too large (> about 120 μm), attachment occurs primarily in the anterior part of the nose. If the droplets are too small (<about 10 μm), they may be inhaled and reach the lungs. This should be avoided for safety reasons. As a surfactant, benzalconium chloride affects the surface tension of droplets from the delivered nasal atomizer plume, resulting in spherical or substantially spherical particles with a narrow droplet size distribution (DSD). Not only can it affect the viscosity of the liquid formulation.

The plume shape, droplet size, and DSD delivered after spraying are subject to the experimental and instrumental conditions specified by appropriate and validated and / or calibrated analytical procedures known in the art. Can be measured with. These include photography, laser diffraction, and impaction systems (cascade impaction, NGI). Plume shape, droplet size, and DSD can affect pharmacokinetic outcomes such as C _max , T _max , and linear dose proportional relationships.

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

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

In certain embodiments, the pharmaceutical product yields a uniform circular plume with an ovality ratio close to 1 when administered from the device by operation. The elliptic ratio is calculated as the quotient of the maximum diameter (D _max ) and the minimum diameter (D _min ) of the spray pattern orthogonal to the direction of the spray flow (eg, from the "top"). In certain embodiments, the elliptic ratio is less than ± 2.0. In certain embodiments, the elliptic ratio is less than ± 1.5. In certain embodiments, the elliptic ratio is less than ± 1.3. In certain embodiments, the elliptic ratio is less than ± 1.2. In certain embodiments, the elliptic ratio is less than ± 1.1. In certain embodiments, the elliptic ratio is about ± 1.0.

Details and mechanical principles of particle generation are described for different types of nasal aerosol devices. Outlined in Vidgren and Kublik, Adv. Drug Deliv. Rev. 29: 157-77, 1998. Traditional spray pumps replace the released liquid with air and therefore require preservatives to prevent contamination. However, driven by studies suggesting possible adverse effects of preservatives (eg, nasal mucosal irritation), pump manufacturers have developed a variety of spray systems that do not require preservatives. These systems use folding bags, movable pistons, or compressed gases to make up for the volume of liquid released (www.aptar.com and www.rexam.com). The solution with a foldable bag and movable piston to make up for the volume of liquid released is to draw air into the dip tube and release it upside down without the risk of damaging the subsequent spray. There is an additional advantage of being able to do it. This may be useful for some products where the patient is bedridden and recommended to use with a low head. Another method used to avoid preservatives is to filter the air that replaces the released liquid with a sterile air filter. In addition, some systems have a ball valve at the tip to prevent liquid contamination inside the applicator tip (www.aptar.com). Most recently, side-actuation pumps have been designed and introduced to deliver fluticasone furoate for the indications of seasonal allergic rhinitis and perennial allergic rhinitis. This pump was designed with a shorter tip to avoid contact with sensitive mucosal surfaces. New designs to reduce the need for priming and repriming and pumps incorporating pressure point features to improve dose reproducibility and dose counters and lockout mechanisms to enhance dose control and safety are available. There are (www.rexam.com and www.aptar.com).

Traditional simple metering spray pumps require some degree of overfill to maintain dose matching with the indicated number of doses. Traditional simple metering spray pumps are well suited for long-term daily medications, but due to priming procedures and inadequate dosing management, treatable time range unless special equipment is selected. Not very suitable for narrow drugs, especially if not used frequently. Single-dose or by-dose spray devices are preferred (www.aptar.com) for expensive drugs and vaccines intended for single-dose or single-use use, and where strict dose and formulation control is particularly important. A simple variant of the Single Doze Sprayer (MAD ™) is provided by LMA (LMA, Salt Lake City, UT, USA; www.lmana.com). A nosepiece with a spray tip fits into a standard syringe. First, the liquid drug to be delivered is drawn into the syringe, and then the spray tip is fitted into the syringe. This device has been used, for example, in academic studies and in vaccine studies to deliver topical steroids in patients with chronic sinusitis. A pre-filled device for one or two doses based on the same principle (Accuspray ™, Becton Dickinson Technologies, Research Triangle Park, NC, USA; www.bdpharma.com) is the influenza vaccine FluMist ™. Used to deliver (www.flumist.com) and approved for both adults and children in the US market. Ten years ago, a Swiss company sold a similar device for two doses to deliver another influenza vaccine.

Pre-primed single-dose and by-dose devices are also available and consist of a reservoir, piston, and swirl chamber (eg, Apache, formerly Pfeiffer's UDS Unit Dose ™ and BDS BiDose ™). See device). A spray is formed as the liquid is extruded through the swirl chamber. These devices are held between the middle and ring fingers and have the thumb on the actuator. The pressure point mechanism built into some devices ensures the reproducibility of operating forces and released plume features. Currently, over-the-counter nasal migraine drugs such as Imitrex® (www.gsk.com) and Zomig® (www.az.com; Pfeiffer / Aptar Single Doze Device), over-the-counter influenza vaccine Flu -Mist (www.flumist.com; Becton Dickinson Single Doze Spray Device), as well as Naloxone Intranasal Formulation for Opioid Overdose Relief, Narcan Nasal® (narcan.com; Adapt Pharma), use this type of device. Delivered using.

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

Historically, intranasal administration of a drug in large volumes, for example intranasal administration from a syringe adapted with a mucosal atomizer device, is a drop of a portion of the formulation coming out of the nostril or down the nasopharynx. I have encountered a difficult situation because I tend to fall. Thus, in certain embodiments, when the pharmaceutical composition is delivered nasally to the patient, less than about 20% of the pharmaceutical composition is expelled from the nasal cavity through drainage to the nasopharynx or to the outside. .. In certain embodiments, when the pharmaceutical composition is delivered nasally to the patient, less than about 10% of the pharmaceutical composition is expelled from the nasal cavity through drainage to the nasopharynx or to the outside. In certain embodiments, when the pharmaceutical composition is delivered nasally to the patient, less than about 5% of the pharmaceutical composition is expelled from the nasal cavity through drainage to the nasopharynx or to the outside.

Current container closure system designs for inhalation spray drug products are both pre-weighed presentations and device weighing presentations that use mechanical or power assist and / or energy from the patient's inhalation to generate the spray plume. including. The pre-weighed presentation comprises a pre-measured dose or dose fraction in some type of unit (eg, one or more blisters or other cavities), the unit being subsequently manufactured. , Or inserted into the device by the patient prior to use. A typical device weighing unit has a reservoir containing sufficient formulation for multiple doses delivered as a spray weighed by the device itself when the patient is activated.

The new nasal drug delivery method is a breath-powered Bi-Directional ™ technology that can be adapted to any type of dispersion technology, both liquid and powder. This concept utilizes the natural functional aspects of the upper respiratory tract to provide delivery methods that can overcome many of the inherent limitations of traditional nasal appliances. The breath-powered Bi-Directional ™ device consists of a mouthpiece and a sealing nosepiece with an optimized truncated cone shape and a comfortable surface that mechanically unfolds the first part of the nasal flap. The user slides the sealing nosepiece into one of the nostrils until the flexible soft tissue of the nostril opening is sealed, at which point the narrow, slit-shaped portion of the triangular nostril. Is mechanically spread. The user then exhales through the attached mouthpiece. When you exhale to the mouthpiece against the resistance of the device, the soft palate (or velum) automatically rises due to the positive pressure of the oropharynx, separating the nasal passages from the rest of the respiratory system. .. This mechanism allows liquid or powder particles to flow into the air stream that enters through one nostril, completely through the septum, and exits through the other nostril.

Aseptic filling does not require the use of preservatives in the device, but overfilling is required, resulting in a waste fraction similar to a quantitative multidose spray. To release 100 μL, the device (Pfeiffer / Aptar single-dose device) used in the intranasal migraine drugs Imitrex ™ (sumatriptan) and Zomig ™ (zolmitriptan) was filled with a volume of 125 μL. In the case of the Bydoze design, about half of it is filled. Aseptic drug products may be produced using sterile treatment or final sterility. The final sterility method usually involves filling the product container under high quality environmental conditions and sealing it. The product is filled and sealed in this type of environment to minimize the microbial and particle contents of the in-process product and to help the subsequent sterilization process to succeed. In most cases, products, containers, and closures are low in biocontamination, but not sterile. The product in the final container is then subjected to a sterilization process such as heat or irradiation. In the aseptic process, first, the drug product, container, and closure are subjected to the sterilization process separately, as appropriate, and then united. Since there is no process to sterilize the product in the final container, it is important that the container is filled and sealed in a very high quality environment. Aseptic treatment involves more variables than final sterilization. Before being aseptically assembled into the final product, individual parts of the final product are generally subjected to various sterilization processes. For example, glass containers are subjected to dry heat, rubber closures are subjected to moist heat, and liquid dosage forms are subjected to filtration. Each of these manufacturing processes requires verification and control.

Treatment Methods Methods are provided herein for treating alcohol use disorders and related conditions, including intranasal administration of therapeutically effective amounts of naltrexone or salts or hydrates thereof.

Sinclair and Variations The Sinclair method is an AUD treatment that utilizes the use of opioid antagonists such as naltrexone to change the habit-forming behavior of drinking into a habit-erasing behavior. be. This effect restores human alcohol cravings to their pre-addictive state.

The method comprises taking an oral dose of naltrexone about 1 hour, about 2 hours, about 3 hours, or about 4 hours before the subject ingests alcohol. This pre-dose oral naltrexone disrupts the body's behavior and reward cycle, which makes one want to reduce alcohol consumption rather than increase it. Most importantly, studies have shown that this methodology is equally effective with and without therapy, so subjects combine this procedure with other therapies without adversely affecting actual physical outcomes. You can choose whether or not. Importantly, unlike other currently approved medications for AUD, the Sinclair method requires the use of oral naltrexone while the individual continues normal drinking behavior. As a result, maintenance of this pharmacotherapy treatment protocol is expected to be significantly higher than abstinence alone.

Using the Sinclair method, the AUD can be extinguished within 6 months. However, the efficacy of oral naltrexone is hampered by slow expression and very low bioavailability. High levels of the peripheral selective active metabolites 6-β-naltrexone and injectable naltrexone are themselves on the needle, including, for example, needing to be administered by the worker at regularly scheduled intervals. Presents with associated obvious difficulties. Therefore, intranasal administration of naltrexone and the use of absorption enhancers in preprimed single-use or multi-use nasal atomizer pumps should significantly improve the outcome of AUD treatment. The timing of administration may also affect efficacy. Naltrexone intranasal formulations are rapidly absorbed, so that the action is rapid and bioavailable without the use of needles.

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

In certain embodiments, the intranasal formulation containing naltrexone is administered prior to alcohol consumption.

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

In certain embodiments, the intranasal formulation containing naltrexone is administered at the same time as alcohol ingestion.

In certain embodiments, the intranasal formulation containing naltrexone is administered immediately after alcohol ingestion. In certain embodiments, the intranasal formulation containing naltrexone is administered within 1 hour after the start of alcohol intake.

As evidenced by the following tests, intranasal naltrexone is rapidly taken up through the nasal mucosa and appears rapidly in plasma, so with intranasal administration, subjects are given just before alcohol ingestion and even with alcohol ingestion. It is expected that it will be possible to take naltrexone at the same time or after ingesting alcohol and experience benefits such as the disappearance or decline of 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-dependent. In certain embodiments, the disorder of alcohol use is alcoholism.

These methods are also expected to be effective in treating other substance use disorders and reward-based disorders.

The methods disclosed herein are accomplished herein by administering, for example, the section "pharmaceutical formulation" above, the embodiments described above, and various embodiments of the formulations disclosed in the following examples. Can be done. The pharmaceutical product can be administered using a device known in the art, for example, a device disclosed herein in the section entitled "Nasal Drug Delivery Device and Kit".

Also provided herein are embodiments in which any of the above embodiments may be combined, provided that the combination of any one or more of the other embodiments is not mutually exclusive.

The following examples are included to demonstrate preferred embodiments of the invention. The following examples are shown for illustration purposes only and to assist one of ordinary skill in the art in using the present invention. The examples are not intended to limit the scope of the invention in any way. Those skilled in the art will be able to make many changes to the disclosed specific embodiments in view of the present disclosure and will nevertheless obtain similar or similar results without departing from the spirit and scope of the invention. You should understand.

Example 1: Intranasal naltrexone protocol for treating alcohol use disorders Individuals with alcohol use disorders (AUD) are treated with intranasal naltrexone and examined for abstinence, decreased alcohol consumption, and / or loss of alcohol consumption. Individuals with AUD are thought to release endogenous opioids when alcohol is consumed. The binding of these opioids to receptors in the brain may have a positive enhancing effect on alcohol. Drinking while the opioid antagonist naltrexone is blocking positive reinforcement from alcohol should also eliminate drinking and craving for alcohol.

In one example of the protocol, subjects with AUD (eg, about 10-20) are admitted to the study facility as inpatients. The first visit serves the purposes of screening, confirming the diagnosis, and obtaining informed consent. One or more alcoholic beverages are consumed after each subject is given a placebo or intranasal dose of naltrexone during a stay in the hospital (eg, for one or several weeks). Naltrexone is administered at the specified dose and by the specified method approximately 0.25 hours to approximately 4 hours before alcohol consumption. An example of a dosing procedure is an intranasal formulation delivering about 1 to about 4 mg naltrexone hydrochloride / dose delivered by a single-use or multi-use spray device. Another example of dosing treatment is an intranasal formulation that delivers a first dose of 3 mg naltrexone hydrochloride in the morning and then, if necessary, a later dose of 3 mg naltrexone hydrochloride by the patient throughout the day. Is. Yet another example of dosing treatment is an intranasal formulation that delivers up to 12 mg naltrexone hydrochloride daily. The intranasal preparation of naltrexone may or may not contain an absorption enhancer such as Intravail®.

Intranasal naltrexone is expected to improve post-treatment suppression of alcohol intake. Intranasal naltrexone is also expected to reduce alcohol cravings and reduce the time required for a subject to exhibit pharmacological extinction of alcohol cravings.

Approximately 1 hour before dosing, measure ECG, blood pressure, heart rate, and respiratory rate and record the time. Repeat ECG approximately 1 hour and 4 hours after dosing and record the time. Sitting (5 minutes) Vital signs, including heart rate, blood pressure, and respiratory rate, are measured before and approximately 1 hour and 4 hours after each dosing. Record adverse events (AEs) and end treatment if necessary. The nasal cavity is examined before, after intranasal administration only, 5 minutes, 30 minutes, 60 minutes, 4 hours, and 24 hours after dosing.

Check ECG and vital signs once daily at screening, admission, and discharge. Vital signs should be checked once the day after naltrexone administration. AE is assessed by measuring vital signs, ECG, and clinical investigation parameters by examining the nasal mucosa by voluntary reporting by the subject.

Example 2: Analysis of pharmacokinetic data Non-compartmental pharmacokinetic (PK) parameters of naltrexone and 6β-naltrexone (C _max , T _max , AUC _ot , AUC _o-∞ , t _1/2 , λ _z , And apparent clearance (CL / F, naltrexone only). PK parameters for various AUD treatment protocols (eg, 4 mg intranasal with or without absorption enhancers such as alkyl saccharides; 50 mg oral tablets) 2 mg Compare intramuscular (IM) doses with naltrexone. Calculate dose-adjusted values for AUC and C _max . Relative degree of intranasal (IN) and oral absorption (PO) absorption from dose-corrected AUC Estimate. Within the ANOVA framework, compare IN-converted PK parameters for IN and PO vs. IM naltrexone treatments. To compare each treatment with IM naltrexone, the ratio of the geometric minimum squared averages of the AUC and C _max parameters (IN). Create 90% confidence intervals for / IM and PO / IM). These 90% confidence intervals are obtained by the square of the 90% confidence interval of the difference between the least squared averages based on the log scale.

AEs are coded using the latest version of the MedDRA Basics and are classified by the name of the System on a Chip (SOC). Severity, frequency, and association between AE and study drug are indicated by basic terms by SOC classification. Separate summaries are provided during the four study periods, ie, after administration of each dose of study drug, to the time of the next dose of study drug or until discharge from the clinic. A list of individual AEs is provided, including start date, discontinuation date, severity, relevance, outcomes, and duration.

Clinically significant changes in vital signs, ECG, and clinical investigation parameters were shown by dosing sessions in numbers and percentages.

Example 3: Pharmaceutical composition comprising dose selection and absorption enhancer Nasal naltrexone can optionally be formulated with an absorption enhancer excipient.

One such excipient is Alkyl Saccharide Intravail®. The concentration of Intravail® in the nasal formulation is generally 0.1% by weight to 0.2% by weight. This test uses an alkyl saccharide with a concentration of 0.25 wt%. The 25% concentration of Intravail® was non-irritating in the rabbit eye model. The oral "no observable effect level" was approximately 20,000-30,000 mg / kg body weight. Although there are no comparable intranasal data, the fundamental lack of oral safety suggests that the amount of alkyl saccharides required for nasal toxicity is significantly higher than the dose administered in this study.

In this study, a single dose of naltrexone was dissolved in four methods: (a) 4 mg IN in sterile injectable water; (b) 4 mg IN in sterile injectable water with 0.25% Intravail®; ( c) 2 mg as IM injection; and (d) 50 mg oral tablets. Intranasal administration is expected to increase the rate of absorption compared to oral administration. The addition of Intravail® is expected to further increase the rate of absorption through the nasal cavity.

Example 4: Objectives of the pharmacokinetic evaluation study of intranasal naltrexone The objectives of this clinical study are two parts: two intranasal formulations of naltrexone compared to 2 mg intramuscular dosing of naltrexone (Intravail (Registration)). To confirm the pharmacokinetics of 4 mg with (trademark) and 4 mg without Intravail (registered trademark) and one oral preparation (50 mg tablet), and to confirm the safety of intranasal naltrexone, especially nasal irritation symptoms, for example, It consisted of confirming with respect to inflammation (erythema, edema, and erosion) and bleeding. Toward this goal, the primary endpoint of the study was the pharmacokinetic parameters of IN and oral naltrexone formulations (C _max , T _max , AUC _0-t , and AUC ₀ ) compared to IM dosing of 2 mg naltrexone. _-inf ). Secondary endpoints included adverse events (AEs), vital signs (heartbeat, sitting blood pressure, and respiratory rate), electrocardiogram (ECG), changes in clinical scrutiny, and nasal irritation symptoms using the nasal irritation symptom scale. ..

Test design
Fourteen healthy volunteers enrolled and completed all study drug administration and blood draws for PK assessment. This was an inpatient, open-label, crossover study involving about 14 healthy volunteers. Each subject was treated with Nartrexone: 4 mg IN (1 spray of 0.1 mL of 40 mg / mL solution in one nostril), 4 mg + Intravail® IN (0.25% Intravail in one nostril). 0.1 mL spray of 40 mg / mL solution containing (registered trademark) once), 2 mg IM, and 50 mg oral tablets were given. Subjects stayed in the inpatient facility for 13 days to complete the entire study. Three to five days after discharge, the subject was called to ask questions about AE and concomitant medications from discharge. Obtained informed outlets from all subjects, including history, laboratory tests, clinical chemistry, coagulation markers, hematology, infectious disease serology, urinalysis, urinary drug and alcohol toxicology screening, vital signs, and ECG. All were screened for eligibility to participate in this study.

The day after admission to the clinic, subjects were administered the study drug with a 3-day washout period between doses until all treatments were administered. Before dosing and about 2.5 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, and 2 hours, 3 hours after administration of the study drug. Blood was collected for analysis after, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 24 hours, 30 hours, 36 hours, and 48 hours. On the day of administration of the study drug, 12-lead ECG was performed approximately 1 hour before dosing, and approximately 1 hour and 4 hours after dosing. Vital signs were measured before dosing and about 1 and 4 hours after dosing.

The dosing day evaluation sequence was ECG, vital signs, and then PK blood draws when scheduled at the same nominal time. The target time for PK blood collection is considered to be the most important, and if the blood collection is for the first 60 minutes of blood collection, ± 5 minutes if it is more than ± 1 minute from the scheduled time, or if it is scheduled after that. After that, it was considered to have deviated from the protocol. ECG and vital signs were collected within a 10 minute period prior to the nominal time of blood collection. ECG and vital signs were checked once daily at screening, admission, and discharge. Vital signs were also checked once the day after naltrexone administration. After the last PK blood draw before discharge from the clinic, clinical scrutiny measurements were repeated. AE was assessed by measuring vital signs, ECG, and clinical investigation parameters by examining the nasal mucosa by voluntary reporting by the subject.

Inclusion and exclusion criteria:
1. This study enrolled men and females aged 18-55 years (including between both ends). Required written informed consent. The target is as follows:
Body mass index (BMI) of 18-30 kg / m ² (including between both ends);
Sufficient venous access;
No clinically significant comorbid medical condition confirmed by medical history, laboratory tests, clinical examination, vital signs, and 12-lead ECG;
Agree to use acceptable contraceptive methods other than oral contraceptives throughout the study and for 90 days (30 days for women) after the last study drug administration; and from 72 hours prior to admission I agree not to consume alcohol, beverages containing> 500 mg / day of xanthin (eg Coca-Cola®, tea, coffee, etc.) or grapefruit / grapefruit juice until the final blood sampling of the study. I had to agree that I wouldn't participate in the vigorous exercise.

The exclusion criteria are:
Any IN condition including abnormal nasal anatomy, nasal symptoms (ie, stuffy nose and / or runny nose, nasal polyps, etc.);
The product has been sprayed into the nasal passages prior to screening and drug administration;
-The investigational drug has been administered within 30 days before the first day;
Have taken prescription or OTC medications, dietary supplements, herbal products, vitamins, or have recently used opioid analgesics for pain relief (use one of these products last) Within 14 days);
Positive drug urinalysis for alcohol, opioids, cocaine, amphetamines, methamphetamine, benzodiazepines, tetrahydrocannabinol (THC), barbiturate, or methadone at screening or on admission;
Previously or now, based on medical history, there is opioid dependence, alcohol dependence, or other drug dependence (excluding nicotine and caffeine);
Consume an average of more than 20 cigarettes a day in the month prior to screening, or be unable to quit smoking at least 1 and 2 hours before and 2 hours after naltrexone dosing (or refrain from using any nicotine-containing substance) Can't);
Systolic blood pressure is less than 90 mmHg or greater than 140 mmHg;
Diastolic blood pressure below 55 mmHg or above 90 mmHg;
Respiratory rate less than 8 breaths / minute or greater than 20 breaths / minute;
QTcF interval> 440 msec for males and> 450 msec for females during standard 12-lead ECG;
Serious acute or chronic medical illness (at the discretion of the investigator);
Concomitant drug therapy treatment is likely to be required during the study;
-Donated or transfused within 60 days prior to day 1 or received plasma or platelet apheresis;
Pregnant, lactating, or planning to become pregnant during the study period or within 30 days of the last naltrexone administration;
At the time of screening, a positive test for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCVAb), or human immunodeficiency virus antibody (HIVAb);
Current or recent upper respiratory tract infections (within 7 days prior to screening); as well as abnormal liver function tests (ALT, AST, total bilirubin)> 1.5 times the reference limit
Including.

Study Drugs and Dosings Naltrexone Hydrochloride (HCI) was obtained from Mallinckrodt Pharmaceuticals. The IN (40 mg / mL) formulation was prepared by the pharmacist staff of Vince & Associates. The vehicle for the IN formulation was sterile injection water. The IM preparation (2 mg / mL) was prepared by the pharmacist staff of Vince & Associates. This vehicle was a sterile injectable saline solution. IN Naltrexone was administered using the Aptar multidose device in a lying position (about 45 degrees). Subjects were instructed not to breathe nasally when receiving the IN dose of naltrexone. Naltrexone HCI for IM injection was administered to the gluteus maximus muscle in a single 1 mL injection using a 23 g needle. Naltrexone HCI (50 mg tablets) for oral administration was obtained from a commercial supplier and administered with 240 mL of 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 orally. .. Subjects stayed in an inpatient facility for 13 days to complete the entire study and were discharged 2 days after the fourth dose.

PK rating
For PK analysis, before dosing, 2.5 minutes, 5 minutes, 10 minutes, 1.5 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, and as well as the start of study drug administration. Heparin blood (4 mL) after 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 24 hours, 30 hours, 36 hours, and 48 hours. Collected in sodium-containing tubes. Plasma was separated from whole blood and stored frozen below 20 ° C until assay. Plasma concentrations of naltrexone and 6β-naltrexol were determined by liquid chromatography and 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 naltrexone dosing. 12-lead ECGs were obtained approximately 1 hour, 1 hour and 4 hours after each naltrexone dosing. ECG and vital signs were performed within 10 minutes prior to the nominal time for post-medication blood sampling. AE was recorded from the start of study drug administration to discharge from the clinic. AEs were recorded compared to each dosing session in an attempt to clarify the association between AE and the type of naltrexone dosing administered. Nasal examinations were performed on day 1 for eligibility, only after IN administration, before dosing, for the purpose of assessing evidence of nasal mucosal irritation, 5 minutes, 30 minutes after IN naltrexone administration, It was performed after 60 minutes, 4 hours, and 24 hours.

analysis
Non-compartment PK parameters for naltrexone and 6β-naltrexone, including T _max , AUC _0-t , and AUC _0-inf , t _1/2 , λ _z , and apparent clearance (CL / F, naltrexone only). I asked. The pharmacokinetic parameters of IN and PO naltrexone (C _max , T _max , and AUC) were compared with the pharmacokinetic parameters of IM naltrexone. Dose adjustments for AUC and C _max were calculated. The relative degree of IN and PO absorption (IN and PO vs. IM) was estimated from the dose-corrected AUC. Within the ANOVA framework, the ln-transformed PK parameters (C _max and AUC) were compared for IN and PO vs. IM naltrexone treatment. To compare each treatment with IM naltrexone, we created 90% confidence intervals for the ratio of geometric least squares means (IN / IM and PO / IM) of the AUC and C _max parameters. These 90% CIs were obtained by raising 90% CI of the difference between the least squares means based on the ln scale.

Results The results are shown in Tables 1-5 below.

(Table 1) Mean (SD) concentration of naltrexone after a single IN, IM, or oral administration to healthy subjects

NA=該当なし;Frel=IM用量と比べたバイオアベイラビリティ。IM経路と比べたINまたはPO経路経路のAUCinf/用量の比として計算した。
a:N=13;b:N=12;c:N=10;d:中央値(最小値、最大値) (Table 2) Mean CV% PK parameters of naltrexone after administration to healthy subjects

NA = Not applicable; Frel = Bioavailability compared to IM dose. Calculated as the AUCinf / dose ratio of the IN or PO pathway compared to the IM pathway.
a: N = 13; b: N = 12; c: N = 10; d: Median (minimum, maximum)

After IN administration of 4 mg naltrexone, the average concentration at 2.5 minutes after administration was 0.117 ng / mL. When 0.25% Intravail® was added to the pharmaceutical product, the average concentration increased 10-fold (1.15 ng / mL) in 2.5 minutes. Five minutes after dosing, the mean concentrations of naltrexone with Intravail® and naltrexone without Intravail® were 11.9 ng / mL and 1.51 ng / mL, respectively, an 8-fold difference. The addition of 0.25% Intravail® to the IN formulation reduced the median T _max from 30 minutes to 10 minutes and almost tripled the C _max (15.7 vs. 5.35 ng / mL). Overall exposure as measured by AUC _0-inf increased by 54%. From this, it was found that the main effect of Intravail® is to increase the absorption rate faster than the above degree.

The mean plasma concentrations of naltrexone 2.5 and 5 minutes after administration of 2 mg naltrexone IM were 0.678 ng / mL and 1.04 ng / mL, respectively. The average C _max value of 4.10 ng / mL 20 minutes after administration of 2 mg IM was 23% lower than that after administration of 4 mg IN, and 74% compared to when Intravail® was part of the IN preparation. There were few.

The mean C _max value after oral dosing was 9.34 ng / mL. This was 50 mg orally administered, but less than that observed after IN dosing with Intravail® compared to only 4 mg IN.

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

When the AUC _0-inf value was dose-corrected, the relative bioavailability of naltrexone after IN dosing with 0.25% Intravail® and after IN dosing without 0.25% Intravail®, respectively, was It was 78% and 48% compared to IM administration. The relative bioavailability of the oral dose was only 9%, indicating that there was a large amount of first-pass metabolism by the gastrointestinal tract and liver.

From statistical analysis of dose-adjusted PK parameters, IN dose exposure is approximately 48% or 60% of IM dose, respectively, in terms of geometric mean squared mean (GM) dose-adjusted AUC and C _max on a / mg basis. It has been suggested. IN administration of naltrexone and 0.25% Intravail® is greater than the IM pathway in C _max (188% geometric least squares mean squares between treatments [GMR]) and smaller than the IM pathway in AUC. A dose-adjusted exposure (76% GMR) was obtained. For the oral route, the GMR of dose-adjusted naltrexone exposure was approximately 9% of the IM dose.

GMR=処置間の幾何最小二乗平均比(参照に対するパーセントで表した) (Table 3) ANOVA results of mixed effect of naltrexone pharmacokinetic parameters after intranasal administration or oral administration vs. intramuscular administration to healthy subjects

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

The mean C _max value of 6β-naltrexol was 1.5 ng / mL after IM administration and about 3 ng / mL after IN administration. Cmax was 90.7 ng / mL after oral dosing of 50 mg (Tables 2-3). Cmax values were similar for IN and IM doses (0.833 and 0.838 ng / mL / mg) when adjusted to the dose administered, but approximately doubled (2.00 ng / mL / mg) after oral administration. )Became.

AUC _0-inf levels were also significantly increased after oral dosing compared to IN and IM doses (675 h · ng / mL and 44.0-27.1 h · ng / mL, respectively). The greater degree of first-pass metabolism of naltrexone was evident in the AUC _0-inf ratio of 6β-naltrexone compared to naltrexone. That is, the ratio was about 2.2 to 3.7 after IN administration and IM administration, whereas it was 25 after oral administration.

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

(Table 4) Mean (SD) concentration of 6β-Naltrexol after single IN, IM, or oral administration to healthy subjects

^*Tmaxについては中央値(最小値,最大値)統計値を示した。他の全ての値は平均(パーセント変動係数)で示した。a:N=13;b:N=12;c:N=10;d:中央値(最小値、最大値) (Table 5) Mean (CV%) PK parameters of 6β-Naltrexol after administration to healthy subjects

^* For Tmax, the median (minimum, maximum) statistics are shown. All other values are averaged (percent coefficient of variation). a: N = 13; b: N = 12; c: N = 10; d: Median (minimum, maximum)

By gender, the PK parameters for naltrexone or 6β-naltrexol after IN, IM, or PO dosing, except for the mean C _max of naltrexone after 4 mg IN dosing, which was approximately doubled in females compared to males. There was no clinically significant difference.

Safety Overall, 10 of the 14 subjects (71%) in the safety population experienced at least one AE (at any dosing duration, any association with the drug). The most frequent AE was AE for nervous system disorder SOC (7 subjects, 50%) and dizziness was the most frequent AE regardless of severity or attribute (5 subjects, 50%). 36%). No severe AE was observed, and only one moderate AE, a case of dizziness after the first dose (4 mg IN) considered to be associated with the study drug, was observed. Three subjects experienced an unexpected AE (UAE, defined as an AE that was not mentioned in the package insert of the latest product in terms of nature, severity, or frequency). Two UAEs were considered unrelated to the study drug, and one treatment-related UAE was mild syncope after administration of day 1 dosing (4 mg IN). Three subjects discontinued the study due to AE (hypertension, syncope, and out-of-range predose vital signs).

Example 5: Nasal Naltrexone Preparation The following table shows examples of naltrexone preparations for intranasal administration to treat disorders. Table 6 shows a simple aqueous solution formulation supplied in approximately 100 μL increments, eg, the aqueous solution formulation used in the above experiment.

(Table 6)

Table 7 shows the intranasal preparations dissolved in 100 μL of an aqueous solution containing excipients such as isotonic agents, stabilizers and / or compounds acting as preservatives or surfactants. EDTA is an abbreviation for disodium edetate and BZK is an abbreviation for benzalkonium chloride.

(Table 7)

Also provided are Examples 1A-45A, which further contain a sufficient amount of hydrochloric acid to bring the pH to 3.5-5.5. The acid must be a pharmaceutically acceptable acid, such as hydrochloric acid.

Example 6: Intranasal Naltrexone Preparation Experiment A series of experiments were performed to identify the naltrexone preparation that is a pharmaceutically suitable intranasal product disclosed herein. The formulation has the following characteristics:
Contains an effective amount of naltrexone;
Naltrexone is rapidly absorbed after administration, resulting in good C _max and relatively short T _max ;
Form a solution at room temperature and remain in solution under cold storage conditions or return to solution when removed from cold storage;
Not contaminated with microorganisms;
It is storage stable, does not acquire the formation of unwanted impurities, and / or does not discolor over time; and at least some of it is non-irritating to nasal tissue, all in certain embodiments. Designed to have.

Various formulations were tested using the following observations. The 50 mg / mL naltrexone HCl preparation is cloudy at room temperature, indicating incomplete dissolution. It was confirmed that the dissolution limit of naltrexone hydrochloride dissolved at ambient temperature was about 40 mg / mL. After that, several preparations were made at 30 mg / mL. In addition, these preparations consist of a certain amount of (dodecyl maltoside 0.25%) and NaCl (about 0.74%) and various amounts of preservatives (benzalkonium chloride, 0-0.02%) and stabilizers (EDTA, EDTA, 0-0.3%) was further contained. Crystallization behavior and discoloration were visually monitored. All of these formulations developed crystals when stored under refrigerated conditions. Naltrexone solution tends to turn yellow over time over a period of 0 to 3 months. Formulations containing 0.2% or 0.3% EDTA did not form a yellow solution, whereas formulations containing 0% or 0.1% EDTA began to turn yellow. The 0.3% EDTA formulation appeared to be less prone to yellowing over the longest period of time. After that, various co-solvents were evaluated for their potential to reduce the crystallization of the drug from the solution. Polyethylene glycol (PEG), propylene glycol, and benzyl alcohol were tested. The PEG-containing formulation did not prevent crystallization. The propylene glycol-containing formulation prevented crystallization but resulted in a high osmolal concentration. High osmolal concentrations were expected to cause nasal tissue irritation. The benzyl alcohol-containing preparation prevented crystallization at low concentrations. It has been observed that total solids are associated with crystallization, and reducing the amount of naltrexone hydrochloride to produce low concentrations and small amounts of NaCl to regulate osmolality can cause the formulation to dissolve during storage under refrigerated conditions. Helped to keep it in. Four kinds of naltrexone preparations suitable for intranasal administration are shown in Example 7 below.

Example 7: Further Formulation of Intranasal Naltrexone The following is an example of a further naltrexone batch formulation, each of which is a given (give) intranasal administration formulation of 2000 liquid grams for treating disorders including alcohol use disorders. Yes, these can be supplied, for example, in increments of about 100 μL.

The following example was prepared as follows. 1800.0 grams of water for injection (WFI) was added to a tare 4L batch container with a stirrer bar, and mixing was started. 24.0 g, 32.0 g, 40.0 g, or 60.0 g of naltrexone hydrochloride (NH) was added, rinsed 4 times with 5 mL WFI, the NH vessel was rinsed, and mixed until the NH was visually dissolved. 5.0 g DDM was added while mixing and mixed until visually dissolved. The same procedure was then performed with 6.0 g EDTA. Next, NaCl with an initial dose of 12.6 g, 11.7 g, 10.5 g, or 7.9 g was added depending on the concentration of the product. NaCl was added intermittently and mixed during the addition until visually dissolved. Next, 40.0 g of BZK 1% stock solution was added while mixing, and the BZK 1% stock solution container was rinsed with a 10 mL rinse solution and mixed visually until BZK was dissolved. Finally, the pH of the solution was measured using a calibrated pH meter, and if it was 5.5 or higher, it was adjusted accordingly with 10% HCl until 3.5-5.5. The target pH was 5.0. This was done by dropping and mixing during the dropping for 3-5 minutes. Then, Q.S. was added to about 2000.0 g of water, and the mixture was stirred for 5 minutes.

The above formulations can be tested according to the procedures of Examples A to E above and according to methods known in the art. Some of these formulations have been tested in Example 8 below. The pharmacokinetic properties of these formulations are aimed at treating opioid overdose, and are "necessary" for treating multiple substance use disorders and other reward-based disorders exemplified by alcohol use disorders. It is expected to be consistent with the pharmacokinetic properties of effective drug therapies intended to be used "according to." These properties include rapid onset (shorter T _max ), higher plasma concentrations, and shorter half-life compared to oral administration that can be achieved with these formulations.

Example 8: Pharmacokinetic assessment of intranasal naltrexone Single-center, open-label, randomized, 4-sequence, 4-treatment, 4-stage crossover pilot study in healthy men and non-pregnant females Completed. 20 (20) healthy subjects were registered. 21 (20) subjects have completed the study and have evaluable data over the entire study period.

Endpoint Primary study endpoint is a naltrexone hydrochloride nasal sprayer at three different doses (1.2 mg, 1.6 mg, and 3 mg) compared to a 50 mg oral dose of naltrexone hydrochloride (reference product, also referred to herein as R). A test product that can confirm the pharmacokinetics of test products 1, 2, and 3, also referred to herein as T1, T2, and T3, respectively, and achieve systemic exposure to naltrexone comparable to an oral dose of 50 mg. Was to identify the intranasal dose of. The secondary study endpoint was to assess the safety and tolerability of the test product, in particular the symptoms of nasal irritation (eg, erythema, edema, and erosion).

Inclusion and Exclusion Criteria The inclusion criteria for this study are:
Written informed consent;
For men or women aged 18-55 years (including between both ends) upon consent;
Weight ≥ 48 kg and Body Mass Index (BMI) 18.0-30.0 kg / m ² (including between both ends);
Resting systolic blood pressure 90-1140 mmHg (including between both ends), and diastolic blood pressure 65-90 (including between both ends);
Resting heart rate 40-100 bpm (including between both ends);
Resting respiratory rate 8-120 (including between both ends);
Have sufficient venous access;
There are no clinically significant abnormalities in the physical examination;
There are no clinically significant abnormalities in the 12-lead ECG recorded at least 3 minutes after lying on the back;
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);
Being a non-smoker or ex-smoker (ie, a person who has lost a product containing tobacco or a product containing nicotine within the previous 3 months);
(Occasionally use of tobacco-containing or nicotine-containing products is acceptable if the subject has no nicotine addiction and agrees to quit smoking during the study period);
Willingness to accept and comply with study restrictions (eg, alcohol consumption, methylxanthin, diet, exercise, contraception, and drug therapy; and if female, infertility, postmenopausal, or If you are pregnant, you agree to use non-hormonal contraceptives or hormonal contraceptives that are effective for at least 4 weeks from admission to period 1, and ensure stable plasma hormone levels during the entire study period. It was to continue a stable continuous regimen until the end of the test in order to make it a good thing.

Exclusion criteria at the time of screening are as follows:
Known hypersensitivity / allergic reactions to test drug substances or any excipient;
Known severe hypersensitivity reactions to any other drug;
Any nasal condition, including abnormal nasal anatomy, nasal symptoms (ie, stuffy nose and / or nasal discharge, nasal polyps, etc.), rhinitis, and other conditions known to affect nasal absorption. Or the product may have been sprayed into the nasal passages prior to drug administration;
Previous or current opioid dependence, alcohol dependence, or other drug dependence based on medical history (excluding nicotine and caffeine);
Comorbidities deemed clinically significant by the investigator in terms of trials;
The need for concomitant medication during the study;
Any medical condition that may affect pharmacokinetics (absorption, distribution, metabolism, or excretion) or subject safety (eg, gastrointestinal ulcer, including gastrointestinal ulcer, kidney ulcer, or liver ulcer, inflammatory Intestinal disease or pancreatitis), or surgical condition (eg, gallbladder resection, gastric resection);
Current or recent upper respiratory tract infection (within 7 days before screening);
≧ 450 msec for male QTc interval,> 470 msec for female;
Positive results for substance abuse urinalysis or ethanol breath test;
Within the previous 3 months, depot injections or grafts of any drug (excluding contraceptives) have been used;
Within the previous 6 months, on average,> 14 units (12 grams / unit) of alcohol for men and> 7 units of alcohol for women were consumed weekly;
On average,> 500 mg of methylxanthin equivalent of a methylxanthin-containing beverage or food (eg coffee, tea, cola, soda, chocolate) was consumed daily (100 mg of methylxanthin is about 150 mL of coffee, 300 mL). Equivalent to tea, 75 mL hot chocolate, 800 mL cola, 300 mL energy drink, or 25 g chocolate bar);
Participated in any clinical trial within the previous 2 months, or participated in more than 2 clinical trials within the previous 12 months;
Have had blood donation or massive blood loss (≧ 450 mL) or plasmaferesis within the previous 2 months;
Any dietary restrictions that may be difficult to fast or interfere with the diet served during the test, such as lactose intolerance, vegan, low fat, low sodium;
Difficult to donate blood with either arm;
Difficulty swallowing capsules or tablets;
If it was a female, it was a pregnant female, a lactating female; as well as any other condition considered by the investigator that the subject was not suitable for the study.

Exclusion criteria at the time of admission are as follows:
Resting systolic blood pressure 90-140 mmHg (including between both ends), and diastolic blood pressure 65-90 (including between both ends);
Resting heart rate 40-100 bpm (including between both ends);
Resting respiratory rate 8-20 (including between both ends);
QTcF interval>500msec;
Serious arrhythmias defined as supraventricular tachycardia with 6 or more beats or ventricular tachycardia with 3 or more beats;
Any recent illness or condition or treatment that occurs during a time period that, according to the investigator, is likely to put the subject at excessive risk by participating in the study or may interfere with the pharmacokinetics of the study drug;
Vitamin, dietary supplements, and herbs within the previous 14 days, unless, in the investigator's opinion, drug therapy does not interfere with the pharmacokinetics of the study drug or impair the safety of the subject. Use of prescription or non-prescription medicinal products containing supplements (including St. Jones wort) (topical products without systemic absorption or use of recommended contraceptives are acceptable);
Consumption of any alcoholic product within the previous 72 hours;
Positive results for substance abuse urinalysis or ethanol breath test;
Positive β-hCG pregnancy urinalysis results for fertile women; as well as any other condition considered by the investigator that the subject was not suitable for the study period.

Clinical Procedure Subjects were admitted to a clinical research facility for 15 nights during the study period. During the study, each subject experienced four treatment periods. Each subject received one of four treatments for each of the four treatment periods.

(Table 8)

According to a randomized program, subjects were assigned to one of several treatment sequences in which the study products T1, T2, T3, and R were administered in various sequences. The study product was administered in the morning after an overnight fast of at least 10 hours. The reference product was orally administered (swallowed) as a single dose with 240 mL of water. Each test product was administered twice. With the subject in an upright position, the first dose was given to one nostril, and two hours later the second dose was given to the other nostril. The subject was instructed to hold his breath during the scheduled administration of the nasal spray to the nostrils. The test product was primed before use. After priming, the dosing device was weighed before and after each dosing to determine the weight of the dose to be administered. Dosing of each study product was separated by a 3-day washout interval.

During each study period, subjects who fasted overnight remained fasted until breakfast. Breakfast was served approximately 3 hours after the reference product dosing and 1 hour after the second dose of the test product dosing. It was not allowed to drink the liquid from 1 hour before dosing to 3 hours after dosing (at the time specified for the first dose of the test product or the dose of the reference product). I was free to drink water at any other time. The same standardized diet and light meals were provided over all periods. Lunch was served about 3 hours after breakfast and all other meals were scheduled at the appropriate time by the clinical facility.

Sample Collection and Analysis Twenty-four venous blood samples (4 mL each) were taken at the following time points to determine plasma levels of naltrexone and 6β-naltrexol during each test period: pre-dosing and reference product dosing and testing. 0:02, 0:05, 0:10, 0:15, 0:20, 0:30, 0:45, 1:00, 2:00, 2:05, 2 after the first dose of the product 10, 2:15, 2:20, 2:30, 2:45, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 24:00, and 48: Collected in 00 hours: minutes.

Plasma concentrations of naltrexone and 6β-naltrexol were measured using a previously validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) assay.

Non-compartment method and ln-linear terminal phase assumption of pharmacokinetic parameters of naltrexone and 6β-naltrexol using Phoenix® WinNonlin® version 8.1 (Certara USA Inc, Princeton, NJ) or later Was estimated by using. Pharmacokinetic parameters were estimated using the actual time of blood sampling.

The following pharmacokinetic parameters:
Maximum plasma concentration observed (C _max );
Occurrence time of C _max (T _max );
Area under the plasma concentration vs. time curve (AUC) (AUC _0-t ) from pre-dose (time 0) to the last sampling time with quantifiable concentrations;
AUC from time 0 to infinity (AUC _0-∞ );
Apparent terminal discharge rate constant (λ _z );
Apparent terminal elimination half-life (t _1/2 ; but it should be noted here that one value is shown for each of the two doses); and the apparent total clearance of the drug from plasma. (CL / F)
Was estimated. The C _max , T _max , AUC _0-t , and AUC _0-∞ of naltrexone and 6β-naltrexol were the primary endpoints.

An analysis of variance (ANOVA) was performed to compare the ln transforms C _max , AUC _0-t , and AUC _0-∞ using a mixed effect model. Sequences, durations, and treatments were included as independent factors in the ANOVA model. For C _max , AUC _0-t , and AUC _0-∞ , the test vs. reference geometric least squares mean squares (GMR) and the corresponding 90% confidence intervals (CI) were calculated. The relative degree of intranasal absorption (Frel) (see test pair) was estimated from dose-corrected AUC _0-t . T _max was compared using a nonparametric test. The secondary endpoints were λ _z , t _1/2 , and CL / F.

Safety Safety was assessed by assessing adverse events, 12-lead ECG, vital signs, nasal examinations, weight measurements, smell tests, and laboratory tests (see flowchart). Adverse events were monitored throughout the study.

Results The results are shown below and in the attached figure.

Table 9 shows the average naltrexone primary pharmacokinetic parameters of 20 (20) subjects after administration of test product 1, test product 2, test product 3, and reference product, as well as summary statistics for each. ..

(Table 9)

Table 10 shows the average naltrexone secondary pharmacokinetic parameters of 20 (20) subjects after administration of test product 1, test product 2, test product 3, and reference product, and their summary statistics. show.

(Table 10)

Table 11 shows the mean naltrexone pharmacokinetic parameters of 20 (20) subjects after the first and second doses of Test Product 1, Test Product 2, Test Product 3, and Reference Products, respectively. Shows the summary statistics of.

(Table 11)

Table 12 shows the average of 6β-Naltrexol primary pharmacokinetic parameters in 20 (20) subjects after administration of Test Product 1, Test Product 2, Test Product 3, and Reference Product, and a summary of each. Show statistics.

(Table 12)

Table 13 shows the average of 6β-Naltrexol secondary pharmacokinetic parameters of 20 (20) subjects after administration of test product 1, test product 2, test product 3, and reference product, respectively. Shows summary statistics.

(Table 13)

Analysis of variance (ANOVA) was performed using a mixed-effects model according to the protocol to compare the ln transforms C _max , AUC _0-t , and AUC _0-∞ for naltrexone. The test vs. reference geometric least squares mean ratio (GMR) and the corresponding 90% confidence interval (CI) were calculated. Table 14 summarizes the results of comparing references with three different test products (Test Product 1, Test Product 2, and Test Product 3).

¹LS平均値はC_maxについてはng/mLで示し、AUCについてはng.h/mLで示した。 (Table 14) ANOVA results of mixed effects of naltrexone pharmacokinetic parameters

¹ LS mean is shown in ng / mL for C _max and ng.h / mL for AUC.

Analysis of variance (ANOVA) was performed using a mixed-effects model according to the protocol to compare the ln transformations C _max , AUC _0-t , and AUC _0-∞ for 6β-Naltrexol. The test vs. reference geometric least squares mean ratio (GMR) and the corresponding 90% confidence interval (CI) were calculated. Table 15 summarizes the results of comparing references with three different test products (Test Product 1, Test Product 2, and Test Product 3).

¹LS平均値はCmaxについてはng/mLで示し、AUCについてはng.h/mLで示した。 (Table 15) ANOVA results of mixed effects of naltrexone pharmacokinetic parameters

¹ LS mean value is shown in ng / mL for Cmax and ng.h / mL for AUC.

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

n-対象の数
AUC_0-t/D-用量基準化AUC0-t。各試験製品について、Dは、製品の投与された全用量に対応する。
F_rel-鼻腔内吸収の相対程度(試験/参照) (Table 16) Naltrexone-Relative degree of intranasal absorption

n-number of targets
AUC _0-t / D-Dose standardized AUC 0-t. For each test product, D corresponds to the total dose of product administered.
F _rel -relative degree of intranasal absorption (test / reference)

According to the protocol, the tmax obtained for each formulation was compared using a nonparametric test as shown in Table 17.

(Table 17) Naltrexone: t _max nonparametric analysis

Other Aspects The detailed description presented herein is provided to assist one of ordinary skill in the art in carrying out the present disclosure. However, the disclosures described and asserted herein shall not be limited in scope by the particular embodiments disclosed herein. This is because these embodiments are intended as illustrations of some aspects of the present disclosure. All equivalent embodiments are intended to be within the scope of this disclosure. Indeed, various modifications of the present disclosure in addition to those shown and described herein will be apparent to those of skill in the art from the above description, which do not deviate from the spirit or scope of the discovery of the present invention. Such changes are also intended to be within the scope of the appended claims.

All US or foreign references, patents, or applications cited herein are incorporated herein by reference in their entirety as they are written herein. In the event of any inconsistency, the material literally disclosed herein will prevail.

Although the invention has been described in connection with the above embodiments, it is understood that changes and changes are included within the spirit and scope of the invention. Therefore, the present invention is limited only by the following claims.

Claims (66)

An intranasal preparation containing an aqueous solution containing about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof. An intranasal preparation containing an aqueous solution containing about 10 mg / mL to about 40 mg / mL naltrexone or a pharmaceutically acceptable salt thereof in a volume of about 50 to about 150 μL. Less than:
Isotonic;
Preservative;
Stabilizer;
The formulation according to claim 1 or 2, further comprising an absorption enhancer; and an amount of water sufficient to achieve a final volume of about 50 to about 150 μL. Less than:
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.1 mg to about 1.2 mg isotonic;
About 0.001 mg to about 0.1 mg of preservatives;
About 0.1 mg to about 0.5 mg of stabilizer;
The formulation according to claim 3, comprising an absorption enhancer of about 0.05 mg to about 2.5 mg; and an amount of water sufficient to achieve a final volume of about 50 to about 150 μL. Less than:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.1% to about 1.2% isotonic;
About 0.001% to about 0.1% preservatives;
About 0.1% to about 0.5% stabilizer;
The preparation according to claim 3, which comprises an absorption promoter of about 0.05% mg to about 2.5%. The isotonic agent is NaCl,
The preservative is benzalkonium chloride,
The stabilizer is disodium edetate,
The absorption enhancer is alkyl saccharides,
The formulation according to claim 4 or 5. The preparation according to claim 6, wherein the alkyl saccharide is dodecyl maltoside. Less than:
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.1 mg to about 1.2 mg of NaCl;
About 0.001 mg to about 0.1 mg of benzalkonium chloride;
About 0.15 mg to about 0.5 mg of disodium edetate;
The formulation according to claim 7, comprising about 0.05 mg to about 2.5 mg of dodecyl maltoside; and an amount of water sufficient to achieve a final volume of about 50 to about 150 μL. The preparation according to claim 8, which comprises about 0.1 mg to about 0.5 mg of dodecyl maltoside. The preparation according to claim 9, which comprises about 0.25 mg of dodecyl maltoside. The preparation according to claim 8, which comprises about 0.2 mg and about 0.3 mg of disodium edetate. Less than:
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.3 mg to about 0.7 mg of NaCl;
Approximately 0.02 mg of benzalkonium chloride;
About 0.3 mg disodium edetate;
The pharmaceutical product according to claim 9, which comprises about 0.25 mg of dodecyl maltoside; and an amount of water sufficient to achieve a final volume of about 50 to about 150 μL. The formulation according to claim 10, wherein the amount of water is sufficient to achieve a final volume of about 80-about 120 μL. The formulation according to claim 11, wherein the amount of water is sufficient to achieve a final volume of about 100 μL. Less than:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.1% to about 1.2% NaCl;
About 0.001% to about 0.1% benzalkonium chloride;
About 0.15% to about 0.5% disodium edetate;
The preparation according to claim 7, which comprises about 0.05% to about 2.5% dodecyl maltoside; and water. The preparation according to claim 15, which comprises about 0.1% to about 0.5% dodecyl maltoside. The formulation according to claim 16, which comprises about 0.25% dodecyl maltoside. The preparation according to claim 15, which comprises about 0.2% and about 0.3% disodium edetate. Less than:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.3% to about 0.7% NaCl;
Approximately 0.02% benzalkonium chloride;
Approximately 0.3% disodium edetate;
The pharmaceutical product according to claim 17, which comprises about 0.25% dodecyl maltoside; and water. The formulation according to claim 19, wherein the amount of water is sufficient to achieve a final volume of about 50-about 150 μL. The formulation according to claim 20, wherein the amount of water is sufficient to achieve a final volume of about 100 μL. The preparation according to any one of claims 1 to 21, wherein the naltrexone is naltrexone hydrochloride. 22. The formulation according to claim 22, which comprises about 1.2 mg, about 1.6 mg, about 2.0 mg, or about 3.0 mg naltrexone or an equivalent amount of naltrexone hydrochloride. A method of treating opioid overdose or reward-based disorders in a subject.
A method comprising administering to a subject an intranasal preparation containing an aqueous solution containing about 1 mg to about 3 mg naltrexone or a pharmaceutically acceptable salt thereof. A method of treating opioid overdose or reward-based disorders in a subject.
The stage of administering to the subject a first intranasal preparation containing an aqueous solution containing about 1 mg to about 4 mg of naltrexone or a pharmaceutically acceptable salt thereof, and about 1 mg to about 4 mg of naltrexone or pharmaceutically acceptable thereof. A method comprising administering a second intranasal formulation comprising an aqueous solution containing a salt. A method of treating opioid overdose or reward-based disorders in a subject.
A method comprising administering to a subject an intranasal preparation containing an aqueous solution containing about 10 mg / mL to about 30 mg / mL naltrexone or a pharmaceutically acceptable salt thereof in a volume of about 50 to about 150 μL. .. A method of treating opioid overdose or reward-based disorders in a subject.
The stage of administering to a first intranasal preparation, which comprises an aqueous solution containing about 10 mg / mL to about 40 mg / mL naltrexone or a pharmaceutically acceptable salt thereof in a volume of about 50 to about 250 ul. And a second intranasal preparation containing an aqueous solution containing about 10 mg / mL to about 40 mg / mL naltrexone or a pharmaceutically acceptable salt thereof in a volume, that is, in about 50 to about 250 μL. Including the method. 25 or 27, wherein the second intranasal preparation is administered about 1 to about 3 hours after the first intranasal preparation is administered. The intranasal preparation is as follows:
Isotonic;
Preservative;
Stabilizer;
The method of any one of claims 24-28, further comprising an absorption enhancer; and an amount of water sufficient to achieve a final volume of about 50-about 150 μL. Intranasal preparation,
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.1 mg to about 1.2 mg isotonic;
About 0.001 mg to about 0.1 mg of preservatives;
About 0.1 mg to about 0.5 mg of stabilizer;
29. The method of claim 29, comprising an absorption enhancer of about 0.05 mg to about 2.5 mg; and an amount of water sufficient to achieve a final volume of about 50 to about 150 μL. The intranasal preparation is as follows:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.1% to about 1.2% isotonic;
About 0.001% to about 0.1% preservatives;
About 0.1% to about 0.5% stabilizer;
29. The method of claim 29, comprising from about 0.05% mg to about 2.5% of an absorption enhancer. The isotonic agent is NaCl,
The preservative is benzalkonium chloride,
The stabilizer is disodium edetate,
The absorption enhancer is alkyl saccharides,
30 or the method of claim 31. 32. The method of claim 32, wherein the alkyl saccharide is dodecyl maltoside. The intranasal preparation is as follows:
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.1 mg to about 1.2 mg of NaCl;
About 0.001 mg to about 0.1 mg of benzalkonium chloride;
About 0.15 mg to about 0.5 mg of disodium edetate;
33. The method of claim 33, comprising about 0.05 mg to about 2.5 mg of dodecyl maltoside; and an amount of water sufficient to achieve a final volume of about 50 to about 150 μL. 34. The method of claim 34, wherein the intranasal formulation comprises from about 0.1 mg to about 0.5 mg of dodecyl maltoside. 35. The method of claim 35, wherein the intranasal formulation comprises about 0.25 mg of dodecyl maltoside. 34. The method of claim 34, wherein the intranasal formulation comprises from about 0.2 mg to about 0.3 mg disodium edetate. Intranasal preparation,
About 1 mg to about 3 mg of naltrexone or its pharmaceutically acceptable salt;
About 0.3 mg to about 0.7 mg of NaCl;
Approximately 0.02 mg of benzalkonium chloride;
About 0.3 mg disodium edetate;
36. The method of claim 36, comprising about 0.25 mg dodecyl maltoside; and an amount of water sufficient to achieve a final volume of about 50-about 150 μL. 38. The method of claim 38, wherein the amount of water is sufficient to achieve a final volume of about 50-about 150 μL. 39. The method of claim 39, wherein the amount of water is sufficient to achieve a final volume of about 100 μL. Less than:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.1% to about 1.2% NaCl;
About 0.001% to about 0.1% benzalkonium chloride;
About 0.1% to about 0.5% disodium edetate;
33. The method of claim 33, comprising about 0.05% to about 2.5% dodecyl maltoside; and water. 41. The method of claim 41, wherein the intranasal formulation comprises from about 0.1% to about 0.5% dodecyl maltoside. 42. The method of claim 42, wherein the intranasal formulation comprises about 0.25% dodecyl maltoside. 41. The method of claim 41, wherein the intranasal formulation comprises from about 0.2% to about 0.3% disodium edetate. The intranasal preparation is as follows:
About 1% to about 3% naltrexone or its pharmaceutically acceptable salt;
About 0.3% to about 0.7% NaCl;
Approximately 0.02% benzalkonium chloride;
Approximately 0.3% disodium edetate;
43. The method of claim 43, comprising about 0.25% dodecyl maltoside; and water. 45. The method of claim 45, wherein the amount of water is sufficient to achieve a final volume of about 50-about 150 μL. 46. The method of claim 46, wherein the amount of water is sufficient to achieve a final volume of about 100 μL. The method according to any one of claims 24-47, wherein naltrexone is naltrexone hydrochloride. 48. 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 naltrexone or an equivalent amount of naltrexone hydrochloride. The method of any one of claims 24-49, which treats opioid overdose. The method of any one of claims 24-49, which treats a reward-based disability. The method of claim 48, wherein the reward-based disorder is a substance use disorder. The method of claim 48, wherein the substance use disorder is an alcohol use disorder. 53. The method of claim 53, wherein the intranasal formulation containing naltrexone is administered prior to alcohol consumption. 54. The method of claim 54, wherein the intranasal formulation containing naltrexone is administered approximately 1-2 hours prior to alcohol ingestion. 54. The method of claim 54, wherein the intranasal formulation containing naltrexone is administered approximately 0.5 to approximately 1 hour before alcohol ingestion. 54. The method of claim 54, wherein the intranasal formulation containing naltrexone is administered about 10 to about 30 minutes before alcohol ingestion. 54. The method of claim 54, wherein the intranasal formulation containing naltrexone is administered about 5 to about 10 minutes before alcohol ingestion. 53. The method of claim 53, wherein the intranasal formulation containing naltrexone is administered at the same time as alcohol ingestion. 30. The method of claim 53, wherein the intranasal formulation containing naltrexone is administered within 0.5 hours after the start of alcohol intake. The method according to any one of claims 24 to 60, wherein the intranasal preparation containing naltrexone is administered to the subject once to four times a day. 13. The method of claim 61, wherein the intranasal formulation containing naltrexone is administered at a dose of about 1.2 mg, about 1.6 mg, about 2 mg, or about 3 mg throughout the day as needed by the subject. An intranasal preparation containing naltrexone is administered in the morning as a first dose of about 1.2 mg, about 1.6 mg, about 2 mg, or about 3 mg, and as needed before alcohol consumption, about 1.2 mg, about 1.6 mg. 35. The method of claim 35, which is administered as a later dose of about 2 mg, or about 3 mg. A plurality of doses are included, and each dose comprises the intranasal preparation according to any one of claims 1 to 23.
A multidose device adapted for nasal delivery of pharmaceutical formulations to subjects experiencing opioid overdose or having a reward-based disability. 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 at each dose. 65. The device of claim 65, wherein about 0.1 mL of formulation at each dose is delivered to the subject.

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