阅读说明：本技术 加波沙朵在治疗物质使用障碍中的用途 (Use of gaboxadol for treating substance use disorders ) 是由 马修·杜林 于 2019-04-06 设计创作，主要内容包括：提供了用于治疗物质使用障碍、预防物质使用渴求、减弱物质使用渴求和/或促进物质使用终止的使用加波沙朵或其药学上可接受的盐的方法以及加波沙朵或其药学上可接受的盐的组合物。物质使用障碍包括酒精使用障碍、咖啡因使用障碍、大麻属使用障碍、致幻剂使用障碍、吸入剂使用障碍、阿片类物质使用障碍、镇静剂使用障碍、兴奋剂使用障碍、烟草使用障碍和尼古丁使用障碍。(Methods of using gaboxadol or a pharmaceutically acceptable salt thereof and compositions of gaboxadol or a pharmaceutically acceptable salt thereof are provided for treating substance use disorders, preventing substance use craving, reducing substance use thirst, and/or promoting substance use termination. Substance use disorders include alcohol use disorders, caffeine use disorders, cannabis use disorders, hallucinogen use disorders, inhalant use disorders, opioid use disorders, sedative use disorders, stimulant use disorders, tobacco use disorders, and nicotine use disorders.)

1. A method of treating a substance use disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the pharmaceutical composition comprises an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof.

3. The method according to claim 2, wherein the amount of gaboxadol or a pharmaceutically acceptable salt thereof is effective to reduce one or more symptoms of the substance use disorder.

4. The method of claim 1, wherein the substance use disorder is selected from the group consisting of: alcohol use disorders, caffeine use disorders, cannabis use disorders, hallucinogen use disorders, inhalant use disorders, opioid use disorders, sedative use disorders, stimulant use disorders, tobacco use disorders, and nicotine use disorders.

5. The method according to claim 1, wherein the pharmaceutical composition comprises from about 0.05mg to about 100mg gaboxadol or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is coadministered with an additional therapeutic agent.

7. A method for preventing substance use craving in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein the substance is selected from the group consisting of: alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, stimulants, tobacco, and nicotine.

9. The method according to claim 7, wherein the pharmaceutical composition comprises from about 0.05mg to about 100mg gaboxadol or a pharmaceutically acceptable salt thereof.

10. The method according to claim 7, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is coadministered with an additional therapeutic agent.

11. A method for attenuating substance use craving in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the substance is selected from the group consisting of: alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, stimulants, tobacco, and nicotine.

13. The method according to claim 11, wherein the pharmaceutical composition comprises from about 0.05mg to about 100mg gaboxadol or a pharmaceutically acceptable salt thereof.

14. The method according to claim 11, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is coadministered with an additional therapeutic agent.

15. A method of treating a nicotine usage disorder comprising administering a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof.

16. The method according to claim 15, wherein the pharmaceutical composition comprises an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof.

17. The method according to claim 16, wherein the amount of gaboxadol or a pharmaceutically acceptable salt thereof is effective to reduce one or more symptoms of the nicotine use disorder.

18. The method according to claim 15, wherein the pharmaceutical composition comprises from about 0.05mg to about 100mg gaboxadol or a pharmaceutically acceptable salt thereof.

19. The method according to claim 15, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is coadministered with an additional therapeutic agent.

20. A method for preventing nicotine craving in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof.

21. The method according to claim 20, wherein the pharmaceutical composition comprises from about 0.05mg to about 100mg gaboxadol or a pharmaceutically acceptable salt thereof.

22. The method according to claim 20, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is coadministered with an additional therapeutic agent.

23. A method for attenuating nicotine craving in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof.

24. The method according to claim 23, wherein the pharmaceutical composition comprises from about 0.05mg to about 100mg gaboxadol or a pharmaceutically acceptable salt thereof.

25. The method according to claim 23, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is coadministered with an additional therapeutic agent.

26. A method of treating a tobacco use disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof.

27. The method according to claim 26, wherein the pharmaceutical composition comprises an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof.

28. The method according to claim 27, wherein the amount of gaboxadol or a pharmaceutically acceptable salt thereof is effective to reduce one or more symptoms of the tobacco use disorder.

29. The method according to claim 26, wherein the pharmaceutical composition comprises from about 0.05mg to about 100mg gaboxadol or a pharmaceutically acceptable salt thereof.

30. The method according to claim 26, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is coadministered with an additional therapeutic agent.

31. A method for preventing tobacco craving in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof.

32. The method according to claim 31, wherein the pharmaceutical composition comprises from about 0.05mg to about 100mg gaboxadol or a pharmaceutically acceptable salt thereof.

33. The method according to claim 31, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is coadministered with an additional therapeutic agent.

34. A method for attenuating tobacco craving in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof.

35. The method according to claim 34, wherein the pharmaceutical composition comprises from about 0.05mg to about 100mg gaboxadol or a pharmaceutically acceptable salt thereof.

36. The method according to claim 34, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is coadministered with an additional therapeutic agent.

37. A method of promoting smoking cessation comprising administering to a patient in need thereof a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof.

38. The method according to claim 37, wherein the pharmaceutical composition comprises an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof.

39. The method according to claim 37, wherein the pharmaceutical composition comprises from about 0.05mg to about 100mg gaboxadol or a pharmaceutically acceptable salt thereof.

40. The method according to claim 37, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is coadministered with an additional therapeutic agent.

Technical Field

Methods of using gaboxadol or a pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising gaboxadol or a pharmaceutically acceptable salt thereof are provided that are useful in treating substance use disorders.

Background

According to the NIH National Institute of Drug Abuse (NIDA), abuse and addiction of alcohol, nicotine, and illicit and prescription drugs costs Americans over 7000 million dollars annually in increased healthcare costs, crime, and lost productivity. Addiction can be defined as chronic, recurrent brain disease, characterized by compulsive drug seeking and use, albeit with deleterious consequences. Addiction is considered a brain disease because drugs alter the brain-they alter the structure of the brain and its way of working. These brain changes may be persistent and may lead to adverse behaviors observed in drug-abused persons. According to NIDA, the term addiction can be regarded as equivalent to a serious substance use disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5, 2013).

Substance use disorders arise when repeated use of alcohol and/or drugs causes clinically and functionally significant damage, such as health problems, disability, and an inability to successfully cope with the primary responsibility of work, school, or home. According to DSM-5, the diagnosis of substance use disorders is based on evidence of impaired control, social impairment (social impairement), risk use (risky use) and pharmacological criteria. DSM-5 established nine types of substance-related disorders: 1. alcohol, 2. caffeine (substance use disorder not applicable to caffeine), 3. cannabis (cannabis) (e.g., cannabis (marijuana)), 4. hallucinogens, 5. inhalants, 6. opioids (opioids) (e.g., heroin), 7. sedatives, hypnotics, or anxiolytics (e.g., benzodiazepines, barbiturates), 8. stimulants (e.g., cocaine, methamphetamine), and 9. tobacco.

According to DSM 5, each specific substance (except caffeine) is referred to as a separate use obstacle (e.g., alcohol use obstacle, stimulant use obstacle, etc.), but almost all substances are diagnosed based on the same central criteria (overrating). A list of 11 symptoms of substance use disorders is provided in DSM-5 and is set forth below. The severity of the disorder is based on the number of symptoms present: mild substance use disorder requires two to three symptoms, four to five symptoms indicating moderate substance use disorder, and more than six symptoms indicating severe substance use disorder.

1. Substances are generally ingested in greater amounts, or over a longer period of time, than expected

2. Continued desire or unsuccessful efforts to curtail or control the use of substances

3. A large amount of time spent in activities required to obtain, use or recover from the effects of substances

4. Craving or urge to use substances

5. Resulting in the repeated use of the work, school and family which cannot fulfill the role of the main role

6. Despite persistent or recurring social or interpersonal problems, the use of substances continues

7. Because of the use of substances, important social, occupational or recreational activities are abandoned or reduced

8. Repeated use of substances in conditions harmful to the body

9. Despite the knowledge of having persistent or recurring physical or psychological problems that may have been caused or exacerbated by a substance, substance use continues

10. Tolerance (tolerance) as defined by any one of the following:

a. a significantly increased amount of a substance is required to achieve the intoxication or desired effect

b. Significantly reduced effect in the case of continued use of the same amount of substance

11. Withdrawal (withdwal) as exhibited by any one of the following:

a. withdrawal syndrome characteristic of a substance

b. The substance or closely related substances are used for relieving or avoiding withdrawal symptoms

Tobacco addiction is a major cause of preventable illness and premature death in our society. According to The U.S. Department of Health and public Services (U.S. Department of Health and Human Services) in 2014, The Health sequences of eating-50 Years of Progress: Report of The Sureon General, more than 2000 million Americans have died as a result of tobacco Smoking since The first Report of The surgical medical Association (Sureon General) on Smoking and Health was released in 1964. Active tobacco smoking affects almost every organ of the body. It has been causally linked to the following cancers: oropharyngeal, laryngeal, esophageal, tracheal, bronchial and lung cancers, acute myeloid leukemia, gastric, pancreatic, renal and ureteral, cervical and bladder cancers. Smoking has been causally linked to the following chronic diseases: stroke, blindness, cataracts, periodontitis, aortic aneurysm, early abdominal aortic atherosclerosis in young adults, coronary heart disease, pneumonia, atherosclerotic peripheral vascular disease, chronic obstructive pulmonary disease, asthma, decreased fertility in women, hip fracture and overall impaired health. Furthermore, active smoking is now causally related to: age-related macular degeneration, diabetes, colorectal cancer, liver cancer, adverse health outcomes in cancer patients and survivors (overture health outbome), tuberculosis, erectile dysfunction, cleft lip and palate (orofacial clefts) in infants, ectopic pregnancy, rheumatoid arthritis, inflammation, and impaired immune function.

According to NIDA, most smokers often use tobacco because they are addicted to nicotine. Addiction is characterized by compulsive drug seeking and use, even in the face of negative health consequences. Smoking cigarettes is the most popular method of using tobacco; however, many people also use smokeless tobacco products, such as snuff and chewing tobacco, which also contain nicotine. Administration of nicotine causes a transient surge of endorphins in the reward circuit of the brain, which results in a slight, transient euphoric effect. However, like other drugs of abuse, nicotine increases the level of the neurotransmitter dopamine in these reward circuits, which enhances the act of ingesting the drug. For many tobacco users, chronic brain changes induced by sustained nicotine exposure lead to addiction, which involves withdrawal symptoms when smoking is absent. A long time without nicotine can cause frequent user experiences irritability, craving, depression, anxiety, cognitive and attention deficits, sleep disorders and increased appetite. Most smokers want to quit smoking, and about half of them try to quit permanently every year. However, only about 6% of smokers are able to quit within a given year.

Substance abuse and addiction are public health problems, having significant social and economic impact on both the addict and the society. There is a need in the art for new methods for treating and preventing substance use disorders and recurrent use of addictive agents (addctive agents). For example, there is a need to help tobacco users quit using tobacco and nicotine.

Gaboxadol (4,5,6, 7-tetrahydroisoxazolo [5, 4-c)]Pyridin-3-ol) (THIP)) are described in EP patent No. 0000338 and in EP patent No. 0840601, us patent No. 4,278,676, No. 4,362,731, No. 4,353,910 and WO 2005/094820. Gaboxadol is selective GABA_AReceptor agonists having activity on GABA comprising delta-subunit_APreference of the receptor. In the early 80's of the 20 th century, gaboxadol was the subject of a series of preliminary studies that tested its efficacy as an analgesic and anxiolytic, and as a treatment for tardive dyskinesia, Huntington's disease, alzheimer's disease and spasticity (spasticity). In the 90 s of the 20 th century, gaboxadol entered development of a late stage for the treatment of insomnia. In the case of the compound in threeDevelopment was discontinued after the monthly efficacy studies failed to show significant effects in sleep onset (sleep onset) and sleep maintenance. In addition, patients with a history of drug abuse who received gaboxadol experienced a dramatic increase in psychiatric adverse events.

SUMMARY

A method of treating a substance use disorder is provided comprising administering to a patient in need thereof a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof. There is provided a method of treating a substance use disorder comprising administering to a patient in need thereof an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof. There is provided a method of treating a substance use disorder comprising administering to a patient in need thereof an amount of gaboxadol or a pharmaceutically acceptable salt thereof that is effective to reduce one or more symptoms of the substance use disorder. The 11 symptoms of substance use disorders are provided above. There is provided a method for preventing substance use craving in a patient in need thereof, the method comprising administering to the patient a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof. There is provided a method for attenuating substance use craving in a patient in need thereof, the method comprising administering to the patient an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof. Also provided herein are pharmaceutical compositions for treating substance use disorders.

A method of treating nicotine usage disorders is provided comprising administering a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. There is provided a method of treating nicotine usage disorders comprising administering to a patient in need thereof an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof. There is provided a method of treating a nicotine usage disorder comprising administering to a patient in need thereof an amount of gaboxadol or a pharmaceutically acceptable salt thereof that is effective to reduce one or more symptoms of the nicotine usage disorder. There is provided a method for preventing nicotine craving in a patient in need thereof, the method comprising administering to the patient a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof. A method for attenuating nicotine craving in a patient in need thereof is provided, the method comprising administering to the patient an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof. Also provided herein are pharmaceutical compositions for treating nicotine usage disorders.

A method of treating a tobacco use disorder is provided comprising administering a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. There is provided a method of treating a tobacco use disorder comprising administering to a patient in need thereof an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof. There is provided a method of treating a tobacco use disorder comprising administering to a patient in need thereof an amount of gaboxadol or a pharmaceutically acceptable salt thereof that is effective to reduce one or more symptoms of the tobacco use disorder. There is provided a method for preventing tobacco craving in a patient in need thereof, the method comprising administering to the patient a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof. A method for attenuating tobacco craving in a patient in need thereof is provided, the method comprising administering to the patient an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof. Also provided herein are pharmaceutical compositions for treating tobacco use disorders.

A method of promoting smoking cessation (smoking cessation) is provided comprising administering to a patient in need thereof a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof.

Detailed Description

Methods of using gaboxadol or a pharmaceutically acceptable salt thereof and compositions of gaboxadol or a pharmaceutically acceptable salt thereof are provided for treating substance use disorders, preventing substance use craving, reducing substance use thirst, and/or promoting substance use termination. Substance use disorders involve abuse of psychoactive compounds (psychoactive compounds) such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, and tobacco. As used herein, "substance" or "substances" are psychoactive compounds that may be addictive, such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. In embodiments, methods of using gaboxadol or a pharmaceutically acceptable salt thereof and compositions of gaboxadol or a pharmaceutically acceptable salt thereof are provided for treating a nicotine usage disorder, preventing nicotine craving, attenuating nicotine craving, and/or promoting termination of nicotine usage. In embodiments, methods of using gaboxadol, or a pharmaceutically acceptable salt thereof, and compositions of gaboxadol, or a pharmaceutically acceptable salt thereof, are provided for treating a disorder of tobacco use, preventing tobacco craving, attenuating tobacco craving, and/or promoting cessation of tobacco use. In embodiments, methods of using gaboxadol, or a pharmaceutically acceptable salt thereof, and compositions of gaboxadol, or a pharmaceutically acceptable salt thereof, are provided for promoting smoking cessation.

In embodiments, methods of using gaboxadol, or a pharmaceutically acceptable salt thereof, and compositions of gaboxadol, or a pharmaceutically acceptable salt thereof, are provided for treating a disorder of alcohol use, preventing alcohol craving, attenuating alcohol thirst, and/or promoting termination of alcohol use. In embodiments, methods of using gaboxadol or a pharmaceutically acceptable salt thereof and compositions of gaboxadol or a pharmaceutically acceptable salt thereof are provided for treating a disorder of caffeine use, preventing caffeine craving, attenuating caffeine craving, and/or promoting cessation of caffeine use. In embodiments, methods of using gaboxadol or a pharmaceutically acceptable salt thereof and compositions of gaboxadol or a pharmaceutically acceptable salt thereof are provided for treating a disorder of cannabis use, preventing cannabis craving, attenuating cannabis thirst, and/or promoting the cessation of cannabis use. In embodiments, methods of using gaboxadol, or a pharmaceutically acceptable salt thereof, and compositions of gaboxadol, or a pharmaceutically acceptable salt thereof, are provided for treating a disorder of use of a hallucinogen, preventing hallucinogen craving, attenuating thirst and/or promoting termination of use of a hallucinogen. In embodiments, methods of using gaboxadol, or a pharmaceutically acceptable salt thereof, and compositions of gaboxadol, or a pharmaceutically acceptable salt thereof, are provided for treating a disorder of inhalant use, preventing inhalant craving, attenuating inhalant craving and/or promoting termination of inhalant use. In embodiments, methods of using gaboxadol or a pharmaceutically acceptable salt thereof and compositions of gaboxadol or a pharmaceutically acceptable salt thereof are provided for treating opioid use disorders, preventing opioid craving, attenuating opioid thirst and/or promoting termination of opioid use. In embodiments, methods of using gaboxadol, or a pharmaceutically acceptable salt thereof, and compositions of gaboxadol, or a pharmaceutically acceptable salt thereof, are provided for treating a sedation use disorder, preventing sedation craving, attenuating sedation thirst, and/or promoting cessation of sedation use. In embodiments, methods of using gaboxadol, or a pharmaceutically acceptable salt thereof, and compositions of gaboxadol, or a pharmaceutically acceptable salt thereof, are provided for treating a disorder of stimulant use, preventing stimulant craving, attenuating stimulant thirst, and/or promoting cessation of stimulant use.

As used herein, cannabis includes materials comprising delta-9-Tetrahydrocannabinol (THC), such as cannabis, cannabis narcotics (hashish), and THC extracts such as cannabis oil (hash oil), cannabis wax, cannabis lipid, cannabis tincture, and the like. Hallucinogens include LSD, DMT, PCP, DMT, MDMA, siloxibin (psilocybin), mescaline (mescaline), and ketamine. Inhalants are volatile substances that produce a chemical vapor that can be inhaled to produce a psychoactive effect. Inhalants include volatile solvents such as toluene, ethers, and gasoline, which may be found, for example, in paint thinners and removers, aerosol cans, dry cleaning fluids, degreasers, glues, correction fluids, and felt-tip pens (felt-tip markers). Inhalants also include gases such as nitrous oxide and butane. Opioids include opium, heroin, morphine, codeine, oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, methadone, meperidine, tramadol, carfentanil and buprenorphine. Anxiolytics, sedatives and hypnotics (collectively referred to herein as sedatives) include benzodiazepines such as diazepam, alprazolam, clobazam, clonazepam, triazolam, temazepam and lorazepam, barbiturates such as secobarbital, amobarbital, sec-barbital, thiopental (thiopental), and others such as chloral hydrate, hydroxyzine, promethazine, dexzopiclone, zaleplon, zolpidem, zopiclone and diphenhydramine. Stimulants include methylphenidate, dexmethylphenidate, cocaine, 3, 4-methylenedioxymethamphetamine (MDMA), atomoxetine, lydexamfetamine, caffeine, phenylephrine, pseudoephedrine, and amphetamines such as methamphetamine and dexamphetamine.

In embodiments, a subject is first determined or diagnosed as having, or as being at risk for developing, a substance use disorder by a diagnostic test, observation or analysis performed by a healthcare provider using, for example, the 11 DSM 5 standard. The subject is then provided with an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof, or an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents, for treating or preventing a substance use disorder. As used herein, an "effective amount" or "therapeutically effective amount" is a dose sufficient to treat, prevent, inhibit or alleviate one or more symptoms of a substance use disorder, such as the 11 symptoms listed in DSM 5. For example, in the context of treating or preventing a substance use disorder using the methods described herein, an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof may be an amount sufficient to cause the subject to reduce or discontinue use of the substance. The precise dosage of gaboxadol or a pharmaceutically acceptable salt thereof will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, clinical symptoms, etc.). The dosage of gaboxadol or a pharmaceutically acceptable salt thereof, or the dosages of gaboxadol or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents, may be specifically determined by a physician for treating or preventing substance use disorders.

In embodiments, a subject may be considered at risk for a substance use disorder or recurrent use of a substance when the subject has previously addicted to the same or a different addictive substance. In embodiments, a subject is considered at risk for substance use disorder or recurrent use of a substance when the subject is psychologically addicted to the substance, even if the subject is no longer physically addicted.

In embodiments, the subject is addicted to, or at risk of becoming addicted to, a therapeutic substance, such as an analgesic, provided to the subject to treat the disease or disorder. In embodiments, the subject may be at risk of abuse of an addictive therapeutic substance, such as an analgesic. In embodiments, the addiction treatment substance of abuse may be understood as indicating that the substance is being used for a reason other than or in addition to its intended use. In such cases, the subject may be provided with an addictive therapeutic substance and gaboxadol, or a pharmaceutically acceptable salt thereof, alone or in combination with an additional therapeutic agent. For example, an opioid agonist and gaboxadol or a pharmaceutically acceptable salt thereof may be provided to a subject having or at risk of pain to provide analgesia and to prevent or treat addiction to the opioid agonist.

Recurrent use refers to the process of restoring use of a substance after a period of time to moderate or limit the use of the substance or to reduce the use of the substance. In some cases, recurrent use of a substance refers to the resumption of use of the substance by a subject who has experienced physical withdrawal from the substance (physical with dry). Typically, a subject will have experienced physical withdrawal from a substance during periods of non-use or limited or reduced use of the substance. In embodiments, recurrent use may occur in a subject who has discontinued use of the substance without the use of any anti-addiction agent (anti-addiction agent). In embodiments, the recurrent use can occur in a subject who has previously undergone a treatment regimen with an effective amount of the anti-addictive agent to reduce or eliminate use of the substance, but who is no longer using an effective amount of the anti-addictive agent. Anti-addiction agents include any and all agents useful in the treatment or prevention of addiction or withdrawal symptoms. It is believed that the molecular mechanisms underlying relapse are common to different classes of drugs of abuse. Relapse-related drug thirst and uncontrolled drug intake behavior can be under the direct influence of stress and environmental conditioning stimuli (environmental conditioning stimuli); stress and environmental condition stimuli are two major factors affecting the resumption of drug use.

In embodiments, the substance use disorder is a nicotine use disorder. Accordingly, the subject may be any patient using nicotine in any form, including cigarettes, electronic cigarettes (e-cigarettes) or vaporizers ("vaping"), chewing tobacco, cigars, snuff, pipes, hookah bags, transdermal patches (transdermal patches), chewing gum (gum), lozenges, and the like. In embodiments, the patient is physically addicted to nicotine. In embodiments, the patient is psychologically addicted to nicotine. In embodiments, the patient is addicted to tobacco. In embodiments, the patient is physically addicted to tobacco. In embodiments, the patient is psychologically addicted to tobacco.

In embodiments, methods and compositions for treating a nicotine usage disorder, preventing nicotine craving, attenuating nicotine craving, and/or promoting termination of nicotine usage in a subject comprise administering an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods and compositions for treating a nicotine usage disorder, preventing nicotine craving, attenuating nicotine craving, and/or promoting termination of nicotine usage in a subject comprise administering a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In embodiments, methods and compositions for treating a disorder of tobacco use, preventing tobacco craving, attenuating tobacco craving, and/or promoting termination of tobacco use in a subject comprise administering an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods and compositions for treating a disorder of tobacco use, preventing tobacco craving, attenuating tobacco craving, and/or promoting termination of tobacco use in a subject comprise administering a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In embodiments, methods of using gaboxadol, or a pharmaceutically acceptable salt thereof, and compositions of gaboxadol, or a pharmaceutically acceptable salt thereof, are provided for reducing the relapse rate of postpartum smoking in a mother. In embodiments, the method of preventing and/or reducing relapse of postpartum smoking in a mother comprises administering gaboxadol or a pharmaceutically acceptable salt thereof. In embodiments, methods of using gaboxadol, or a pharmaceutically acceptable salt thereof, to increase smoking abstinence in a postpartum mother are provided. Postpartum mother smoking cessation and/or postpartum smoking relapse may be defined as continuously maintaining a smokeless state for a specified period of time. For example, the smokeless status may be measured at the time of postpartum follow-up, e.g., after 1 month, 2 months, 3 months, 6 months, etc. The throttling can be verified biochemically. For example, the biometric authentication may be determined by carbon monoxide (CO) exhaled at, for example, 6 months after delivery. Additional metrics may include the number of cigarettes the mother smoked; a maternal Self-Efficacy score according to the Romanian version of the General Self-Efficacy scale (General Self Efficacy scale); scoring for maternal motivation according to the smoking cessation reason scale (Reasons for Quitting scale); and/or self-reported smoking status by the husband/partner.

In embodiments, alcohol is the subject of a substance use disorder. In embodiments, the patient is addicted to alcohol. In embodiments, the patient is physically addicted to alcohol. In embodiments, the patient is psychologically addicted to alcohol. In embodiments, methods and compositions for treating alcohol use disorders, preventing alcohol craving, attenuating alcohol craving, and/or promoting termination of alcohol use in a subject comprise administering an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods and compositions for treating alcohol use disorders, preventing alcohol craving, attenuating alcohol craving, and/or promoting termination of alcohol use in a subject comprise administering a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In embodiments, caffeine is the subject of a substance use disorder. In embodiments, the patient is addicted to caffeine. In embodiments, the patient is physically addicted to caffeine. In embodiments, the patient is psychologically addicted to caffeine. In embodiments, methods and compositions for treating a caffeine usage disorder, preventing caffeine craving, attenuating caffeine thirst, and/or promoting cessation of caffeine usage in a subject comprise administering an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods and compositions for treating a caffeine usage disorder, preventing caffeine craving, attenuating caffeine thirst, and/or promoting cessation of caffeine usage in a subject comprise administering a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In embodiments, cannabis is a subject with substance use disorders. In embodiments, the patient is addicted to cannabis. In embodiments, the patient is physically addicted to the cannabis. In embodiments, the patient is psychologically addicted to cannabis. In embodiments, methods and compositions for treating a cannabis usage disorder, preventing cannabis craving, attenuating cannabis thirst, and/or promoting the cessation of cannabis usage in a subject comprise administering an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods and compositions for treating a cannabis usage disorder, preventing cannabis craving, attenuating cannabis thirst, and/or promoting the cessation of cannabis usage in a subject comprise administering a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In embodiments, the hallucinogen is the subject of a substance use disorder. In embodiments, the patient is addicted to a hallucinogen. In embodiments, the patient is physically addicted to the hallucinogen. In embodiments, the patient is psychologically addicted to the hallucinogenic agent. In embodiments, methods and compositions for treating a hallucinogenic agent use disorder, preventing hallucinogenic agent craving, attenuating hallucinogenic agent thirst, and/or promoting termination of hallucinogenic agent use in a subject comprise administering an effective amount of gaboxadol, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In embodiments, methods and compositions for treating a hallucinogenic agent use disorder, preventing hallucinogenic agent craving, attenuating hallucinogenic agent thirst, and/or promoting termination of hallucinogenic agent use in a subject comprise administering a prophylactically effective amount of gaboxadol, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

In embodiments, the inhalant is the subject of a substance use disorder. In embodiments, the patient is addicted to an inhalant. In embodiments, the patient is physically addicted to the inhalant. In embodiments, the patient is psychologically addicted to the inhalant. In embodiments, methods and compositions for treating an inhalant use disorder, preventing inhalant craving, attenuating inhalant thirst, and/or promoting termination of inhalant use in a subject comprise administering an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods and compositions for treating an inhalant use disorder, preventing inhalant craving, attenuating inhalant thirst, and/or promoting termination of inhalant use in a subject comprise administering a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In embodiments, opioids are the subject of substance use disorders. In embodiments, the patient is addicted to an opioid. In embodiments, the patient is physically addicted to an opioid. In embodiments, the patient is psychologically addicted to an opioid. In embodiments, methods and compositions for treating opioid use disorders, preventing opioid craving, attenuating opioid thirst, and/or promoting termination of opioid use in a subject comprise administering an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods and compositions for treating opioid use disorders, preventing opioid craving, attenuating opioid thirst, and/or promoting termination of opioid use in a subject comprise administering a prophylactically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In embodiments, the sedative is a subject with substance use disorders. In embodiments, the patient is addicted to a sedative. In embodiments, the patient is physically addicted to a sedative. In embodiments, the patient is psychologically addicted to a sedative. In embodiments, methods and compositions for treating a sedation disorder, preventing sedation craving, attenuating sedation thirst, and/or promoting cessation of sedation use in a subject comprise administering to a patient in need thereof an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof. In embodiments, methods and compositions for treating a sedation disorder, preventing sedation craving, attenuating sedation thirst, and/or promoting cessation of sedation use in a subject comprise administering a prophylactically effective amount of gaboxadol, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

In embodiments, the stimulant is a subject with a substance use disorder. In embodiments, the patient is addicted to a stimulant. In embodiments, the patient is physically addicted to a stimulant. In embodiments, the patient is psychologically addicted to a stimulant. In embodiments, methods and compositions for treating a stimulant use disorder, preventing stimulant craving, attenuating stimulant thirst, and/or promoting cessation of stimulant use in a subject include administering an effective amount of gaboxadol, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In embodiments, methods and compositions for treating a stimulant use disorder, preventing stimulant craving, attenuating stimulant thirst, and/or promoting cessation of stimulant use in a subject comprise administering a prophylactically effective amount of gaboxadol, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

Many pharmaceutical products are administered at regular intervals in fixed doses to achieve therapeutic efficacy. Duration of action is reflected by its plasma half-life. Since efficacy often depends on sufficient exposure within the central nervous system, administration of CNS drugs with short half-lives may require frequent maintenance dosing. Disclosed herein advantageously are methods for treating substance use disorders, preventing substance use cravings, attenuating substance use cravings, and/or promoting substance use termination by administering gaboxadol or a pharmaceutically acceptable salt thereof. For example, in an embodiment, a method for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination is provided that includes administering to a patient in need thereof a pharmaceutical composition including from about 0.05mg to about 75mg gaboxadol or a pharmaceutically acceptable salt thereof. In embodiments, the composition provides an improvement that lasts more than 6 hours after administration to a patient.

For example, a dose may include an amount of gaboxadol or a pharmaceutically acceptable salt thereof within a range of about, e.g., 1mg to 30mg, 1mg to 20mg, 1mg to 15mg, 0.01mg to 10mg, 0.1mg to 15mg, 0.15mg to 12.5mg, or 0.2mg to 10mg, where a specific dose of 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1.5mg, 1.0mg, 1.75mg, 2mg, 2.5mg, 2.75mg, 3mg, 3.5mg, 3.75mg, 4mg, 4.5mg, 4.75mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 10mg, 11mg, 12mg, 15mg, 25mg, and 30mg is a specific example.

Typically, a dose of gaboxadol or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once daily or twice daily. The methods and compositions described herein can provide reduced dosing frequency and reduced adverse events and/or increased efficacy. In embodiments, the dose is about, e.g., 0.1 mg/day to 20 mg/day, or 0.2 mg/day to 15 mg/day, or 0.5 mg/day to 10 mg/day, or 0.75 mg/day to 5 mg/day, e.g., 0.2 mg/day, 0.5 mg/day, 0.75 mg/day, 1 mg/day, 1.5 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7 mg/day, 8 mg/day, 9 mg/day, 10 mg/day, 11 mg/day, 12 mg/day, 13 mg/day, 14 mg/day, 15 mg/day, 16 mg/day, 17 mg/day, 18 mg/day, 19 mg/day, or 20 mg/day. In embodiments, gaboxadol or a pharmaceutically acceptable salt thereof, or a derivative or analogue thereof is administered at a dose of 0.2 to 1mg in an infant or at a dose of 1mg to 20mg in an adult once daily.

In embodiments, gaboxadol or a pharmaceutically acceptable salt thereof is administered to the patient on demand. In embodiments, gaboxadol or a pharmaceutically acceptable salt thereof may be administered prior to the onset of substance craving. For example, a patient may ingest a dose of gaboxadol or a pharmaceutically acceptable salt thereof in anticipation of a craving condition, before a stress condition occurs, or when confronted with another trigger for the substance. In embodiments, the patient ingests a dose of gaboxadol or a pharmaceutically acceptable salt thereof after the occurrence of craving of the substance, e.g., during the craving, in order to reduce or eliminate the craving. In embodiments, the dose of gaboxadol or a pharmaceutically acceptable salt thereof is sufficiently low, e.g., less than 15mg, less than 10mg or less than 5mg, that the patient may take one dose before the craving occurs and another dose later on the same day if he/she feels or anticipates another craving.

In embodiments, gaboxadol is provided as gaboxadol monohydrate. One skilled in the art will readily appreciate that the amount of active ingredient in the pharmaceutical composition will depend on the form of gaboxadol provided. For example, a pharmaceutical composition comprising 5.0mg, 10.0mg, or 15.0mg gaboxadol corresponds to 5.6mg, 11.3mg, or 16.9mg gaboxadol monohydrate.

In embodiments, gaboxadol is crystalline, such as the crystalline hydrochloride salt, the crystalline hydrobromide salt, or the crystalline zwitter ion monohydrate. In embodiments, gaboxadol is provided as the crystalline monohydrate.

In embodiments, gaboxadol may be formulated for administration to a patient using a pharmaceutically acceptable salt comprising an acid addition salt, a zwitter ion hydrate, a zwitter ion anhydrate, a hydrochloride salt, or a hydrobromide salt, or in the form of the zwitter ion monohydrate. Acid addition salts include, but are not limited to, addition salts of maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, or theophylline acetic acid, and 8-halotheophyllines such as 8-bromo-theophylline. In other suitable embodiments, inorganic acid addition salts may be used, including but not limited to addition salts of hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric or nitric acids.

In embodiments, gaboxadol or a pharmaceutically acceptable salt thereof is administered via a pharmaceutical composition. Pharmaceutical compositions (also referred to simply as compositions) are contemplated herein as dosage forms. Dosage forms herein encompass unit doses. In embodiments, as discussed below, various dosage forms (including conventional formulations and modified release formulations) may be administered one or more times per day. Any suitable route of administration may be used, for example oral, rectal, nasal, pulmonary, vaginal, sublingual, transdermal, intravenous, intraarterial, intramuscular, intraperitoneal and subcutaneous routes. Suitable dosage forms include tablets, capsules, oral liquids, powders, aerosols, transdermal forms such as topical liquids, patches, creams and ointments, parenteral formulations and suppositories.

The pharmaceutical compositions herein may be provided in a conventional release profile or a modified release profile. Modified release profiles include immediate release profiles, delayed release profiles, and extended release profiles. In embodiments, pharmaceutical compositions having different drug release profiles may be combined to produce a biphasic or triphasic release profile. For example, the pharmaceutical composition may be provided in an immediate release profile and an extended release profile. In embodiments, the pharmaceutical composition may be provided with an extended release profile and a delayed release profile. Such compositions may be provided as pulsatile formulations, multi-layered tablets or capsules comprising tablets, beads, granules, and the like. Compositions may be prepared using pharmaceutically acceptable "carriers" that contain materials that are considered safe and effective. "carriers" include all components present in a pharmaceutical preparation except for the active ingredient or ingredients. The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers (filler) and coating compositions.

Conventional (or unmodified) release oral dosage forms, such as tablets or capsules, typically release the drug into the stomach or intestine as the tablet or capsule shell dissolves. The pattern of drug release from a Modified Release (MR) dosage form is intentionally altered from the pattern of drug release from a conventional dosage form to achieve a desired therapeutic goal and/or better patient compliance. Types of MR drug products include Orally Disintegrating Dosage Forms (ODDF) providing immediate release, extended release dosage forms, delayed release dosage forms (e.g., enteric coated), and pulsatile release dosage forms.

ODDF is a solid dosage form containing a therapeutic agent or active ingredient that disintegrates rapidly, usually within a few seconds, when placed on the tongue. The disintegration time of ODDF is typically in the range of from one or two seconds to about one minute. ODDF is designed to disintegrate or dissolve rapidly upon exposure to saliva. This mode of administration can be beneficial to persons who may have problems swallowing tablets, whether from debilitating or psychiatric nature. Examples of ODDFs include orally disintegrating tablets, capsules, and fast dissolving films and sheets.

Extended Release Dosage Forms (ERDF) have an extended release profile and are those that allow for a reduction in the frequency of administration compared to the frequency of administration exhibited by conventional dosage forms, such as solutions or unmodified release dosage forms. ERDF provides a sustained duration of drug action. Suitable formulations providing extended release profiles are well known in the art, for example, coated slow release beads or granules ("beads" and "granules" are used interchangeably herein), wherein gaboxadol or a pharmaceutically acceptable salt thereof is applied to beads, for example, capsules nonpareil beads, and then coated with a conventional release retarding material such as wax, enteric coating, and the like. In embodiments, beads may be formed in which gaboxadol, or a pharmaceutically acceptable salt thereof, is mixed with a material to provide a mass from which the drug is leached. In embodiments, the beads may be engineered to provide different release rates by varying the characteristics of the coating or the mass, such as thickness, porosity, use of different materials, and the like. Beads having different release rates can be combined into a single dosage form to provide variable or continuous release. The beads may be contained in a capsule or compressed into a tablet.

In embodiments, the modified dosage forms herein include delayed release dosage forms having a delayed release profile. The delayed release dosage form may comprise a delayed release tablet or a delayed release capsule. Delayed release tablets are solid dosage forms that release a drug (or drugs), such as gaboxadol or a pharmaceutically acceptable salt thereof, at a time other than immediate release after administration. Delayed release capsules are solid dosage forms in which the drug is enclosed in a hard or soft soluble container made of a suitable form of gelatin and releases the drug(s) at a time other than immediate release after administration. For example, enteric coated tablets, capsules, granules and beads are well known examples of delayed release dosage forms. Enteric coated tablets, capsules, and granules and beads pass through the stomach and release the drug in the intestine. In embodiments, the delayed release tablet is a solid dosage form comprising an agglomeration of pharmaceutical particles that release a drug (or drugs) at a time other than immediate release following administration. In an embodiment, the agglomerates of the pharmaceutical granules are covered with a coating that delays the release of the drug. In embodiments, the delayed release capsule is a solid dosage form comprising an agglomeration of pharmaceutical particles that release a drug (or drugs) at a time other than immediate release following administration. In an embodiment, the agglomerates of the pharmaceutical granules are covered with a coating that delays the release of the drug.

Delayed release dosage forms are known to those skilled in the art, for example, coated delayed release beads or granules, wherein gaboxadol or a pharmaceutically acceptable salt thereof is applied to the beads, for example, conditioners nonpareil beads, and then coated with a conventional release delaying material such as wax, enteric coating and the like. In embodiments, beads may be formed in which gaboxadol, or a pharmaceutically acceptable salt thereof, is mixed with a material to provide a medicamentThe mass from which the material is leached. In embodiments, the beads may be engineered to provide different release rates by varying the characteristics of the coating or the mass, such as thickness, porosity, use of different materials, and the like. In embodiments, an enteric coated granule of gaboxadol or a pharmaceutically acceptable salt thereof may be contained in an enteric coated capsule or tablet that releases the granule in the small intestine. In embodiments, the granules have a coating that remains intact until the coated granules reach at least the ileum, and thereafter provide delayed release of the drug in the colon. Suitable enteric coating materials are well known in the art, for exampleCoatings such as methacrylic acid and methyl methacrylate polymers and others. The granules may be contained in capsules or compressed into tablets.

In embodiments, gaboxadol or a pharmaceutically acceptable salt thereof is incorporated into a porous inert carrier that provides a delayed release profile. In embodiments, the porous inert carrier incorporates channels or passageways from which the drug diffuses into the surrounding fluid. In embodiments, gaboxadol or a pharmaceutically acceptable salt thereof is incorporated into the ion exchange resin to provide a delayed release profile. The delay effect may be caused by a predetermined release rate of the drug from the resin when the drug-resin complex contacts gastrointestinal fluids and ionic components dissolved therein. In embodiments, the membrane is used to control the rate of release from a reservoir containing a drug. In embodiments, the liquid product may also be used to provide a delayed release profile. For example, liquid articles consist of solid particles dispersed throughout a liquid phase in which the particles are insoluble. The suspension is formulated to allow at least a reduction in the frequency of administration of the drug compared to the frequency of administration of the drug presented as a conventional dosage form (e.g., a conventional solid dosage form as a solution or immediate release drug), e.g., a suspension of ion exchange resin components or microbeads.

In embodiments, a method for treating substance use disorders, preventing substance use cravings, reducing substance use thirst, and/or promoting substance use termination comprises administering to a patient in need thereof a pharmaceutical composition comprising from about 0.05mg to about 50mg gaboxadol or a pharmaceutically acceptable salt thereof. In embodiments, a method for treating substance use disorders, preventing substance use cravings, reducing substance use thirst, and/or promoting substance use termination comprises administering to a patient in need thereof a pharmaceutical composition comprising from about 0.1mg to about 30mg gaboxadol or a pharmaceutically acceptable salt thereof.

In embodiments, the pharmaceutical composition comprises 0.1 to 25mg, 0.1 to 20mg, 0.1 to 15mg, 0.5 to 25mg, 0.5 to 20mg, 0.5 to 15mg, 1 to 25mg, 1 to 20mg, 1 to 15mg, 1.5 to 25mg, 1.5 to 20mg, 1.5 to 15mg, 2 to 25mg, 2 to 20mg, 2 to 15mg, 2.5 to 25mg, 2.5 to 20mg, 2.5 to 15mg, 3 to 25mg, 3 to 20mg, 3 to 15mg gaboxadol or a pharmaceutically acceptable salt thereof.

In embodiments, the pharmaceutical composition comprises 5mg to 20mg, 5mg to 10mg, 4mg to 6mg, 6mg to 8mg, 8mg to 10mg, 10mg to 12mg, 12mg to 14mg, 14mg to 16mg, 16mg to 18mg, or 18mg to 20mg gaboxadol or a pharmaceutically acceptable salt thereof.

In an embodiment, the pharmaceutical composition comprises gaboxadol or a pharmaceutically acceptable salt thereof in an amount of 0.1mg, 0.25mg, 0.5mg, 1mg, 2.5mg, 3mg, 4mg, 5mg, 7mg, 7.5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg or a multiple of such dose. In an embodiment, the pharmaceutical composition comprises 2.5mg, 5mg, 7.5mg, 10mg, 15mg, or 20mg of gaboxadol or a pharmaceutically acceptable salt thereof.

In embodiments, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof and/or gaboxadol administered to the subject over a 24 hour period is 1mg to 50 mg. In embodiments, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof and/or gaboxadol administered to the subject over a 24 hour period is 1mg to 20 mg. In embodiments, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof and/or gaboxadol administered to the subject over a 24 hour period is 5mg, 10mg or 15 mg. In embodiments, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof that is administered to the subject over the 24 hour period is 1mg to 50 mg. In embodiments, the subject may start with a low dose and the dose is escalated. In this way, it can be determined whether the drug is well tolerated in the subject. The dose for children may be lower than the dose for adults. In embodiments, the dose of gaboxadol for children may be 0.1mg/kg to 1 mg/kg.

In embodiments, the compositions herein are suitable for parenteral administration, including, for example, intramuscular (i.m.), intravenous (i.v.), subcutaneous (s.c.), intraperitoneal (i.p.), or intrathecal (i.t). The parenteral compositions herein must be sterile, for administration by injection, infusion or implantation into the body, and may be packaged in single-dose or multi-dose containers.

In embodiments, there is provided a liquid pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof in a concentration from about 0.005 μ g/ml to about 500 μ g/ml for parenteral administration to a subject. In embodiments, the composition comprises gaboxadol or a pharmaceutically acceptable salt thereof at a concentration of, for example, about 0.005 μ g/ml to about 250 μ g/ml, about 0.005 μ g/ml to about 200 μ g/ml, about 0.005 μ g/ml to about 150 μ g/ml, about 0.005 μ g/ml to about 100 μ g/ml, or about 0.005 μ g/ml to about 50 μ g/ml.

In embodiments, the composition comprises gaboxadol or a pharmaceutically acceptable salt thereof at a concentration of, for example, about 0.05 to about 50 μ g/ml, about 0.1 to about 50 μ g/ml, about 0.05 to about 25 μ g/ml, about 0.05 to about 10 μ g/ml, about 0.05 to about 5 μ g/ml, or about 0.05 to about 1 μ g/ml. In embodiments, the composition comprises gaboxadol or a pharmaceutically acceptable salt thereof at a concentration of, for example, about 0.05 to about 15 μ g/ml, about 0.5 to about 10 μ g/ml, about 0.5 to about 7 μ g/ml, about 1 to about 10 μ g/ml, about 5 to about 10 μ g/ml, or about 5 to about 15 μ g/ml. In embodiments, the pharmaceutical composition for parenteral administration is formulated to a total volume of about, e.g., 10ml, 20ml, 25ml, 50ml, 100ml, 200ml, 250ml, or 500 ml. In embodiments, the composition is contained in a bag, glass vial, plastic vial, or bottle.

In embodiments, methods are provided for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination by: administering a parenteral pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof in a concentration from about 0.05 to about 500 μ g/ml to a patient in need thereof. In embodiments, the composition is disposed in a sealed glass container.

In embodiments, there is provided a composition for parenteral administration comprising from about 0.05mg to about 100mg gaboxadol or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises about, e.g., 0.1 to 25mg, 0.1 to 20mg, 0.1 to 15mg, 0.5 to 25mg, 0.5 to 20mg, 0.5 to 15mg, 1 to 25mg, 1 to 20mg, 1 to 15mg, 1.5 to 25mg, 1.5 to 20mg, 1.5 to 15mg, 2 to 25mg, 2 to 20mg, 2 to 15mg, 2.5 to 25mg, 2.5 to 20mg, 2.5 to 15mg, 3 to 25mg, 3 to 20mg, 3 to 15mg gaboxadol or a pharmaceutically acceptable salt thereof.

In embodiments, a pharmaceutical composition for parenteral administration comprises gaboxadol or a pharmaceutically acceptable salt thereof in an amount of about, e.g., 5 to 20mg, 5 to 10mg, 4 to 6mg, 6 to 8mg, 8 to 10mg, 10 to 12mg, 12 to 14mg, 14 to 16mg, 16 to 18mg, or 18 to 20 mg. In embodiments, a pharmaceutical composition for parenteral administration comprises gaboxadol or a pharmaceutically acceptable salt thereof in an amount of about, e.g., 0.1mg, 0.25mg, 0.5mg, 1mg, 2.5mg, 3mg, 4mg, 5mg, 7mg, 7.5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg, or a multiple of such dose. The composition may be contained in a bag, glass vial, plastic vial or bottle.

In embodiments, the pharmaceutical composition for parenteral administration to a subject comprises gaboxadol or a pharmaceutically acceptable salt thereof in a concentration from about 0.005mg/ml to about 500 mg/ml. In embodiments, the composition comprises gaboxadol or a pharmaceutically acceptable salt thereof, for example, in a concentration of about 0.05mg/ml to about 50mg/ml, about 0.05mg/ml to about 100mg/ml, about 0.005mg/ml to about 500mg/ml, about 0.1mg/ml to about 50mg/ml, about 0.1mg/ml to about 10mg/ml, about 0.05mg/ml to about 25mg/ml, about 0.05mg/ml to about 10mg/ml, about 0.05mg/ml to about 5mg/ml, or about 0.05mg/ml to about 1 mg/ml. In embodiments, the composition comprises gaboxadol or a pharmaceutically acceptable salt thereof at a concentration of, for example, about 0.05mg/ml to about 15mg/ml, about 0.5mg/ml to about 10mg/ml, about 0.25mg/ml to about 5mg/ml, about 0.5mg/ml to about 7mg/ml, about 1mg/ml to about 10mg/ml, about 5mg/ml to about 10mg/ml, or about 5mg/ml to about 15 mg/ml. In embodiments, the pharmaceutical composition for parenteral administration is formulated to a total volume of about, e.g., 10ml, 20ml, 25ml, 50ml, 100ml, 200ml, 250ml, or 500 ml. In embodiments, the composition is packaged and stored in a bag, glass vial, plastic vial, or bottle.

In embodiments, there is provided a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof wherein the gaboxadol or a pharmaceutically acceptable salt thereof is present at a molar concentration of less than about 1.0M. In embodiments, gaboxadol, or a pharmaceutically acceptable salt thereof, is present in a molar concentration greater than, e.g., about 0.0001M, about 0.001M, about 0.01M, about 0.1M, about 0.2M, greater than about 0.5M, greater than about 1.0M, greater than about 1.2M, greater than about 1.5M, greater than about 1.75M, greater than about 2.0M, or greater than about 2.5M. In embodiments, gaboxadol, or a pharmaceutically acceptable salt thereof, is present in a molar concentration of, for example, between about 0.00001M to about 0.1M, about 0.01 to about 0.1M, about 0.1M to about 1.0M, about 1.0M to about 5.0M, or about 5.0M to about 10.0M. In embodiments, gaboxadol, or a pharmaceutically acceptable salt thereof, is present in a molar concentration of less than, e.g., about 0.01M, about 0.1M, about 1.0M, about 5.0M, or about 10.0M.

In embodiments, the solubility of gaboxadol or a pharmaceutically acceptable salt thereof in the composition is greater than, e.g., about 10mg/mL, about 15mg/mL, about 20mg/mL, about 25mg/mL, about 30mg/mL, about 40mg/mL, about 50mg/mL, about 75mg/mL, about 100mg/mL, about 150mg/mL when measured, e.g., in water at 25 ℃.

In embodiments, the solubility of gaboxadol or a pharmaceutically acceptable salt thereof in the composition is, for example, between about 1mg/mL to about 50mg/mL, about 5mg/mL to about 50mg/mL, about 10mg/mL to about 50mg/mL, about 20mg/mL to about 50mg/mL, from about 20mg/mL to about 30mg/mL, or from about 10mg/mL to about 45mg/mL when measured, for example, in water at 25 ℃.

In an embodiment, a pharmaceutical composition for parenteral administration is provided, wherein the pharmaceutical composition is stable for at least six months. In embodiments, the pharmaceutical compositions herein exhibit a reduction of no more than about 5% of gaboxadol or a pharmaceutically acceptable salt thereof after, for example, 3 months or 6 months. In embodiments, the amount of degradation of gaboxadol or a pharmaceutically acceptable salt thereof is no more than about, e.g., 2.5%, 1%, 0.5% or 0.1%. In embodiments, the degradation of gaboxadol or a pharmaceutically acceptable salt thereof is less than about, e.g., 5%, 2.5%, 1%, 0.5%, 0.25%, 0.1% over at least six months.

In an embodiment, a pharmaceutical composition for parenteral administration is provided, wherein the pharmaceutical composition remains soluble. In embodiments, provided are pharmaceutical compositions that are stable, soluble, locally-compatible, and/or ready-to-use. In embodiments, the pharmaceutical compositions herein are ready-to-use for direct administration to a patient in need thereof.

The parenteral compositions herein may comprise one or more excipients, such as solvents, solubility enhancers, suspending agents, buffers, isotonicity agents, stabilizers, or antimicrobial preservatives. When used, the excipients of the parenteral composition will not adversely affect the stability, bioavailability, safety and/or efficacy of the gaboxadol or a pharmaceutically acceptable salt used in the composition. Accordingly, parenteral compositions are provided in which there is no incompatibility between any of the components of the dosage form.

Thus, in an embodiment, a parenteral composition of gaboxadol or a pharmaceutically acceptable salt thereof is provided comprising a stabilizing amount (stabilizing amount) of at least one excipient. For example, the excipient may be selected from the group consisting of buffers, solubilizers, tonicity agents, antioxidants, chelating agents, antimicrobial agents, preservatives, and combinations thereof. One skilled in the art will appreciate that excipients may have more than one function and be classified into one or more defined groups.

In embodiments, there is provided a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof and an excipient wherein the excipient is present at a weight percentage (w/v) of less than about, e.g., 10%, 5%, 2.5%, 1%, or 0.5%. In embodiments, the excipient is present at a weight percentage of between about, e.g., 1.0% to 10%, 10% to 25%, 15% to 35%, 0.5% to 5%, 0.001% to 1%, 0.01% to 1%, 0.1% to 1%, or 0.5% to 1%. In embodiments, the excipient is present at a weight percentage of between about, e.g., 0.001% to 1%, 0.01% to 1%, 1.0% to 5%, 10% to 15%, or 1% to 15%.

In embodiments, there is provided a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof and an excipient wherein the excipient is present in a molar ratio of excipient to gaboxadol or a pharmaceutically acceptable salt, e.g., from about 0.01:1 to about 0.45:1, from about 0.1:1 to about 0.15:1, from about 0.01:1 to about 0.1:1 and from about 0.001:1 to about 0.01: 1. In embodiments, the excipient is present in a molar ratio of excipient to gaboxadol or a pharmaceutically acceptable salt of about 0.0001:1 to about 0.1:1 or about 0.001:1 to about 0.001: 1.

In an embodiment, there is provided a pharmaceutical composition comprising gaboxadol, or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient comprises a stabilizing amount of a buffer. The buffering agent may be used to maintain the pH of the pharmaceutical composition in which gaboxadol or a pharmaceutically acceptable salt thereof remains soluble, stable, and/or physiologically compatible. For example, in embodiments, the parenteral composition comprises a buffer, wherein the composition remains stable without significant gaboxadol degradation. In embodiments, it is desirable to add a buffer for controlling pH to enhance stability without significantly catalyzing or degrading gaboxadol or a salt thereof and/or causing pain to the patient upon infusion.

In embodiments, the buffer may be a citrate buffer, a phosphate buffer, an acetate buffer, a tartrate buffer, a carbonate buffer, a glutamate buffer, a lactate buffer, a succinate buffer, a bicarbonate buffer, and combinations thereof. For example, sodium citrate, trisodium citrate anhydrous, trisodium citrate dihydrate, sodium citrate dehydrate, Triethanolamine (TRIS), trisodium citrate pentahydrate, acetic acid, citric acid, glutamic acid, phosphoric acid may be used as buffer. In embodiments, the buffer may be an amino acid buffer, an alkali metal buffer, or an alkaline earth metal buffer. For example, the buffer may be sodium acetate or sodium hydrogen phosphate.

In embodiments, provided herein are parenteral compositions of gaboxadol or a pharmaceutically acceptable salt thereof wherein the pH of the composition is between about 4.0 to about 8.0. In embodiments, the pH of the composition is between, for example, about 5.0 to about 8.0, about 6.0 to about 8.0, about 6.5 to about 8.0. In embodiments, the pH of the composition is between, for example, about 6.5 to about 7.5, about 7.0 to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. In embodiments, the pH of an aqueous solution of gaboxadol is, for example, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0, about 8.2, about 8.4, or about 8.6.

In an embodiment, there is provided a pharmaceutical composition comprising gaboxadol, or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient comprises a solubilizing agent. For example, solubilizing agents in accordance with the disclosure herein may include, for example, sodium hydroxide, L-lysine, L-arginine, sodium carbonate, potassium carbonate, sodium phosphate, and/or potassium phosphate. The amount of solubilizer in the composition will be sufficient to keep the solution soluble at all concentrations, i.e., without becoming cloudy and/or forming a precipitate.

In embodiments, provided herein are pharmaceutical compositions comprising gaboxadol or a pharmaceutically acceptable salt thereof and an excipient, wherein the excipient comprises a particulate formation inhibitor (particulate formation inhibitor). A particle formation inhibitor refers to a compound having the desired properties of inhibiting the formation of particles in a parenteral composition. Particle formation inhibitors of the disclosure herein include ethylenediaminetetraacetic acid (EDTA) and salts thereof, such as calcium disodium ethylenediaminetetraacetate (preferably as a hydrate); ethylenediaminetetraacetic acid diammonium salt (preferably as a hydrate); ethylenediaminetetraacetic acid dipotassium salt (preferably as the dihydrate); ethylenediaminetetraacetic acid disodium salt (preferably as the dihydrate and, if desired, as the anhydrous form); ethylenediaminetetraacetic acid tetrasodium salt (preferably as the hydrate); ethylenediaminetetraacetic acid tripotassium salt (preferably as the dihydrate); trisodium ethylenediaminetetraacetate (preferably as the hydrate) and disodium ethylenediaminetetraacetate, USP (preferably as the dihydrate). In embodiments, the pharmaceutical compositions described herein have an effective amount of a particle formation inhibitor. In embodiments, excipients may include, for example, amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins such as serum albumin, collagen, and gelatin; salts such as EDTA or EGTA, as well as sodium chloride, liposomes, polyvinylpyrrolidone, sugars such as dextran, mannitol, sorbitol and glycerol, propylene glycol and polyethylene glycols (e.g., PEG-4000, PEG-6000), glycerol, glycine and/or lipids.

In embodiments, provided herein are pharmaceutical compositions comprising gaboxadol, or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient comprises a solubilizing agent. For example, the solubilizing agent may include, but is not limited to, acids such as carboxylic acids, amino acids. In other examples, the solubilizing agent can be a saturated carboxylic acid, an unsaturated carboxylic acid, a fatty acid, a keto acid, an aromatic carboxylic acid, a dicarboxylic acid, a tricarboxylic acid, an alpha-hydroxy acid, an amino acid, and combinations thereof.

In embodiments, provided herein are pharmaceutical compositions comprising gaboxadol or a pharmaceutically acceptable salt thereof and an excipient, wherein the excipient comprises a solubilizing agent such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, stearic acid, acrylic acid, docosahexaenoic acid, eicosapentaenoic acid, pyruvic acid, benzoic acid, salicylic acid, aldaric acid (aldaric acid), oxalic acid, malonic acid, malic acid, succinic acid, glutaric acid, adipic acid, citric acid, lactic acid, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and combinations thereof.

In embodiments, the solubilizing agent is selected from the group consisting of acetic acid, salts thereof, and combinations thereof (e.g., acetic acid/sodium acetate), citric acid, salts thereof, and combinations thereof (e.g., citric acid/sodium citrate), DL arginine, L-arginine, and histidine. In embodiments, the solubilizing agent is DL-arginine. In embodiments, the solubilizing agent is L-arginine. In embodiments, the solubilizing agent is acetic acid/sodium acetate. In embodiments, the solubilizing agent is citric acid/sodium citrate.

In embodiments, provided herein are pharmaceutical compositions comprising gaboxadol, or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient renders the composition isotonic. The isotonic pharmaceutical composition herein may be achieved by adding an appropriate amount of sodium chloride, glucose, levulose, dextrose, mannitol, or potassium chloride, or calcium gluconate glucoheptonate, or mixtures thereof. For example, the excipient may include one or more tonicity agents (tonicity agents), such as, for example, sodium chloride, potassium chloride, glycerol, mannitol, and/or dextrose. Tonicity agents may be used to minimize tissue damage and irritation, reduce hemolysis of blood cells, and/or prevent electrolyte imbalance. For example, the parenteral composition can be an aqueous solution comprising sodium chloride, wherein the composition is isotonic. In an embodiment, the isotonic agent is sodium chloride. In embodiments, the concentration of the isotonic agent is between about 0.01 weight percent and about 2.0 weight percent. In embodiments, the pharmaceutical composition may comprise up to about 10% isotonic agent. In embodiments, the pharmaceutical composition may comprise up to about, e.g., 0.25%, 0.5%, 1%, 2.5% isotonic agent. In embodiments, the amount of isotonic agent in the medicament is between about, e.g., 0.01% to 1%, 0.1% to 1%, 0.25% to 1%, or 0.5% to 1%.

In embodiments, provided herein are pharmaceutical compositions comprising gaboxadol, or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient comprises a free radical antagonist. In embodiments, the free radical antagonist is ascorbic acid, ascorbic acid derivatives, organic compounds having at least one thiol group, polyhydroxylated alkyl compounds, and polyhydroxylated cycloalkyl compounds, and combinations thereof.

In embodiments, provided herein are pharmaceutical compositions comprising gaboxadol or a pharmaceutically acceptable salt thereof and an excipient, wherein the excipient comprises a free radical scavenger selected from thioglycolic acid, thioacetic acid, dithiothreitol, reduced glutathione, thiourea, a-thioglycerol, cysteine, acetylcysteine, mercaptoethanesulfonic acid, and combinations thereof.

In embodiments, provided herein are pharmaceutical compositions comprising gaboxadol or a pharmaceutically acceptable salt thereof and an excipient, wherein the excipient comprises riboflavin, dithiothreitol, sodium thiosulfate, thiourea, ascorbic acid, methylene blue, sodium metabisulfite, sodium bisulfite, propyl gallate, acetylcysteine, phenol, sodium acetone sulfate, ascorbic acid esters, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), cysteine, nordihydroguaiaretic acid (NDGA), monothioglycerol, sodium bisulfite, sodium metabisulfite (sodium metabisulfite), tocopherol, and/or glutathione.

In embodiments, provided herein are pharmaceutical compositions comprising gaboxadol, or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient comprises a preservative. In embodiments, the preservative is selected from the group consisting of benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, chlorocresol, m-cresol, phenol, phenylmercuric nitrate, phenylmercuric acetate, methylparaben, propylparaben, butylparaben, and thimerosal. In other embodiments, the preservative is selected from the group consisting of: phenol, m-cresol, benzyl alcohol, parabens (e.g., methyl paraben, propyl paraben, butyl paraben), benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric salts (e.g., phenylmercuric acetate, phenylmercuric borate, or phenylmercuric nitrate), and combinations thereof.

In embodiments, the compositions herein comprise a co-solvent. In some cases, the solubility of gaboxadol may be much lower than the therapeutic dose, and therefore a co-solvent system may be used. A co-solvent is a mixture of solvents that can be used to achieve sufficiently high solubility and that can increase stability. For example, the co-solvent may be a water-miscible organic solvent such as ethanol, propylene, ethylene glycol, Capmul PG, propylene glycol, glycerol, polyethylene glycol, sorbitol, dimethylacetamide, and/or Dimethylsulfoxide (DMSO). In embodiments, the co-solvent may comprise up to about 75% of the pharmaceutical composition. In other embodiments, the amount of co-solvent used comprises up to about, e.g., 1%, 5%, 10%, 15%, 25%, 40%, 50% of the pharmaceutical composition.

Parenteral dosage forms can be prepared, for example, by: the gaboxadol and one or more excipients (e.g., buffers, solubilizers, tonicity agents, antioxidants, chelating agents, antimicrobial agents, and/or preservatives) are mixed in a blender under aseptic conditions until a homogeneous blend is obtained. The pre-sterilized vials can then be filled with the appropriate amount of sterile blend. A predetermined amount of the sterile blend can then be mixed with a solvent, such as water, saline, an about 5% -10% sugar (e.g., glucose, dextrose) solution, and combinations thereof, prior to administration. In addition, the solution may be frozen and thawed prior to further processing.

The excipients may be used in solid form or in the form of a solution. When used in solid form, the excipient and gaboxadol may be mixed together as described above and then the solvent added prior to parenteral administration. When used in solution form, gaboxadol may be mixed with a solution of excipients prior to parenteral administration.

The parenteral solution (parenteral solution) comprising gaboxadol herein may be prepared by: the desired amount of gaboxadol may be mixed in a parenteral fluid such as D5W, distilled water, saline, or PEG, and the pH of the solution adjusted between 6.8-8, and gaboxadol may be purified prior to use. The process may be carried out at room temperature, or the solution may be suitably warmed in order to increase the concentration. Other solvents such as PEG 400, PEG 600, polypropylene glycol or other glycols may be used to improve solubility. After cooling to room temperature the resulting solution may be sterilized by known means, such as ultrafiltration using, for example, a 0.45 micron filter or ethylene oxide treatment or heating, and may be packaged into ampoules, vials or pre-filled syringes suitable for dispensing sterile parenteral formulations.

When administered, the parenteral compositions herein provide a time (T) of maximum plasma concentration of gaboxadol for about 1 or more hours (e.g., about 1.5 hours or more) in a human patient_{Maximum of}). In embodiments, T of gaboxadol in a human patient_{Maximum of}In a range of, for example, between about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1 hour to about 2 hours. In embodiments, a T of gaboxadol is observed in greater than about 1.5 in human patients_{Maximum of}. In embodiments, T of gaboxadol is observed in human patients for less than about 3 hours_{Maximum of}. Once the infusion is complete, the time to maximum plasma concentration is measured.

In embodiments herein, the dosage form comprises from about 1mg to about 500mg gaboxadol, wherein parenteral administration (e.g., intramuscular, intravenous, subcutaneous, intraperitoneal, or intrathecal administration) of the dosage form provides a mean AUC comprising greater than about 25 ng-hr/ml_0-∞In vivo plasma profile of gaboxadol (in vivo plasma profile). In embodiments, single dose administration of the dosage form provides an average AUC comprising greater than about, e.g., 50 ng-hr/ml, 75 ng-hr/ml, 150 ng-hr/ml, 250 ng-hr/ml, 500 ng-hr/ml, 1000 ng-hr/ml, or 1500 ng-hr/ml_0-∞In vivo plasma profile of gaboxadol.

In an embodiment, the dosage form comprises from about 1mg to about 500mg gaboxadol, wherein administration of the dosage form provides a mean C comprising less than about 10000ng/ml_{Maximum of}In vivo plasma profile of gaboxadol. In embodiments, a single dose administration of the composition provides an average C of less than about, e.g., 5000ng/ml, 2500ng/ml, 1000ng/ml, 500ng/ml, 250ng/ml, or 100ng/ml_{Maximum of}In vivo plasma profile of gaboxadol.

In an embodiment, a pharmaceutical composition for parenteral administration comprises gaboxadol or a pharmaceutically acceptable salt thereof, wherein the parenteral administration exhibits a T from about 1 minute to about 120 minutes after administration of the parenteral composition_{Maximum of}A pharmacokinetic profile of (a); followed by at least 50% C for a duration of about 90 minutes to about 360 minutes_{Maximum of}Plasma drug concentration of (a). In embodiments, the parenteral administration of gaboxadol is followed by at least 50% C over a duration of, e.g., about 10 minutes to about 60 minutes, about 15 minutes to about 90 minutes, about 30 minutes to about 120 minutes, about 60 minutes to about 180 minutes, about 90 minutes to about 180 minutes_{Maximum of}Plasma drug concentration of (a).

In embodiments, the stable pharmaceutical composition is provided in a unit dosage form having a therapeutically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof dissolved in sterile water to form a solution in a vial or ampoule suitable for parenteral administration, wherein the composition is substantially free of any excipients, organic solvents, buffers, acids, bases, salts other than gaboxadol or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition remains sufficiently soluble and is capable of direct administration. In embodiments, the pharmaceutical composition is capable of being stored in the absence of an inert atmosphere for at least 6 months.

In embodiments, provided herein is a stable pharmaceutical composition in unit dosage form in vials or ampoules suitable for parenteral administration, the unit dosage form having a therapeutically effective amount of gaboxadol or a pharmaceutically acceptable salt thereof dissolved in sterile water to form a solution, wherein the composition is free of any excipients, organic solvents, buffers, acids, bases, salts other than gaboxadol or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition remains sufficiently soluble and is capable of direct administration. In embodiments, the pharmaceutical composition is capable of being stored in the absence of an inert atmosphere for at least 6 months.

In an embodiment, a stable pharmaceutical composition suitable for parenteral administration comprises gaboxadol or a pharmaceutically acceptable salt thereof in an aqueous solution having an osmolality (osmolarity) between 225 and 350mOsm/kg and a pH in the range between 7.0 and 8.0. In embodiments, the aqueous solution has an osmolarity between 270 and 310. In embodiments, the aqueous solution has a pH in the range between 7.2 and 7.8.

In embodiments, provided herein are methods for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination, e.g., for alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco, comprising administering a pharmaceutical composition comprising gaboxadol, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the composition provides improvement in at least one symptom of substance use disorders. In embodiments, the provided methods can also surprisingly and unexpectedly reduce or prevent symptoms of substance use disorders in a subject in need thereof.

In embodiments, the methods described herein can reduce one or more symptoms of a substance use disorder in a subject after treatment compared to when the treatment is absent (e.g., prior to treatment), or compared to treatment with an alternative conventional treatment.

In embodiments, provided herein are methods for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination, wherein the patient is provided with an improvement in at least one symptom lasting more than 4 hours after administration of the pharmaceutical composition to the patient. In embodiments, there is provided according to the present disclosure an improvement in at least one symptom lasting more than 6 hours after administration of a pharmaceutical composition to a patient. In embodiments, there is provided according to the present disclosure an improvement in at least one symptom lasting more than, e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of a pharmaceutical composition to a patient. In embodiments, there is provided according to the present disclosure an improvement in at least one symptom lasting for at least, e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of a pharmaceutical composition to a patient. In embodiments, there is provided according to the present disclosure an improvement in at least one symptom lasting 12 hours after administration of a pharmaceutical composition to a patient.

In embodiments, provided herein are methods for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination, comprising administering gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition provides an improvement in function the next day to the patient.

In embodiments, provided herein are methods for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting termination of substance use, comprising administering gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient is alleviated of one or more symptoms of the substance use disorder within about 2 weeks or less, 1 week or less, 1 day or less, or 1 hour or less (e.g., 15 minutes or less, half an hour or less) after administration. In embodiments, such methods may alleviate at least one symptom of substance use disorder in the patient within about 1 day or more, 1 week or more, or 2 weeks or more after administration. In embodiments, provided herein is a method comprising parenterally administering an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof to a patient suffering from a substance use disorder, wherein the patient is substantially alleviated of one or more symptoms of the substance use disorder earlier after the first administration of gaboxadol or a pharmaceutically acceptable salt thereof than the same patient administered a different anti-addiction compound.

In embodiments, provided herein are methods for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination, wherein the amount of an active substance, e.g., gaboxadol or a pharmaceutically acceptable salt thereof, in a patient is less than about 75% of the dose administered about 4 hours after administration of the pharmaceutical composition. In embodiments, provided herein are methods wherein the amount of gaboxadol or a pharmaceutically acceptable salt thereof is less than about 75% in the patient about, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours after administration of the pharmaceutical composition.

In embodiments, provided herein are methods for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination, wherein the amount of an active substance, e.g., gaboxadol or a pharmaceutically acceptable salt thereof, in a patient is less than about 80% of the dose administered about 4 hours after administration of the pharmaceutical composition. In embodiments, provided herein are methods wherein the amount of the active agent, e.g., gaboxadol or a pharmaceutically acceptable salt thereof, in the patient is less than about 80% of the administered dose about, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours or 20 hours after administration of the pharmaceutical composition.

In embodiments, provided herein are methods for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination, wherein the amount of an active substance, e.g., gaboxadol or a pharmaceutically acceptable salt thereof, in a patient is between about 65% and about 85% of the administered dose about 4 hours after administration of a pharmaceutical composition. In embodiments, the amount of active substance, e.g., gaboxadol or a pharmaceutically acceptable salt thereof, in the patient is between about 65% to about 85% of the administered dose after about, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours after administration of the pharmaceutical composition.

In embodiments, provided herein are methods for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination, comprising administering to a patient in need thereof a pharmaceutical composition comprising an active agent, e.g., gaboxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides a C of less than about 500ng/ml_{Maximum of}In vivo plasma profile of (a). In embodiments, the composition provides an improvement that lasts more than 6 hours after administration to a patient.

In embodiments, the composition is provided having less than about, e.g., 450ng/ml, 400ng/ml350ng/ml or 300ng/ml C_{Maximum of}And wherein the composition provides an improvement in the next day function of the patient. In embodiments, the composition provides a C having less than about, e.g., 250ng/ml, 200ng/ml, 150ng/ml, or 100ng/ml_{Maximum of}And wherein the composition provides an improvement in the next day function of the patient.

In embodiments, provided herein are methods for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination, comprising administering to a patient in need thereof a pharmaceutical composition, wherein the composition provides an AUC of less than about 900 ng-hr/ml_0-∞Constant in vivo plasma profile of (a). In embodiments, the composition provides an improvement in the next day function of the patient. In embodiments, the composition provides an AUC having less than about, e.g., 850 ng-hr/ml, 800 ng-hr/ml, 750 ng-hr/ml, or 700 ng-hr/ml_0-∞And wherein the composition provides an improvement in the next day function of the patient. In embodiments, the composition provides an improvement in one or more symptoms lasting more than 6 hours after administration.

In embodiments, provided herein are methods for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination, comprising administering to a patient in need thereof a pharmaceutical composition comprising an active substance, e.g., gaboxadol, or a pharmaceutically acceptable salt thereof, wherein the composition provides an AUC of less than about, e.g., 650 ng-hr/ml, 600 ng-hr/ml, 550 ng-hr/ml, 500 ng-hr/ml, or 450 ng-hr/ml_0-∞In vivo plasma profile of (a). In embodiments, the composition provides an AUC having less than about, e.g., 400 ng-hr/ml, 350 ng-hr/ml, 300 ng-hr/ml, 250 ng-hr/ml, or 200 ng-hr/ml_0-∞In vivo plasma profile of (a). In embodiments, the composition provides an AUC having less than about, e.g., 150 ng-hr/ml, 100 ng-hr/ml, 75 ng-hr/ml, or 50 ng-hr/ml_0-∞In vivo plasma profile of (a). In embodiments, the composition is provided for more than, e.g., 4 hours, 6 hours after administration of the composition to a patientImprovement in the next day of the patient's function following administration by time, 8 hours, 10 hours, or 12 hours.

In embodiments, provided herein are methods for treating substance use disorders, preventing substance use craving, attenuating substance use thirst, and/or promoting substance use termination, comprising administering to a patient in need thereof a first pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof. In some embodiments, the second pharmaceutical composition provides a mean AUC that is at least about 20% less than the first pharmaceutical composition_0-∞In vivo plasma profile of (a).

In embodiments, the first pharmaceutical composition and/or the second pharmaceutical composition is administered once daily, twice or three times daily or every other day. In embodiments, the first pharmaceutical composition or the second pharmaceutical composition is provided to the patient at night. In embodiments, the second pharmaceutical composition comprises an amount of gaboxadol that is at least one-third the amount of gaboxadol or a pharmaceutically acceptable salt thereof in the first pharmaceutical composition. In embodiments, the second pharmaceutical composition comprises an amount of gaboxadol that is at least half the amount of gaboxadol or a pharmaceutically acceptable salt thereof provided in the first pharmaceutical composition.

In embodiments, the first pharmaceutical composition or the second pharmaceutical composition is provided to the patient once in the evening and once in the morning. In embodiments, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof administered to the subject over a 24 hour period is 1mg to 100 mg. In embodiments, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof administered to the subject over a 24 hour period is 1mg to 75 mg. In embodiments, the total amount of active substance, e.g., gaboxadol or a pharmaceutically acceptable salt thereof and/or gaboxadol administered to the subject over a 24 hour period is less than about 75mg, 50mg, 25mg, 20mg, 10mg or 5 mg. In embodiments, the total amount of active substance, e.g. gaboxadol or a pharmaceutically acceptable salt thereof and/or gaboxadol administered to the subject over a 24 hour period is less than 15 mg.

In embodiments, the subject is provided gaboxadol, or a pharmaceutically acceptable salt thereof, in combination with an additional therapeutic agent. In embodiments, the effective amount of either or both of gaboxadol or a pharmaceutically acceptable salt thereof and the additional therapeutic agent may be different when either is provided alone compared to when provided in combination. For example, when gaboxadol or a pharmaceutically acceptable salt thereof and the additional therapeutic agent act synergistically, then a lower amount of gaboxadol or a pharmaceutically acceptable salt thereof, a lower amount of the additional therapeutic agent, or both a lower amount of gaboxadol or a pharmaceutically acceptable salt thereof and the additional therapeutic agent may be required to achieve the same therapeutic effect as gaboxadol or a pharmaceutically acceptable salt thereof alone or the additional therapeutic agent alone would provide. In embodiments, the same amount of gaboxadol or a pharmaceutically acceptable salt thereof and the additional therapeutic agent is used to provide an enhanced therapeutic effect relative to the therapeutic effect provided by gaboxadol or a pharmaceutically acceptable salt thereof alone or an additional therapeutic agent alone.

Gaboxadol or a pharmaceutically acceptable salt thereof may be combined with one or more additional therapeutic agents effective for use in methods of treating substance use disorders, preventing substance use craving, reducing substance use thirst, and/or promoting substance use termination, including addiction to one or more substances described herein. Thus, in embodiments, a method for treating a substance use disorder, preventing substance use craving, attenuating substance use craving, and/or promoting substance use termination comprises administering gaboxadol or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents to a subject addicted to a substance, wherein gaboxadol or a pharmaceutically acceptable salt thereof and the additional therapeutic agents help to effectively treat the substance use disorder, prevent substance use craving, attenuate substance use craving, and/or promote substance use termination. In embodiments, gaboxadol, or a pharmaceutically acceptable salt thereof, and one additional therapeutic agent are provided or administered to the subject. In embodiments, the subject is addicted to two or more substances.

Gaboxadol or a pharmaceutically acceptable salt thereof and the additional therapeutic agent may be administered at the same time (i.e., simultaneously), or either may be administered before the other (i.e., sequentially). Generally, gaboxadol or a pharmaceutically acceptable salt thereof and the additional therapeutic agent may be present in the subject for the same time and at levels sufficient to provide a therapeutic benefit, i.e., a therapeutic benefit in treating the substance use disorder, preventing substance use craving, attenuating substance use craving, promoting termination of substance use, and/or preventing recurrent use of the substance, to the subject for a period of time. Gaboxadol or a pharmaceutically acceptable salt thereof and the additional therapeutic agent may be administered by the same or different routes of administration. In embodiments, gaboxadol, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent may be co-administered using a composition comprising both agents.

The additional therapeutic agent provided in combination with gaboxadol or a pharmaceutically acceptable salt thereof may be any therapeutic agent that contributes to an effective treatment or prevention aspect of the substance use disorder. For example, the additional therapeutic agent may be a drug for treating a disorder of use, or a drug for alleviating side effects associated with physiological withdrawal of a substance. In addition, the additional therapeutic agent can be any drug that affects brain serotonin (serotonin) neurotransmission, such as Selective Serotonin Reuptake Inhibitors (SSRIs), and tricyclic serotonin and tetracyclic Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), as well as serotonin agonists. In embodiments, the additional therapeutic agent may be an opioid antagonist, including mixed opioid partial agonists/antagonists, antidepressants, antiepileptics, antiemetics, dopaminergic agents (dopaminergic agents) such as dopamine D1 receptor agonists, corticotropin releasing factor-1 (CRF-1) receptor antagonists, selective serotonin-3 (5-HT3) antagonists, 5-HT2A/2C antagonists, or cannabinoid-1 (CB1) receptor antagonists.

In embodiments, the substance is nicotine and gaboxadol or a pharmaceutically acceptable salt thereof may be combined with one or more nicotine substitutesThe combination is used for the treatment of nicotine usage disorders. Nicotine replacement (also known as "nicotine replacement therapy" or "NRT") can make tobacco withdrawal easier by partially replacing nicotine previously obtained from tobacco or other nicotine sources. Nicotine replacement therapies that can be combined with gaboxadol or a pharmaceutically acceptable salt thereof include but are not limited to transdermal nicotine patches (e.g.,Nicodermand) A nicotine chewing gum (e.g.,) A nicotine lozenge (e.g.,) A nicotine-containing sublingual tablet (e.g.,microtabs) and nicotine nasal spray or inhalation.

In embodiments, gaboxadol or a pharmaceutically acceptable salt thereof may be combined with one or more nicotinic drugs (nicotinic drugs). One particular class of nicotinic drugs that may be used includes the alpha 4-beta 2 nicotinic receptor partial agonists, including varenicline (varenicline)Another approved therapeutic agent for the treatment of nicotine dependence is bupropion (bupropion)Which are alpha 3-beta 4 nicotinic receptor antagonists and may be used in combination withA combination of bosadol or a pharmaceutically acceptable salt thereof. In embodiments, a substance such as nicotine and gaboxadol, or a pharmaceutically acceptable salt thereof, are administered together using a transdermal patch delivery system.

In an embodiment, the substance is alcohol and the additional therapeutic agent is disulfiram (disulfiram). In embodiments, the substance is an opioid and the additional therapeutic agent is an opioid antagonist such as naltrexone, naloxone, or a mixed opioid partial agonist/antagonist such as buprenorphine, nalorphine (nalorphine).

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

"PK" refers to the pharmacokinetic profile. C_{Maximum of}Is defined as the highest plasma drug concentration (ng/ml) estimated during the experiment. T is_{Maximum of}Is defined as when C_{Maximum of}Time when estimated (min). AUC_0-∞Is the total area under the plasma drug concentration-time curve (ng hr/ml) from drug administration until drug is eliminated. The area under the curve is determined by the clearance. Clearance is defined as the volume of blood or plasma (ml/min) per unit time that is completely cleared of its drug content.

An "excipient" is a substance in a pharmaceutical composition that is different from the active drug substance, e.g. gaboxadol, which has been properly evaluated for safety and is included in a drug delivery system to aid handling of the drug delivery system during its manufacture; protection; supporting; enhancing stability, bioavailability, or patient acceptability; assisting in product identification; or any other attribute that enhances the overall safety and effectiveness of the drug delivery system during storage or use.

"stabilizer" or "stabilizing amount" refers to the amount of one or more excipients included in the composition that provides sufficient stability, but does not adversely affect the bioavailability, safety and/or efficacy of gaboxadol or a pharmaceutically acceptable salt used in the composition.

By "stable" is meant that gaboxadol or a pharmaceutically acceptable salt thereof does not substantially degrade after a specified period of time, for example after 3 months or 6 months.

By "soluble" is meant that the solution of gaboxadol does not become cloudy and/or that there is substantially no precipitation in the solution.

By "sufficiently soluble" is meant that the particulate content is sufficiently low and the material is sufficiently sterile that it can be used for parenteral administration. For example, the number of particles in the liquid composition should be, for example, less than 60,000 10 μm particles, preferably less than 10,000, less than 5,000, less than 3,000, less than 1,000 or less than 400 10 μm particles should be present in a volume of 10ml of solvent. In some examples, the number of particles in the liquid composition should be less than 1000, less than 600, or less than 200 25 μm particles in a 10ml volume.

By "locally site compatible" herein should be meant that the composition is tolerated at the site of injection or infusion, thereby minimizing side effects, such as local skin irritation or venous irritation, including inflammatory reactions at the infusion site. The parenteral compositions herein may have fewer side effects than conventional products, such as skin irritation or phlebitis.

"treating," "treatment," or "treatment" refers to reducing or delaying the appearance of clinical symptoms of a disease, disorder, or condition in a subject who may be suffering from or susceptible to the disease, disorder, or condition, but does not yet experience or display clinical or subclinical symptoms of the disease, disorder, or condition. In certain embodiments, "treating" or "treatment" may refer to preventing the appearance of clinical symptoms of a disease, disorder, or condition in a subject who may be suffering from or susceptible to the disease or condition but does not yet experience or display clinical or subclinical symptoms of the disease, disorder, or condition. "treating", "treatment" or "treatment" also refers to inhibiting a disease, disorder or condition, e.g., arresting or reducing its development or at least one clinical or subclinical symptom thereof. "treating," "treatment," or "treatment" also refers to alleviating a disease, disorder, or condition, e.g., causing regression of the disease, disorder, or condition, or at least one of its clinical or subclinical symptoms. The benefit to the subject to be treated may be statistically significant, mathematically significant, or at least perceptible to the subject and/or to a physician. Nevertheless, prophylactic (preventative) and therapeutic (curative) treatments are two separate embodiments herein.

"improving" refers to a method for treating a substance use disorder, preventing substance use craving, reducing substance use craving, and/or promoting substance use termination, relative to at least one symptom of the disorder.

By "amelioration of one or more symptoms of a substance use disorder one day after administration" is meant an improvement wherein the beneficial effect of at least one symptom persists for a period of time, e.g., 6 hours, 12 hours, 24 hours, etc.

By "pharmaceutically acceptable" is meant molecular entities and compositions that are "generally regarded as safe", e.g., that are physiologically tolerable and do not typically produce allergic or similar untoward reactions (such as gastric upset and the like) when administered to a human. In embodiments, the term refers to molecular entities and compositions approved by a regulatory agency of the Federal or a state government, as GRAS lists or similar lists under sections 204(s) and 409 of the Federal Food, Drug and Cosmetic Act (Federal Food, Drug and Cosmetic Act) that have undergone pre-market review and approval by the FDA for use in animals and, more particularly, in humans.

"co-administration with.... co-administration", "co-therapy", "combination with.... a.. combination", "combination with.. a.. or" administration with.. a.. may be used interchangeably and means that two or more agents are administered during the course of therapy. These agents may be administered together at the same time or separately at spaced intervals. These agents may be administered in a single dosage form or in separate dosage forms.

"patient in need thereof" includes individuals who have been diagnosed as having or at risk of developing a substance use disorder. "patient" and "subject" are used interchangeably herein and include, but are not limited to, primates, canines, porcines, ungulates, rodents, poultry, and birds. The methods may be provided to any individual, including for example where the patient is a neonate, an infant, a pediatric patient (6 months to 12 years old), an adolescent patient (12 years-18 years old), or an adult (18 years old or older). It should be understood that infants may receive pediatric doses.

As used herein, "purified" refers to material that has been separated under conditions that reduce or eliminate the presence of extraneous material, i.e., contaminants, including natural material (native material) from which the material was obtained. As used herein, the term "substantially free" is operably used in the context of analytical testing of a material. Preferably, the purified material substantially free of contaminants is at least 95% pure; more preferably at least 97% pure, and still more preferably at least 99% pure. Purity can be assessed by, for example, chromatography or any other method known in the art. In embodiments, purified means that the level of contaminants is below a level acceptable by regulatory agencies for safe administration to humans or non-human animals.

"ready-to-use" with respect to the composition herein shall mean an article of manufacture pre-packaged in a disposable container, such as a glass vial, infusion bag or syringe, of standardized concentration and quality, in reconstituted form, ready for direct administration to a patient.

"direct administration" in reference to a composition herein shall mean immediate administration, i.e., without additional dilution, premixing with other substances, or otherwise altering the composition or formulation of the composition. Such compositions are typically expelled directly from the infusion device and administered via a vascular access port or through the centerline.

"dose" (dosage) is intended to include formulations expressed as μ g/kg/day, μ g/kg/hr, mg/kg/day, or mg/kg/hr. Dose (dosage) is the amount of the ingredient administered according to a particular dosage regimen. "dose" is the amount of an agent administered to a mammal per unit volume or unit mass, e.g., an absolute unit dose expressed in mg or μ g of the agent. The dose (dose) depends on the concentration of the agent in the formulation, e.g. in moles/liter (M), mass/volume (M/v) or mass/mass (M/M). These two terms are closely related in that a particular dose (dosage) results from a regimen of administration of one or more doses of the formulation. The specific meaning in any case will be apparent from the context.

"about" or "about" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, according to practice in the art. Alternatively, "about" may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and still more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or biological processes, the term may mean within an order of magnitude of the value, preferably within 5 times the value, and more preferably within 2 times the value.

Examples

The examples provided herein are included merely to supplement the disclosure herein and should not be considered limiting in any way.

Example 1

Gaboxadol plasma concentration profile

The following examples provide a plasma concentration profile and dose rationality (dose proportionality) of gaboxadol monohydrate after a single oral dose ranging from 2.5mg to 20 mg. Absolute bioavailability of gaboxadol monohydrate capsules ranging from 2.5mg to 20mg was also evaluated.

The study included a separate group of 10 healthy adult subjects (at least 4 per sex) who participated in a 6-cycle, double-blind, randomized, crossover study designed to evaluate the dose rationality and absolute bioavailability of 5 single oral doses of gaboxadol in a dose range of 2.5mg to 20 mg. The order in which subjects received 5 single oral doses of gaboxadol (2.5 mg; 5 mg; 10 mg; 15 mg; and 20mg) over treatment cycles 1 to 5 was randomized. Each subject was expected to complete all 6 treatment cycles, and there was a washout period (washout) of at least 4 days between each treatment cycle.

Each oral administration during the treatment cycle consisted of 2 test drug capsules taken simultaneously at each scheduled administration. The treatment design (treatment designation) for the orally administered study drug was as follows: treatment a-1 capsules of 2.5mg gaboxadol and 1 matched placebo capsule; treatment B-1 5mg gaboxadol capsule and 1 matched placebo capsule; treatment of C-1 10mg gaboxadol capsules and 1 matched placebo capsule; treatment of D-1 15mg gaboxadol capsules and 1 matched placebo capsule; and treatment E-20mg gaboxadol (2 capsules of 10mg gaboxadol). Subjects received their study medication with 240mL of water in the morning at about 8:00 am after an overnight fast. Except that water was allowed to freely drink within 1 hour before and after study drug administration. Food was not allowed to eat within 4 hours after dosing.

For each subject in each treatment, plasma and urine samples were collected for determination of pharmacokinetic parameters (e.g., AUC, C) within 16 hours post-dose_{Maximum of}、T_{Maximum of}Apparent t_1/2Cumulative urine excretion, renal clearance, clearance and steady-state volume of distribution, as the case may be). AUC and C for gaboxadol_{Maximum of}Potency adjustments were made to facilitate comparison of pharmacokinetic data for each study. Table 1 provides individual potency-adjusted pharmacokinetic parameters for gaboxadol following a single oral dose (2.5mg, 5mg, 10mg, 15mg and 20 mg).

Example 2

Prospective study of the use of gaboxadol in smoking cessation treatment

Adult daily smokers with motivation to quit smoking will be randomized to gaboxadol tablets or placebo tablets and will participate in an 8-week treatment period combining medication with short-term behavioral support (brief behavial support). Participants will be randomized into 6 separate treatment groups (a-F). Randomized inclusion criteria required participants between 18 and 65 years of age, had to smoke ten or more cigarettes per day, and wanted withdrawal.

Treatment group A received 10mg gaboxadol in the evening. Treatment group B received 15mg gaboxadol in the evening. Treatment group C received 10mg gaboxadol in the evening and 5mg gaboxadol in the morning. Treatment group D received 10mg gaboxadol in the evening and 10mg gaboxadol in the morning. Treatment group E received 15mg gaboxadol in the evening and 10mg gaboxadol in the morning. Treatment group F received placebo in the evening and morning.

The primary outcome measure (primary output measure) will be the extended rate of smoking abstinence at the end of the 8-week treatment period. The secondary outcome measure would be: 1) prevalence and continuous continuance at the 7 day time point at the end of the 8-week treatment period. The metrics will be evaluated using a combination of self-reported tobacco usage and biochemical confirmation including respiratory carbon monoxide (CO) levels and cotinine levels, and 2) extended smoking abstinence at the end of the 6 month follow-up period, 7 day time point prevalence and continuous abstinence. In addition, cigarette craving will be assessed at baseline, weeks 1-8 and 1 month, 2 months and 6 months follow-up. A self-reported metric (Tiffany smoking impulse questionnaire-simple) will be used to assess cigarette cravings.

Example 3

Prospective study of the use of gaboxadol in the treatment of alcohol dependence

The objective of this study will be to obtain a preliminary indication of the safety and efficacy of oral gaboxadol (20 mg/day) in alcohol dependent patients. The randomized inclusion criteria required participants between 18 and 65 years of age to meet the current alcohol-dependent DSM-5 criteria. Volunteers may meet the criteria for abuse of other substances or dependence on other drugs (nicotine, cannabis or cocaine) as long as the dependence on cannabis or cocaine is secondary to alcohol dependence; medically healthy based on physical examination and medical history, vital signs, ECG, and laboratory testing; blood pregnancy test for women is negative; indicating a desire to stop drinking; no psychotropic drugs are needed; and can provide informed consent and follow the study procedure.

This study will be a 16-week double-blind parallel group study, two-group comparison of gaboxadol and placebo in alcohol-dependent patients (two arm compare). This outpatient clinical trial included a 2-week placebo-in phase (lead-in phase) followed by a 12-week treatment phase and a 2-week elicitation phase. The patient will be observed at 2 x/week. There will also be a follow-up visit of 3 months to re-assess the state of abstinence or relapse from drinking. The study was designed as follows:

single-blind placebo run-in phase (week 2 and week 1). Patients given informed consent and who temporarily met the inclusion-exclusion criteria will enter a 2-week single-blind placebo introduction phase. After this placebo introduction phase, patients will be randomized to receive gaboxadol or placebo and they will be graded by gender, age, race and alcohol dependence level (stratify).

Treatment period of 12 weeks (week 1-week 12). At these visits, drugs will be provided, standardized assessment tools will be completed, and biochemical measurements will be made to monitor alcohol consumption and study drug compliance. During one of these two weekly visits, the patient will receive a separate, manually guided relapse prevention therapy with the clinician and meet with a study psychiatrist (study psychiatrist).

Single-blind elicitation phase (week 13-week 14). During this 2-week induction period, patients taking active drugs will be gradually reduced with drug instead of placebo, but all other measurements and assessments (including weekly psychotherapy sessions) will remain unchanged. All patients, whether they completed the study or were excluded from management, will be followed up and assessed at week 14. There will also be a follow-up visit of 3 months to re-assess the state of abstinence or relapse from drinking.

And (5) visiting the clinic. During these visits, research nurses and research assistants will measure Breath Alcohol Content (BAC), urine and blood samples on a periodic basis for monitoring alcohol, illicit drug use and drug compliance. Drug compliance will initially be assessed by measuring riboflavin fluorescence in urine samples. The staff will supervise the completion of the self-reported questionnaire. The nurse will check vital signs at each visit, check body weight once a week, and will ask the patient for compliance, any missed doses, and possible side effects or other adverse events, and will complete the compliance and adverse event table. Medication compliance will be monitored via self-reported data, side information provider data, and medication blood levels. Likewise, drinking behavior will be monitored using BAC, self-reporting and side information provider data. This data will be available to the treatment team and will be used to enhance the importance of compliance. The patient will meet weekly with a psychiatrist who will assess current alcohol use and emotional state, evaluate side effects and adjust dosages as needed (using a pre-scheduled blind dose adjustment schedule), review events related to the patient's function that occurred since the last study visit, and perform CGI-observer assessments. During one of the two weekly visits, the patient will also see a therapist in order to have an individual relapse prevention therapy. At any point during the trial, if the treating psychiatrist determines that the primary alcohol dependence, secondary dependence on other drugs of abuse, or new drug dependence has escalated such that more intensive intervention is required, he/she will make a decision regarding exiting the trial and referral to another form of treatment.

The drug will be given on a fixed-flexible schedule, adjusted to the maximum recommended dose to minimize side effects. The patient will receive enough medication for the next visit. For patients who were assigned gaboxadol, they will be gradually adjusted from 5 mg/day to a maximum dose of 10mg b.i.d. (20 mg/day) over the first two weeks of the treatment period. All patients will receive the same amount of matching pills (matchingpill) daily. If there are several missed visits, side effects or adverse events, the study nurse and study psychiatrist will see the patient and will schedule a dose reduction using a pre-scheduled blind dose adjustment schedule. Patients who cannot tolerate 50% of the maximum dose (i.e., 10 mg/day of gaboxadol) will discontinue use of the study drug.

Example 3

Prospective study of the use of gaboxadol in opioid withdrawal treatment

This would be a two-part, multi-center study to evaluate the dose-response, efficacy and safety of gaboxadol in alleviating symptoms in subjects experiencing complete and sudden withdrawal of short-acting opioids. Any subject that is to experience opioid withdrawal who is dependent on short-acting opioids will be eligible. Subjects will be evaluated for their compliance with the regimen inclusion/exclusion criteria during a screening period lasting up to 7 days.

The first part of the study will use a hospitalized, randomized, double-blind and placebo-controlled design (day 1-day 7), followed by the second part, non-blind, continued treatment (day 8-day 14). A total of 100 subjects will be randomized to receive gaboxadol either at a 3:3:2 ratio (225:225:150) at a 20mg total daily dose (5mg, 4 times daily), a 10mg total daily dose (5mg, twice daily) or matched placebo for 7 days (i.e., during the most intense withdrawal phase). During the second part of the study (days 8-14), all subjects successfully meeting the definition for "completer" (i.e., receiving at least one dose of study medication on day 7 and SOWS-Gossop assessment 3.5 hours after completion of dosing on day 7) based on days 1-7, regardless of their treatment allocation (which would remain double blind), would be eligible to receive non-blind, variable dose gaboxadol treatment (as determined by a Site Investigator (Site Investigator), but not more than 20 mg/day) in an inpatient setting or an outpatient setting for up to an additional 7 days, depending on the desires of the Investigator and the subjects. No subject will receive gaboxadol for more than 14 days in total from the beginning of continence. There will be no initial dose escalation (dose run-up) and no prescribed end dose decrementing.

Throughout the study, efficacy and safety assessments will be made daily. Safety will be assessed by assessing adverse events, clinical laboratory, electrocardiogram, vital signs, physical examination data and Columbia-suicidality Rating Scale. Efficacy will be assessed daily by subject-completed scales including the Gossop Short Opiate Withdrawal Scale (Short opinion wide Scale of Gossop) (SOWS-G) (the primary outcome measure is the area of the SOWS-G score under the curve from day 1 to day 7), the Clinical Opiate Withdrawal Scale (COWS), the Objective Opiate Withdrawal Scale (Objective opinion wide Scale) (OOWS-Handdelsman), the Visual analogue Scale of Efficacy (Visual analogue Scale for Efficacy) (VAS-E), and the Modified Clinical Global impression Scale for Efficacy and side effects (Modified Clinical Global impression Scale). Efficacy will also be assessed by study retention (study retention), completion, concomitant drug use (comomatant diagnosis use), incidence of withdrawal-related Adverse Events (AE), and subject treatment status 30 days after the last administration of the study drug. Qualitative urine drug screening will be performed every other day to monitor illicit drug use (inpatient settings) or illicit drug use (outpatient settings). After the subjects quit the study, study discontinuation/study termination assessments will be performed.

During the study, study drug compliance will be recorded daily in the baseline. During the first part of the study (days 1-7), the subjects will be hospitalized and each dose of study medication will be administered by the study field personnel and recorded in the baseline. Study drug will be administered four times a day at 8 am, 1 pm, 6 pm and 11 pm. During the second part of the study (days 8-14), each dose of study drug will be administered by the study field personnel to subjects who are still hospitalized, and the dosing will be according to the original data. The outpatient-based subjects completing the second part of the study will be returned to the clinic daily for study evaluation. During the non-blind period, subjects will be assigned study medication that can last from 1 day to 2 days as needed to allow flexibility in scheduling daily visits to allow them to spend (get through) until they are asked to return on the next day for additional study evaluation and dosing.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the claims.