TW201618787A - Compositions and methods - Google Patents

Abstract

Provided are compositions comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof, optionally in combination with a supplemental agent, and methods for reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco; aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product; aiding in smoking cessation and preventing associated weight gain; controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal; or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use comprising administering (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof, optionally in combination with a supplemental agent.

Description

Composition and method

Tobacco use is the leading cause of disease prevention and early death worldwide. According to the World Health Organization Fact Sheet (July 2013), 50% of all tobacco users die from tobacco-related diseases, which amounts to about 6 million people each year. It is estimated that more than 5 million deaths per year are due to direct tobacco use and the remaining deaths are caused by exposure to secondhand smoke ( World Health Organization website. Fact sheet No 339: Tobacco.www.who.int/mediacentre/factsheets/fs339/ En/index.html. Updated in July 2013. Accessed on September 10, 2013 ). According to the Centers for Disease Control and Prevention (CDC), approximately 438 million adult smokers are in the United States (US). In the United States, tobacco use causes one in five smokers per year to die ( World Health Organization website. Fact Sheet No 339: Tobacco.www.who.int/mediacentre/factsheets/fs339/en/index.html. in 2013 7 Monthly update. Accessed on September 10, 2013. ) Tobacco use is directly related to cardiovascular disease, lung cancer and other cancers, as well as chronic lower respiratory diseases (chronic bronchitis, emphysema, asthma and other chronic lower respiratory diseases) ( Health Effects of Cigarette Smoking. US Disease Prevention Website. www.cdc .gov / tobacco / data_statistics / fact_sheets / health_effects / effects_cig_smoking / on September 10, 2013 access). These diseases have accounted for the top three leading causes of death in the United States since 2008, when chronic lower respiratory disease replacement is also associated with tobacco use directly related to cerebrovascular disease ( Molgaard CA, Bartok A, Peddecord KM, Rothrock J. The association between Cerebrovascular disease and smoking: a case-control study. Neuroepidemiology. 1986; 5(2): 88-94 ).

A study of smoking behaviors of 2,138 American smokers who began an eight-year survey in 2002 found that about one-third of individuals reported having quit smoking in the previous year, and about 85% of the original cohort was within the survey period. At least one quit attempt was made and the average smoking cessation rate in the maintained cohort was 3.8%. As a result, most smokers have tried many cessation attempts, but it is still difficult to achieve continuous bans ( Cummings KM, Cornelius ME, Carpenter MJ, et al., Abstract: How Many Smokers Have Tried to Quit? Society for Research on Nicotine and Tobacco .Poster Session 2. March 2013. POS2-65 ).

Existing smoking cessation treatments include CHANTIX (varenicline) and ZYBAN (bupropion SR). However, both CHANTIX and ZYBAN information includes black box warnings. CHANTIX Prescribing Information carries warnings about severe neuropsychiatric events, including typical excitement, hostility, mood changes in depression, behavior or thoughts, and suicidal ideation or suicidal behavior ( CHANTIX (varenicline) (package insert) ), New York, NY: Pfizer Labs, Division of Pfizer; 2012 ). In addition, the warnings indicate that the cardiovascular events found by the integrated analysis were infrequent, but some were reported to be more frequent in individuals treated with CHANTIX; the differences were not statistically significant ( CHANTIX (varenicline) (package insert), New York, NY: Pfizer Labs, Division of Pfizer; 2012 ). ZYBAN prescribing information includes a similar black box warning for severe neuropsychiatric events during treatment and after discontinuation of treatment ( ZYBAN (bupropion hydrochloride) (package insert), Research Triangle Park, NC: GlaxoSmithKline; 2012 ). Other warnings include monitoring individuals who use antidepressants because of increased suicidal thoughts and behavioral and other mental disorders in children, adolescents and youth ( ZYBAN (bupropion hydrochloride) (package insert), Research Triangle Park, NC :GlaxoSmithKline;2012 ).

In addition, weight gain is a recognized side effect of smoking cessation. Quitting smoking resulted in an increase in the weight of about 80% of smokers. The average weight gain during the first year after quitting smoking was 4-5 kg, most of which increased during the first 3 months. This amount of body weight is generally considered to be moderately inconvenient compared to the health benefits of smoking cessation, but 10% to 20% of quitters increase by more than 10 kg. In addition, one-third of all individuals stated that they were unable to lose excess body weight after re-starting smoking, supporting the hypothesis that cumulative smoking attempts to cause cumulative weight gain ( Veldheer S, Yingst J, Foulds G, Hrabovsky S, Berg A Sciamanna C, Foulds J.Once bitten, twice shy:concern about gaining weight after smoking cessation and its association with seeking treatment. Int J Clin Pract. (2014) 68:388-395) .

Given these statistics, it may not be surprising that 50% of female smokers and 25% of male smokers will be afraid of weight loss after smoking cessation (PCWG) as a major barrier to quitting, and about the same proportion will weigh Increased reasons for recurrence of previous cessation attempts ( Meyers AW, Klesges RC, Winders SE, Ward KD, Peterson BA, Eck LH. Are weight concerns predictive of smoking cessation? A prospective analysis. J Consult Clin Psychol. (1997) 65 : 448-452; Clark MM, Decker PA, Offord KP, Patten CA, Vickers KS, Croghan IT, Hays JT, Hurt RD, Dale LC. Weight concerns among male smokers. Addict Behav. (2004) 29: 1637-1641; Clark MM, Hurt RD, Croghan IT, Patten CA, Novotny P, Sloan JA, Dakhil SR, Croghan GA, Wos EJ, Rowland KM, Bernath A, Morton RF, Thomas SP, Tschetter LK, Garneau S, Stella PJ, Ebbert LP , Wender DB, Loprinzi CL. The prevalence of weight concerns in a smoking abstinence clinical trial. Addict Behav. (2006) 31: 1144-1152.; Pomerleau CS, Kurth CL. Willingness of female s Mokers to tolerate postcessation weight gain.J Subst Abuse. (1996) 8:371-378; Pomerleau CS, Zucker AN, Stewart AJ. Characterizing concerns about post cessation weight gain: results from a national survey of women smokers. Nicotine Tob Res. (2001) 3: 51-60 ). Specifically, women hate to increase weight while quitting smoking; about 40% state that if they have any weight gain, they will start smoking again ( Veldheer S, Yingst J, Foulds G, Hrabovsky S, Berg A, Sciamanna C, Foulds J.Once bitten,twice shy:concern about gaining weight after smoking cessation and its association with seeking treatment.Int J Clin Pract.(2014)68:388-395;Pomerleau CS, Kurth CL.Willingness of female smokers to tolerate postcessation weight gain.J Subst Abuse (1996) 8:371-378; Pomerleau CS, Zucker AN, Stewart AJ. Characterizing concerns about post-cessation weight gain: results from a national survey of women smokers. Nicotine Tob Res. (2001) 3: 51-60;T Nnesen P, Paoletti P, Gustavsson G, Russell MA, Saracci R, Gulsvik A, Rijcken B, Sawe U. Higher dosage nicotine patches increase one-year smoking cessation rates: results from the European CEASE trial. Collaborative European Anti-Smoking Evaluation. european Respiratory Society.Eur Respir J. (1999) 13: 238-246).

The industry believes that smokers usually mild and moderate proportion of smokers quit smoking more aggressively, leaving increasingly less likely to stop a high proportion of "hardcore (hard-core)" smoke of smokers (Hughes JR.The hardening Hypothesis: is the ability to quit decreasing due to increasing nicotine dependence? A review and commentary. Drug Alcohol Depend. (2011) 117: 111-117 ). One factor commonly associated with weight gain problems (WGC) is high nicotine dependence; therefore, the expectation of quitting smoking may be even more difficult for smokers with high nicotine dependence and weight concerns. In addition, it is paradoxical that heavy smokers tend to have higher body weight and higher likelihood of obesity in lighter smokers, suggesting a more complex relationship between body weight and smoking ( Chiolero A, Jacot-Sadowski) I, Faeh D, Paccaud F, Cornuz J. Association of cigarettes smoked daily with obesity in a general adult population. Obesity (Silver Spring) (2007) 15: 1311-1318; John U, Hanke M, Rumpf HJ, Thyrian JR. Smoking status,cigarettes per day, and their relationship to overweight and obesity among former and current smokers in a national adult general population sample. Int J Obea (Lond). (2005) 29:1289-1294 ). Several studies have found that overweight and obese smokers exhibit a higher degree of smoking-related weight gain than normal-weight smokers ( Aubin HJ, Berlin I, Smddja E, West R. Factors associated with higher body mass index, weight concern, and weight Gain in a multinational cohort study of smokers intending to quit.Int.J.Environ.Res.Public Health.(2009).6:943-957;Levine MD, Bush T, Magnusson B, Cheng, Y, Chen X.Smoking -related weight concerns and obesity:differences among normal weight,overweight,and obese smokers using a telephone tobacco quitline.Nicotine Tob Res.(2013)15:1136-1140 ). Given the concentration of high nicotine dependence and high weight gain in obese smokers, a smoking cessation intervention that addresses weight gain after smoking cessation may be particularly beneficial for this subgroup.

Although there are several smoking cessation therapies in the industry, the long-term success rate is low and there are still major cessation barriers. There is a significant need in the industry for safe and effective therapies to address these obstacles. The present invention fulfills this need and also provides related advantages.

Prior to this discovery, it was not clear whether selective serotonin 2C receptor agonists could promote clinically meaningful smoking cessation in humans, not to mention specific individuals, or in specific dosing regimens.

The present invention provides a method of reducing the frequency of smoking in an individual attempting to reduce the frequency of smoking, comprising the steps of prescribing an individual and/or administering an effective amount of ( R )-8-chloro-1-methyl- 2,3, 4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides a method of assisting in terminating or reducing the use of a tobacco product to terminate or reduce the use of a tobacco product, comprising the steps of: prescribing an individual and/or administering an effective amount of ( R )-8-chloro-1 Methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides a method for assisting in quitting smoking and preventing weight gain in an individual to quit smoking and preventing related weight gain, comprising the steps of: prescribing an individual and/or administering an effective amount of ( R )-8-chloro-1-methyl Base-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides a method of controlling weight gain associated with smoking cessation in an individual attempting to quit smoking, comprising the steps of: prescribing an individual and/or administering an effective amount of ( R )-8-chloro-1-methyl-2, 3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides a method of treating nicotine dependence, addiction, and/or withdrawal in an individual attempting to treat nicotine dependence, addiction, and/or withdrawal, comprising the steps of: prescribing an individual and/or administering an effective ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof .

The present invention also provides a method of reducing the likelihood of attempting to terminate nicotine use by an individual to re-use nicotine, comprising the steps of: prescribing an individual and/or administering an effective amount of ( R )-8-chloro-1-methyl -2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides a method of reducing weight gain associated with smoking cessation in an individual attempting to quit smoking, comprising the steps of: prescribing an individual and/or administering an effective amount of ( R )-8-chloro-1-methyl-2, 3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides methods for reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking, helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control attempts to quit smoking. The individual's weight gain associated with smoking cessation reduces the weight gain associated with smoking cessation in individuals attempting to quit, and the treatment attempts to treat nicotine dependence, addiction, and/or withdrawal in individuals with nicotine dependence, addiction, and/or withdrawal, Or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine, including: selecting the initial BMI Individuals of 27 kg/m ² ; and prescribe and/or administer an effective amount of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzene to the individual And azepine or a pharmaceutically acceptable salt, solvate or hydrate thereof for at least one year.

The present invention also provides methods for reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking, helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control attempts to quit smoking. The individual's weight gain associated with smoking cessation reduces the weight gain associated with smoking cessation in individuals attempting to quit, and the treatment attempts to treat nicotine dependence, addiction, and/or withdrawal in individuals with nicotine dependence, addiction, and/or withdrawal, Or reduce the likelihood that an individual attempting to terminate the use of nicotine will re-use nicotine, which comprises: administering to the individual ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; monitoring the BMI of the individual during the administration; and if the individual's BMI becomes <18.5 kg/m during the administration period ² , the interruption of the vote.

The present invention also provides methods for reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking, helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control attempts to quit smoking. The individual's weight gain associated with smoking cessation reduces the weight gain associated with smoking cessation in individuals attempting to quit, and the treatment attempts to treat nicotine dependence, addiction, and/or withdrawal in individuals with nicotine dependence, addiction, and/or withdrawal, Or reduce the likelihood that an individual attempting to terminate the use of nicotine will re-use nicotine, including: to the initial BMI Individuals of 25 kg/m ² are administered ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt thereof, a solvate or hydrate; the body weight of the individual is monitored during the administration; and if the individual's body weight is reduced by more than about 1% during the administration, the administration is discontinued.

The present invention also provides methods for reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking, helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control attempts to quit smoking. The individual's weight gain associated with smoking cessation reduces the weight gain associated with smoking cessation in individuals attempting to quit, and the treatment attempts to treat nicotine dependence, addiction, and/or withdrawal in individuals with nicotine dependence, addiction, and/or withdrawal, Or reduce the likelihood that an individual attempting to terminate the use of nicotine will re-use nicotine, which comprises: administering to the individual ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; monitoring the body weight of the individual during the administration; and if the individual's body weight is reduced by more than about 1 kg during the administration period, Interrupt the vote.

The present invention also provides a composition comprising ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzoazepine or a pharmaceutically acceptable salt thereof a solvate or hydrate and at least one extender.

The invention also provides ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt, solvate thereof or Hydrate, which is used in combination with a supplement.

The present invention also provides a supplement selected from the group consisting of nicotine replacement therapy with ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or A pharmaceutically acceptable salt, solvate or hydrate combination is used.

[Detailed description]

As used in this specification, the following words and phrases are generally intended to have the meaning as described below, unless otherwise indicated in the context of their use.

Individual: As used herein, an "individual" is a human. The individual can be an adult or prepubertal (child) and can have any gender. An individual can be a patient or other individual seeking treatment. "Individual" is used interchangeably with "subject" in this article.

A plurality of individuals: As used herein, "a plurality of individuals" means more than one individual.

Administration: As used herein, "administering" means providing a compound or other therapy, treatment or therapy. For example, a health care practitioner may provide a compound in the form of a sample directly to the individual, or may provide the compound indirectly by providing the individual in an oral or written manner to the compound. Moreover, for example, an individual can obtain a compound by itself without the involvement of a health care practitioner. Administration of the compound may or may not involve an individual that actually internalizes the compound. In the case where an individual internalizes a compound, the body is converted by the compound in some manner.

Prescription: As used herein, "prescription" means the use of a prescription, approval or recommendation for a drug or other therapy, treatment or treatment. In some embodiments, a health care practitioner may verbally recommend, recommend, or approve the use of a compound, dosage regimen, or other treatment to an individual. In this case, the health care practitioner may or may not provide a compound, dosage regimen or treatment. In addition, the health care practitioner may or may not provide the recommended compound or treatment. For example, a health care practitioner may suggest where an individual obtains a compound without providing a compound. In some embodiments, a health care practitioner can provide a compound, dosage regimen, or treatment site to an individual. For example, a health care practitioner may give an individual a written or oral prescription. The prescription can be written on paper or on an electronic medium, such as a computer file on a handheld computer device. For example, a health care practitioner can convert a piece of paper or electronic media into a compound, dosage regimen, or treatment. In addition, the prescription can be notified by phone (verbal) or by telex (written) in the drug delivery room or in the dispensing room. In some embodiments, an individual compound or a sample of treatment can be administered. As used herein, a sample administered to a compound constitutes an implicit prescription for the compound. Different health care systems use different methods worldwide to prescribe and administer compounds or treatments, and the present invention encompasses such methods.

The prescription may include, for example, the name of the individual and/or authentication information (eg, birthday). Additionally, for example, the prescription may include the name of the medicament, the strength of the medicament, the dose, the frequency of administration, the route of administration, the number or amount of doses to be dispensed, the number of refills, the name of the physician, and/or the signature of the physician. Additionally, for example, the prescription may include a DEA number or a status number.

Health care practitioners include, for example, physicians, nurses, nurse practitioners, or other related health care professionals who can prescribe or administer a compound (drug) for weight management, smoking cessation or nicotine dependence. In addition, health care practitioners can include anyone who can recommend, prescribe, administer a compound or drug to an individual, or prevent an individual from receiving a compound or drug, including, for example, an insurance provider.

PREVENT, PREVENTING, or PRECTORION: As used herein, the term "prevent, prevention, or prevention" (eg, prevention of weight gain associated with smoking cessation) means prevention of one or more specific conditions The occurrence or onset of a related symptom does not necessarily mean complete prevention of the condition. For example, an individual can prevent weight gain even if he increases a certain amount of body weight.

For example, the term "prevent, prevention, and prevention" refers to the administration of a therapy to an individual who may ultimately exhibit at least one symptom of the disease or condition but has not yet exhibited the at least one symptom on a protective or preventive basis. Such individuals can be identified based on risk factors known to be associated with subsequent occurrence of the disease. Alternatively, preventive therapy can be administered as a protective measure without prior identification of risk factors. Delaying the onset of at least one symptom can also be considered preventive or protective.

Pharmaceutically acceptable salts, solvates and hydrates: it is to be understood as a phrase "a plurality of pharmaceutically acceptable salts, solvates and hydrates" or in the phrase "pharmaceutically acceptable salts, solvates or "Hydrate" as used herein, when referring to a compound/multiple compounds as described herein, encompasses a pharmaceutically acceptable solvate and/or hydrate of the compound/multiple compounds, a pharmaceutically acceptable salt of the compound/multiple compounds, And pharmaceutically acceptable solvates and/or hydrates of the pharmaceutically acceptable salts of the compounds/multiple compounds. It should also be understood that the phrase "a plurality of pharmaceutically acceptable solvates and hydrates" or the phrase "pharmaceutically acceptable solvate or hydrate" is used to mean a compound as described herein. In the meantime, it encompasses pharmaceutically acceptable solvates and/or hydrates of such salts. Those skilled in the art will also appreciate the subgenus of hydrate solvates.

TREAT, TREATING, or TREATMENT: As used herein, the term "treat, treating, or treating" refers to a disease, condition, condition, dependence, or behavior that has been or has been previously manifested. An individual with at least one symptom is administered therapy. For example, "treatment" can include any of the following regarding a disease, disorder, condition, dependence, or behavior: mitigating, attenuating, ameliorating, inhibiting (eg, preventing development), relieving, or causing regression. "Treatment" may also include treating a symptom, preventing other symptoms, preventing a potential physiological cause of the condition, or terminating the disease, condition, condition, dependence or behavior (in a protective manner and/or treatment). For example, the term "treatment" when referring to a condition means reducing the severity of one or more symptoms associated with a particular condition. Thus, treating a condition does not necessarily mean reducing the severity of all symptoms associated with the condition and does not necessarily mean completely reducing the severity of one or more symptoms associated with the condition. For example, methods for treating obesity can cause weight loss; however, weight loss need not be sufficient to render the individual no longer obese. It has been shown that even a modest reduction in body weight or related parameters (eg, BMI, waist circumference, and body fat %) can improve health, such as lowering blood pressure, improving blood lipid profile, or reducing sleep apnea. In addition, smoking has been shown to be an independent and major risk factor for cardiovascular disease. Therefore, reducing or terminating tobacco use (eg, smoking) can improve health, specifically cardiovascular health.

Weight Management: As used herein, the term "weight management" refers to controlling body weight (also known as weight management) and/or controlling weight-related parameters (eg, BMI, body fat %, and/or waist circumference). In the context of the present invention, body weight control is directed to preventing weight gain, controlling weight gain, reducing weight gain, maintaining body weight or causing weight loss. In addition, weight management includes prevention of an increase in BMI, reduction of BMI, maintenance of BMI or reduction of BMI; prevention of an increase in body fat %, reduction of body fat %, maintenance of body fat % or reduction of body fat %; Prevent the increase in waist circumference, reduce the increase in waist circumference, maintain waist circumference or reduce waist circumference.

Adverse events or toxic events: As used herein, "adverse events" or "toxic events" are any adverse medical events that can manifest themselves during treatment. Treatment-related adverse events may include, for example, headache, nausea, constipation, fatigue, dry mouth, dizziness, dreams, insomnia, nasopharyngitis, toothache, sinusitis, back pain, narcolepsy, viral gastroenteritis, seasonal allergies or Physical pain. Other possible adverse effects include, for example, gastrointestinal disorders (such as constipation, bloating and diarrhea), weakness, chest pain, fatigue, drug hypersensitivity, fibromyalgia, temporomandibular joint syndrome, headache, dizziness, migraine, anxiety, depression, Irritable, suicidal ideation, two-way emotional illness, depression, drug abuse and difficulty breathing. In the methods disclosed herein, the term "adverse event" can be replaced by other general terms such as "toxicity." The term "reducing the risk of adverse events" means reducing the likelihood that an adverse event or a toxic event can occur.

Agonist: As used herein, the term "agonist" refers to a compound that interacts with and activates a receptor (eg, a 5-HT _2C serotonin receptor) and initiates the physiological or pharmacological response of the receptor. section.

Immediate Release Formulation: The term "immediate release dosage form" refers to a formulation that rapidly disintegrates after oral administration to a human or other animal, thereby releasing the active pharmaceutical ingredient (API) from the formulation. In some embodiments, the T80% of the immediate release dosage form is less than 3 hours. In some embodiments, the T80% of the immediate release dosage form is less than one hour. In some embodiments, the T80% of the immediate release dosage form is less than 30 minutes. In some embodiments, the T80% of the immediate release dosage form is less than 10 minutes.

T80%: The term "T80%" refers to the time required to achieve an 80% cumulative release of API from a specific formulation containing the API.

Modified release dosage form: The term "modified release dosage form" refers to the release of an API (ie, delayed release) after a given time of oral administration to a human or other animal or the release of an API over an extended period of time (extended release), eg, with an API Any formulation in which the immediate release dosage form releases the API (e.g., sustained release) over a prolonged period of time at a slower rate. Exemplary modified release dosage forms are set forth in WO2012/030927. In some embodiments, the modified release dosage form comprises: a core comprising about 20.8 mg lorcaserin HCl hemihydrate, about 60 mg microcrystalline cellulose, about 65.5 mg mannitol, about 150 mg hydroxypropyl methyl Cellulose, about 0.75 mg of colloidal cerium oxide and about 3 mg of magnesium stearate; a functional coating comprising about 12.75 mg of a Type B ethylcellulose dispersion and about 2.25 mg of OPADRY; and a film coating comprising Approximately 13.5 mg of OPADRY II.

Nicotine Replacement Therapy: As used herein, "nicotine replacement therapy" (often abbreviated as NRT) refers to the remedial administration of nicotine to the body by means other than tobacco products. For example, nicotine replacement therapy can include transdermal nicotine delivery systems, including patches, and other systems described in the art, for example, in U.S. Patent Nos. 4,597,961, 5,004,610, 4,946,853, and 4,920,989. Inhaled nicotine is also known in the art (e.g., delivery of nicotine via the pulmonary route). Transmucosal administration is also known in the art (e.g., delivery of nicotine to the systemic circulation via oral pharmaceutical dosage forms). Oral pharmaceutical dosage forms (eg, diamond tablets, capsules, chewable tablets, troches, suppositories, ointments, gels, pessaries, films, and powders) typically remain in contact with the mucosa and rapidly disintegrate and/or dissolve to allow immediate Whole body absorption. Those skilled in the art will appreciate that a plurality of different treatments and modes of administration can be used to treat a single individual. For example, nicotine administered transdermally and nicotine administered to the mucosa can be used simultaneously to treat an individual. In some embodiments, the nicotine replacement therapy is selected from the group consisting of a nicotine chewable tablet (eg, NICORETTE), a nicotine transdermal system (eg, a nicotine patch such as HABITROL and NICODERM), a nicotine diamond tablet (eg, COMMIT), a nicotine sublingual tablet ( For example, NICORETTE sublingual tablets, nicotine sprays or inhalants (such as NICOTROL) and other nicotine replacement therapies known in the art. In some embodiments, the nicotine replacement therapy comprises an electronic cigarette, a vaporizer, and an electronic nicotine delivery system.

Combination: As used herein, "combination" is used to refer to a pharmaceutical combination and / or ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzene The combination of azepine or a pharmaceutically acceptable salt, solvate or hydrate thereof with at least one extender means that (1) comprises two or more combinations or mixtures physically or chemically or otherwise a product produced by a single entity (ie, a drug/device, biologic/device, drug/biological agent, or drug/device/biological agent); (2) packaged together in a single package or packaged as a unit and containing the drug and Two or more separate products of device products, devices and biological products or biological and pharmaceutical products; (3) individually packaged drugs, devices or biological products, according to their research plan or proposal, only need to achieve both In the case of an intended use, indication or effect and after approval of the proposed product, the label of the approved product needs to be changed, for example, to reflect the intended use, dosage form, strength, change in the route of administration or significant dose change, and approved Individually designated drugs, devices or biological products Use; or (4) any research-type drug, device, or biological product packaged separately, in accordance with its proposed label, in the case where both are required to achieve the intended use, indication, or effect, and another research drug specified Use with devices or biologic products. Combinations include, but are not limited to, fixed dose combination products (FDC) in which two or more separate drug components are combined in a single dosage form; co-packaged products containing two or more separate drugs in their final dosage form a product, packaged with a suitable label to support a combination; and an adjunctive therapy wherein the patient is maintained on another pharmaceutical product for use with the primary treatment (ie, assisted), but does not fix the relative dose and does not have to be administered simultaneously Or a biological agent. The adjunctive therapy products can be co-packaged and can or can be used for simultaneous use without labeling.

Reactant: As used herein, "reactant" means ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or A pharmaceutically acceptable salt, solvate or hydrate that undergoes a continuous ban on tobacco use during a specified period of administration. In some embodiments, "reactor" means self-administered lorcaserin hydrochloride hemihydrate from week 9 to week 12 reporting no smoking or other nicotine use and exhibiting An exhaled end of 10 ppm exhaled an individual whose measurement was confirmed by carbon monoxide.

Tobacco Product: As used herein, "tobacco product" means an agricultural product that is incorporated into a tobacco product, that is, a plant leaf of Nicotiana . Tobacco products can generally be divided into two types: tobacco, including but not limited to pipe tobacco, cigarettes (including electronic cigarettes) and cigars, and Mu'assel, Dokha, and Shisha. Tobacco, hookah tobacco or simply Shisha; and smokeless tobacco, including but not limited to chewing tobacco, buccal tobacco (also known as buccal), wet snuff (or snuff), American snus , Swedish snuff (snus), Iqmik, Naswar, Gutka, Toombak, shammah, tobacco, sporadic tobacco , snuff cream or tobacco extract, soluble tobacco and smoke gum.

FAGERSTRÖM test: As used herein, the "Fagerström test" is a standard test for nicotine dependence, which is used to evaluate the strength of nicotine addiction. See Heatherton, TF, Kozlowski, LT, Frecker, RC, Fagerström, KO The Fagerström test for Nicotine Dependence: A revision of the Fagerström Tolerance Questionnaire . Br J Addict 1991; 86: 1119-27 . The test consisted of a simple self-reported survey measuring nicotine dependence on the scale of 0-10, with 10 lines being the highest dependency level. A score of 0-2 corresponds to a very low dependency. A score of 3-4 corresponds to a low dependency. A score of 5 corresponds to a medium dependency. A score of 6-7 corresponds to a high dependency. A score of 8-10 corresponds to a very high dependency.

Other methods can be used to evaluate the desire for nicotine, including but not limited to the nicotine craving test specified by the Diagnostic and Statistical Manual of Mental Disorders, Third Revision (DSM-III-R).

Emotional and Physical Symptoms Scale: As used herein, the Emotional and Physical Symptoms Scale (MPSS) is a scale used to evaluate cigarette withdrawal symptoms ( West R, Hajek P: Evaluation of the mood and physical phenomena scale) (MPSS) to assess cigarette withdrawal. Psychopharmacology 2004, 177(1-2): 195-199 ). The core elements of MPSS are the five-point grading of depression, irritability, restlessness, inattention, and hunger, as well as the intensity of craving for smoking and the 6-point grading of the time spent on such cravings.

Chlorosin: As used herein, lorcaserin refers to ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine. Similarly, lorcaserin hydrochloride refers to the hydrochloride salt of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine ( See Statement on Nonproprietary Name Adopted by the USAN Council for Lorcaserin Hydrochloride ).

As used herein, the term "greater than" can be used interchangeably with the symbol > and the term "less than" can be used interchangeably with the symbol <. Similarly, the term is less than or equal to the symbol Used interchangeably, and the term is greater than or equal to the signable Used interchangeably.

When an integer is used in the methods disclosed herein, the term "about" can be inserted before the integer. For example, the term "greater than 29 kg/m ² " may be replaced by "greater than about 29 kg/m ² ".

As used in this specification, the following abbreviations are generally intended to have the meanings as described below, unless otherwise indicated in the context of their use.

Throughout the specification, unless the context requires otherwise, the words "comprise" or variations such as "comprises" or "comprising" are to be understood as implying the inclusion of the steps or elements or An integer or a step or a group of elements or integers, but does not exclude any other steps or elements or groups of integers or elements or integers.

Throughout the specification, a reference to a single step, a combination of materials, a group of steps, or a group of combinations of substances, unless otherwise specified or the context requires otherwise, One or more of the group of substances, groups of steps, or combinations of substances (ie, one or more).

Each of the embodiments described herein is intended to be applied to each and every other embodiment, as appropriate.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The present invention also includes, individually or collectively, all of the steps, features, compositions and compounds referred to or indicated in the specification, and any and all combinations or any of the steps or features. Or more.

The scope of the invention is not intended to be limited to the particular embodiments described herein, and is intended for the purpose of illustration. Functionally equivalent products, compositions and methods are well within the scope of the invention.

It is to be understood that certain features of the invention may be Instead, the various features set forth in the context of a single embodiment for the sake of brevity may be provided individually or in any suitable sub-combination. For example, the method of prescribing or administering ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine can be divided into two methods, one Listed as ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine and the other cited ( R )-8- Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine. Further, for example, include prescription (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro-benzo N -1 H -3- Boom method of administration, and include (R) - 8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine The individual methods of the invention may be combined for enumeration and/or administration ( R )-8 -Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine in a single method.

Figure 1 shows a schematic of the study design used in the Phase 2 clinical trial described in Example 3.

Figures 2 and 3 show the baseline characteristics of individuals in phase 2 clinical trials.

Figure 4 shows the configuration of individuals in Phase 2 clinical trials.

Figure 5 shows a 4-week CAR confirmed by CO for weeks 9 to 12 in the MITT population from Phase 2 clinical trials. The "n" in Figure 5-8 reports no smoking (even without a cigarette or other nicotine use) and shows The number of individuals with an end-expiratory CO content of 10 ppm.

Figure 6 shows a 4-week CAR for CO confirmation from week 5 to week 8 in the MITT population.

Figure 7 shows the 4-week CAR for CO confirmation from week 5 to week 12 in the MITT population.

Figure 8 shows a 4-week CAR for CO confirmation from week 3 to week 12 in the MITT population.

Figure 9 shows the 7-day quit rate at week 12 in the MITT population. The "n" in Figure 9 continues to be banned for 7 days before the clinical visit and shows The number of individuals with an end-expiratory CO content of 10 ppm.

Figure 10 shows the change in the number of cigarettes smoked from baseline at week 12 in the MITT population.

Figure 11 shows the change in body weight (expressed in kg) from baseline at week 12 in the MITT population.

Figure 12 shows the change in body weight (expressed in kg) from baseline at the 12th week for responders in the MITT population. The "Responders" in Figure 12 have continued to ban and show up for 4 weeks from Week 9 to Week 12. Individual with a 10 ppm expiratory end CO content.

Figure 13 shows the change in body weight (expressed in kg) from baseline at week 12 as a function of responder status in the MITT population. The "Responders" in Figure 13 have continued to ban and show up for 4 weeks from Week 9 to Week 12 Individual with a 10 ppm expiratory end CO content.

Figure 14 shows the change in body weight (expressed in kg) from baseline at week 12 by baseline BMI in the MITT population.

Figure 15 shows the change in body weight (expressed in kg) from baseline at week 12 by baseline BMI in the MITT population.

Figure 16 shows the change in body weight (expressed in kg) from baseline at week 12 by baseline BMI and responder status in the MITT population. The "Responders" in Figure 16 have continued to ban and show up for 4 weeks from Week 9 to Week 12. Individual with a 10 ppm expiratory end CO content.

Figure 17 shows an overview of treatment for emergency adverse events in a phase 2 clinical trial.

Figure 18 shows the efficacy and efficacy of lorcaserin in human, rat and monkey 5-HT _2A , 5-HT _2B and 5-HT _2C receptors.

Figure 19 shows the difference in exposure and 5-HT ₂ receptor selectivity in humans and rats.

The present invention provides a method for assisting in terminating or reducing the use of a tobacco product to terminate or reduce the use of a tobacco product, comprising the steps of: prescribing an individual and/or administering an effective amount of ( R )-8-chloro-1- Methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, helping to terminate the use of the tobacco product is to help quit smoking, and attempts to terminate the individual in which the tobacco product is used to attempt to quit.

The present invention also provides a method of assisting in the use of a tobacco product and preventing associated weight gain, comprising the steps of prescribing and/or administering an effective amount of ( R )-8-chloro-1 to an individual attempting to terminate the use of the tobacco product. Methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, helping to terminate the use of the tobacco product is to help quit smoking, and attempts to terminate the individual in which the tobacco product is used to attempt to quit.

The present invention also provides a method of reducing an individual attempt to reduce the incidence of smoking frequency of smoking, comprising the steps of: prescribing and / or administering an effective amount of of (R) -8-chloro- l-methyl-2,3 , 4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides a method of controlling weight gain associated with smoking cessation in an individual attempting to quit smoking, comprising the steps of: prescribing an individual and/or administering an effective amount of ( R )-8-chloro-1-methyl-2, 3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides a method of reducing weight gain associated with smoking cessation in an individual attempting to quit smoking, comprising the steps of: prescribing an individual and/or administering an effective amount of ( R )-8-chloro-1-methyl-2, 3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides a method of treating nicotine dependence, addiction, and/or withdrawal in an individual attempting to treat nicotine dependence, addiction, and/or withdrawal, comprising the steps of: prescribing an individual and/or administering an effective ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof .

The present invention also provides a method of reducing the likelihood of attempting to terminate nicotine use by an individual to re-use nicotine, comprising the steps of: prescribing an individual and/or administering an effective amount of ( R )-8-chloro-1-methyl -2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides methods for reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking, helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control attempts to quit smoking. The individual's weight gain associated with smoking cessation reduces the weight gain associated with smoking cessation in individuals attempting to quit, and the treatment attempts to treat nicotine dependence, addiction, and/or withdrawal in individuals with nicotine dependence, addiction, and/or withdrawal, Or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine, which includes: Selecting the initial BMI Individuals of 27 kg/m ² ; and prescribe and/or administer an effective amount of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzene to the individual And azepine or a pharmaceutically acceptable salt, solvate or hydrate thereof for at least one year.

The present invention also provides methods for reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking, helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control attempts to quit smoking. The individual's weight gain associated with smoking cessation reduces the weight gain associated with smoking cessation in individuals attempting to quit, and the treatment attempts to treat nicotine dependence, addiction, and/or withdrawal in individuals with nicotine dependence, addiction, and/or withdrawal, Or reduce the likelihood that an individual attempting to terminate the use of nicotine will re-use nicotine, which comprises: administering to the individual ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; monitoring the BMI of the individual during the administration; and if the individual's BMI becomes <18.5 kg/m during the administration period ² , the interruption of the vote.

The present invention also provides methods for reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking, helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control attempts to quit smoking. The individual's weight gain associated with smoking cessation reduces the weight gain associated with smoking cessation in individuals attempting to quit, and the treatment attempts to treat nicotine dependence, addiction, and/or withdrawal in individuals with nicotine dependence, addiction, and/or withdrawal, Or reduce the likelihood that an individual attempting to terminate the use of nicotine will re-use nicotine, including: to the initial BMI Individuals of 25 kg/m ² are administered ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt thereof, a solvate or hydrate; the body weight of the individual is monitored during the administration; and if the individual's body weight is reduced by more than about 1% during the administration, the administration is discontinued.

In some embodiments, if the individual's body weight is reduced by more than about 2% during the administration, the administration is discontinued. In some embodiments, if the individual's body weight is reduced by more than about 3% during the administration, the administration is discontinued. In some embodiments, if the individual's body weight is reduced by more than about 4% during the administration, the administration is discontinued. In some embodiments, if the individual's body weight is reduced by more than about 5% during the administration, the administration is discontinued.

The present invention also provides methods for reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking, helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control attempts to quit smoking. The individual's weight gain associated with smoking cessation reduces the weight gain associated with smoking cessation in individuals attempting to quit, and the treatment attempts to treat nicotine dependence, addiction, and/or withdrawal in individuals with nicotine dependence, addiction, and/or withdrawal, Or reduce the likelihood that an individual attempting to terminate the use of nicotine will re-use nicotine, which comprises: administering to the individual ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; monitoring the body weight of the individual during the administration; and if the individual's body weight is reduced by more than about 1 kg during the administration period, Interrupt the vote.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvate The substance or hydrate is used as an auxiliary agent for smoking cessation treatment. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvate The substance or hydrate is used as a smoking cessation aid. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvate The substance or hydrate is used as an adjuvant for smoking cessation treatment and prevention of related weight gain. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvate The substance or hydrate is used as a weight neutralization intervention for smoking cessation. In some embodiments, weight gain occurs during smoking cessation. In some embodiments, weight gain occurs after quitting smoking.

Any embodiment of the invention with respect to quitting smoking or terminating or reducing the use of a tobacco product may be adapted to terminate or reduce the use of nicotine administration of any and all sources or any individual source, including tobacco products (or specific examples thereof) ), tobacco replacement therapy (or a specific example thereof) and/or any electronic nicotine delivery system (eg, an electronic cigarette or personal vaporizer). The present invention expressly covers all such embodiments.

"Selectivity" as disclosed herein refers to a relative comparison of the effects of an agonist on two or more receptors. In some embodiments, selectivity refers to the relative in vitro potency of an agonist for both receptors. In some embodiments, the in vitro potency is quantified using a second messenger analysis. In some embodiments, the in vitro potency EC ₅₀ by lines quantified. In some embodiments, selectivity refers to the relative binding affinity of an agonist to both receptors. In some embodiments, the binding affinity is quantified by Ki. In some embodiments, selectivity is measured by comparing data generated from an IP cumulative analysis. In some embodiments, the selectivity is measured by comparing data generated from calcium analysis. In some embodiments, selectivity is measured by comparing data generated from DOI analysis. In some embodiments, the selectivity values are determined using the in vitro potency values generated in the analysis according to Example 2. For methods to ensure the accuracy of in vitro efficacy values, see Cavero I and Guillon JM. Safety Pharmacology assessment of drugs with biased 5-HT _2B receptor agonism mediating cardiac valvulopathy. J Pharmacological and Toxicological Methods 69 (2014); 150-161 ).

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine and a pharmaceutically acceptable salt thereof, solvate And hydrates encompassing any of the following salts or a Markush group comprising any combination of the following salts, such as WO2006/069363, WO2012/030927, WO2012/030938, WO2012/030951 and WO2012/ ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine hydrochloride; ( R )-8-chloro- 1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hydroiodide; ( R )-8-chloro-1-methyl-2,3,4,5 -tetrahydro-1 H -3-benzoazepine maleate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzonitrile呯Fumarate; and ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hemifumarate; ( R )- 8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine lactate; ( R )-8-chloro-1-methyl-2,3 , 4,5-tetrahydro-1 H -3-benzoazepine di-acetamidobenzoate-co-crystal; ( R )-8-chloro-1-methyl-2,3,4, 5-tetrahydro-1 H -3-benzoazepine trans-cinnamate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3- Benzoazinium naphthalene disulfonate ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine (±)-mandelate; ( R )-8-chloro- 1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hemi-hydroxynaphthoate; ( R )-8-chloro-1-methyl-2,3,4 ,5-tetrahydro-1 H -3-benzoazepine (1 S )-(+)-10-camphorsulfonate; ( R )-8-chloro-1-methyl-2,3,4, 5-tetrahydro-1 H -3-benzoazepines-L-malate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3 - benzo nitrogen Boom L- glutamate; (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro-benzo -1 H -3- L- asparagine amine nitrogen Boom ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hemi-mucosate; ( R )-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine glutamate; ( R )-8-chloro-1-methyl-2,3,4,5 -tetrahydro-1 H -3-benzoazepine glucuronide; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine Bis(2-)camphorate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hydrogensulfate; ( R )-8- Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hemisulfate; ( R )-8-chloro-1-methyl-2,3,4, benzo-tetrahydro -1 H -3- nitrogen Boom methanesulfonate; (R) -8- chloro-l-methyl-2,3,4,5-tetracarboxylic N -1 H -3- benzo Boom hydrobromide; (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro-benzo -1 H -3- nitrate nitrogen and Boom ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine sesqui-oxalate-co-crystal; ( R )-8- Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine adipate; ( R )-8-chloro-1-methyl-2,3,4 , benzo-tetrahydro -1 H -3- nitrogen Boom malonate; (R) -8- chloro-l -methyl-2,3,4,5-tetrahydro -1 H -3- benzene And ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine glycolate; ( R )- 8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine-semi-ethanedisulfonate; ( R )-8-chloro-1-methyl- 2,3,4,5-tetrahydro-1 H -3-benzoazepine phosphate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H - 3-benzoxazide citrate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hemi-oxalate; R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine succinate; and ( R )-8-chloro-1-methyl- 2,3,4,5-tetrahydro-1 H -3-benzoazepine glutarate; and pharmaceutically acceptable solvates and hydrates thereof.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine and a pharmaceutically acceptable salt thereof, solvate And the hydrates of any of the following salts or a combination of the following salts, as disclosed in WO2006/069363, WO2012/030927, WO2012/030938, WO2012/030951, and WO2012/030957 :( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hydrochloride; ( R )-8-chloro-1-methyl -2,3,4,5-tetrahydro-1 H -3-benzoazepine hydrochloride hemihydrate; ( R )-8-chloro-1-methyl-2,3,4,5-tetra Hydrogen-1 H -3-benzoazepine hydrochloride hydrate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hydrogen bromate; (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro-benzo -1 H -3- nitrogen Boom hydroiodide; (R) -8- chloro - 1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine maleate; ( R )-8-chloro-1-methyl-2,3,4,5 -tetrahydro-1 H -3-benzoazepine fumarate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine Indole hemifumarate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine lactate; ( R )-8 -Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine orotate hydrate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine-2 - acetaminophen benzoate-co-crystal methyl ethyl ketone solvate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3- Benzodiazepine trans-cinnamate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hemi-naphthalenedisulfonate ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazaquinonenaphthalene disulfonate solvate 1; ( R )-8 -Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hemi-naphthalene disulfonate solvate 2; ( R )-8-chloro-1-methyl -2,3,4,5-tetrahydro-benzo nitrogen Boom -1 H -3- (±) - mandelate monohydrate; (R) -8- chloro-l-methyl-2,3,4,5 ,5-tetrahydro-1 H -3-benzoazepine hemi-hydroxynaphthoate hydrate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine (1 S )-(+)-10-camphorsulfonate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H - 3-benzoxazinium-L-malate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine L-gluten Amine; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine L-aspartate; ( R )-8 -Chloro-1-methyl-2,3, 4,5-tetrahydro-1 H -3-benzoazepine hemi-mucosate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3- Benzodiazepine pyroglutamate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine glucuronide; ( R -8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine di-camphorate solvate; ( R )-8-chloro-1- Methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hydrogensulfate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydrogen -1 H -3-benzoazepine hemisulfate salt hydrate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine sulfonate; (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro-benzo -1 H -3- nitrogen Boom hydrobromide hemihydrate; (R) -8 -Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine nitrate; ( R )-8-chloro-1-methyl-2,3,4, 5-tetrahydro-1 H -3-benzoazepine sesqui-oxalate-co-crystal; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine adipate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine malonate; ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine semi-malonate; ( R )-8-chloro-1-methyl Base-2,3,4,5-tetrahydro-1 H -3-benzoazepine Glycolate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hemi-ethanedisulfonate; ( R )-8 -Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine phosphate; ( R )-8-chloro-1-methyl-2,3,4, 5-tetrahydro-1 H -3-benzoazepine citrate hemihydrate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3- Benzodiazepine hemi-oxalate; ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3--3-benzoazepine succinate; ( R ) -8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine glutarate; and ( R )-8-chloro-1-methyl- 2,3,4,5-Tetrahydro-1 H -3-benzoazepine glutarate solvate.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt or solvate thereof or a hydrate thereof selected from (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro -1H-3- HCl salts and solvates or hydrates of the benzo nitrogen and Boom.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt or solvate thereof Or the hydrate is selected from the group consisting of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrates and pharmaceutically acceptable salts thereof.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt or solvate thereof Or a hydrate of the HCl salt of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt or solvate thereof Or the hydrate is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvate The compound or hydrate is ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine hydrochloride or a solvate or hydrate thereof.

It will be apparent to those skilled in the art that the dosage forms described herein can comprise a compound described herein, a pharmaceutically acceptable salt of a compound described herein, a solvate or hydrate of a compound described herein, or A solvate or hydrate of a pharmaceutically acceptable salt of the compound is used as an active ingredient. In addition, various hydrates and solvates of the compounds described herein and salts thereof will be used as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for the preparation and identification of suitable hydrates and solvates other than the hydrates and solvates mentioned herein are well known to those skilled in the art; for example, see KJ Guillory, "Generation of Polymorphs, Hydrates, Solvates. , and Amorphous Solids, "Polymorphism in Pharmaceutical Solids, edited by Harry G. Britain, Vol. 95, Marcel Dekker, New York, 1999 , pp. 202-209. Accordingly, one aspect of the present invention relates to a method of administering a hydrate and a solvate of a compound described herein and/or a pharmaceutically acceptable salt thereof, which can be isolated and characterized by methods known in the art. Known methods are, for example, thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high-resolution X-ray diffraction, and the like. . There are several commercial entities in the industry that provide fast and efficient services for identifying solvates and hydrates on a routine basis. Exemplary companies that provide such services include Wilmington PharmaTech (Wilmington, DE), Avantium Technologies (Amsterdam), and Aptuit (Greenwich, CT).

The invention includes all isotopes of atoms occurring in the salts of the invention and their crystalline forms. Isotopes include those atoms that have the same atomic number but different mass numbers. One aspect of the invention includes each combination of one or more of the salts of the invention and their crystalline forms replaced by atoms having the same atomic number but different mass numbers. One such example replaces a salt of the invention and its crystals with a different atom that is not the most abundant isotope of nature (eg ² H or ³ H (instead of ¹ H), or ¹¹ C, ¹³ C or ¹⁴ C (instead of ¹² C)) The atom found in the type is the most abundant isotope of nature (for example, ¹ H or ¹² C). The salt in which this substitution occurs is commonly referred to as isotopically labeled. The isotope labeling of the salts of the invention and their crystalline forms can be accomplished using any of a variety of different synthetic methods known to those skilled in the art, and it is believed that it is readily understood that the synthetic methods required to carry out the isotope labeling are available Reagents. By way of example and not limitation, hydrogen isotopes include ² H (氘) and ³ H (氚). Carbon isotopes include ¹¹ C, ¹³ C and ¹⁴ C. The nitrogen isotopes include ¹³ N and ¹⁵ N. Oxygen isotopes include ¹⁵ O, ¹⁷ O and ¹⁸ C. The fluorine isotopes include ¹⁸ F. The sulfur isotopes include ³⁵ S. The isotope of chlorine includes ³⁶ Cl. The isotopes of bromine include ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. The isotopes of iodine include ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I. Another aspect of the invention includes compositions, such as those prepared during synthesis, pre-formulations, and the like; and pharmaceutical compositions, for example, intended for use in the treatment of one or more of the conditions described herein in a mammal And the like, comprising one or more of the salts of the invention and their crystalline forms, wherein the natural distribution of the isotopes in the composition is disturbed. Another aspect of the invention includes compositions and pharmaceutical compositions comprising a salt as described herein and a crystalline form thereof, wherein the salt is enriched at one or more locations in addition to the most abundant isotopes of nature. A variety of methods can be readily employed to measure the isotope scrambling or enrichment, such as mass spectrometry, and other methods can be used for the isotope of the radioisotope, such as using a radio detector in conjunction with HPLC or GC.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof is administered Before the solvate or hydrate, the individual smokes daily 10 cigarettes. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof is administered Before the solvate or hydrate, the individual smokes 11-20 cigarettes a day. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof is administered Prior to the solvate or hydrate, the individual smoked 21-30 cigarettes per day. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof is administered Before the solvate or hydrate, the individual smokes daily 31 cigarettes.

In some embodiments, the individual's initial BMI is selected from one of the following: 24kg/m ² , 23kg/m ² , 22.5kg/m ² , 22kg/m ² , 21kg/m ² , 20kg/m ² , 19kg/m ² or 18.5kg/m ² . In some embodiments, the individual's initial BMI prior to administration 23kg/m ² . In some embodiments, the individual's initial BMI prior to administration 22.5kg / m ^2. In some embodiments, the individual's initial BMI prior to administration 22kg/m ² . In some embodiments, the individual's initial BMI prior to administration 18.5kg/m ² . In some embodiments, the individual's initial BMI prior to administration 18kg/m ² . In some embodiments, the individual's initial BMI prior to administration 17.5 kg/m ² . In some embodiments, the individual has an initial body mass index prior to administration 25 kg/m ² and at least one body weight related comorbid condition.

In some embodiments, the individual's initial body mass index prior to administration 27kg/m ² . In some embodiments, the individual has an initial body mass index prior to administration 27 kg/m ² and at least one body weight related comorbid condition.

In some embodiments, the weight-related comorbid condition is selected from the group consisting of hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea. In some embodiments, the weight-related comorbid condition is selected from the group consisting of hypertension, dyslipidemia, and type 2 diabetes.

In some embodiments, the individual's initial body mass index prior to administration 30kg/m ² .

In some embodiments, prior to the initial administration of the subject based BMI 18.5kg / m ² to 25kg / m ^2.

In some embodiments, the individual is administered ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable compound thereof Salt, solvate or hydrate precedes depression.

In some embodiments, the individual is administered ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable compound thereof Salts, solvates or hydrates have previously suffered from both mental illnesses.

In some embodiments, the psychiatric disorder is selected from the group consisting of schizophrenia, a two-way affective disorder, or major depression.

In some embodiments, the individual's nicotine dependence is assessed based on the Fagerström test. In some embodiments, the individual score is 0, 1, or 2. In some embodiments, the individual score is 3 or 4. In some embodiments, the individual has a score of 5. In some embodiments, the individual score is 6 or 7. In some embodiments, the individual has a score of 8, 9, or 10. In some embodiments, the individual's score 3. In some embodiments, the individual's score 5. In some embodiments, the individual's score 6. In some embodiments, the individual's score 8.

In some embodiments, the individual has a Fagerström score of 0, 1 or 2 and a BMI < 25 kg/m ² . In some embodiments, the individual's Fagerström score is 0, 1, or 2 and BMI 25kg / m ² and <30kg / m ^2. In some embodiments, the individual's Fagerström score is 0, 1, or 2 and BMI 30kg/m ² .

In some embodiments, the individual has a Fagerström score of 3 or 4 and a BMI < 25 kg/m ² . In some embodiments, the individual's Fagerström score is 3 or 4 and the BMI 25kg / m ² and <30kg / m ^2. In some embodiments, the individual's Fagerström score is 3 or 4 and the BMI 30kg/m ² .

In some embodiments, the individual ratings of 5 and Fagerström BMI <25kg / m ^2. In some embodiments, the individual's Fagerström score is 5 and BMI 25 kg/m ² and <30 kg/m ² . In some embodiments, the individual's Fagerström score is 5 and BMI 30kg/m ² .

In some embodiments, the individual has a Fagerström score of 6 or 7 and a BMI < 25 kg/m ² . In some embodiments, the individual's Fagerström score is 6 or 7 and BMI 25 kg/m ² and <30 kg/m ² . In some embodiments, the individual's Fagerström score is 6 or 7 and BMI 30kg/m ² .

In some embodiments, the individual has a Fagerström score of 8, 9 or 10 and a BMI < 25 kg/m ² . In some embodiments, the individual's Fagerström score is 8, 9 or 10 and BMI 25 kg/m ² and <30 kg/m ² . In some embodiments, the individual's Fagerström score is 8, 9 or 10 and BMI 30kg/m ² .

In some embodiments, the individual's Fagerström score 3 and BMI <25 kg/m ² . In some embodiments, the individual's Fagerström score 3 and BMI 25 kg/m ² and <30 kg/m ² . In some embodiments, the individual's Fagerström score 3 and BMI 30kg/m ² .

In some embodiments, the individual's Fagerström score 5 and BMI <25 kg/m ² . In some embodiments, the individual's Fagerström score 5 and BMI 25 kg/m ² and <30 kg/m ² . In some embodiments, the individual's Fagerström score 5 and BMI 30kg/m ² .

In some embodiments, the individual's Fagerström score 6 and BMI <25 kg/m ² . In some embodiments, the individual's Fagerström score 6 and BMI 25 kg/m ² and <30 kg/m ² . In some embodiments, the individual's Fagerström score 6 and BMI 30kg/m ² .

In some embodiments, the individual's Fagerström score 8 and BMI <25 kg/m ² . In some embodiments, the individual's Fagerström score 8 and BMI 25 kg/m ² and <30 kg/m ² . In some embodiments, the individual's Fagerström score 8 and BMI 30kg/m ² .

In some embodiments, a questionnaire is used to assess symptoms experienced during smoking cessation, such as smoking cravings, withdrawal or boosting effects. In some embodiments, the questionnaire is selected from the group consisting of: Minnesota Nicorine Withdrawal Score (Minnesota Nicorine Withdrawal Score, MNWS), Brief Questionnaire of Smoking Urges (QSU-Simple), McNett Coping Effectiveness Questionnaire (mCEQ), Three-Factor Eating Questionnaire (TFEQ) and Food Food Craving Inventory (FCI).

In some embodiments, nicotine dependence, addiction, and/or withdrawal are derived from the use of tobacco products. In some embodiments, nicotine dependence, addiction, and/or withdrawal are derived from smoking.

In some embodiments, nicotine dependence, addiction, and/or withdrawal are derived from the use of nicotine replacement therapy.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutical thereof is first administered to an individual on a target smoking cessation day. An acceptable salt, solvate or hydrate. In some embodiments, at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days before the target smoking cessation date , 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 Administration of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3- to the individual on days, 31 days, 32 days, 33 days, 34 days or 35 days Benzodiazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the individual is administered ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzene at least 7 days prior to the target smoking cessation date. Nitrogen or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the individual is administered ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H - from about 7 days to about 35 days prior to the target smoking cessation date. 3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the individual is administered ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzidazole 7 days prior to the target smoking cessation date. Or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the individual is administered ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzene at least 14 days prior to the target smoking cessation date. Nitrogen or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the individual is administered ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H - from about 14 days to about 35 days prior to the target smoking cessation date. 3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the target quit date 14 days before, and administered to the individual (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro-benzo N -1 H -3- Or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments, the individual quits between the 8th day and the 35th day of treatment. In some embodiments, the individual quits between the 15th day and the 35th day of treatment. In some embodiments, the individual quits between the 22nd day and the 35th day of treatment. In some embodiments, the individual quits on the 8th day of treatment. In some embodiments, the individual quits on the 15th day of treatment. In some embodiments, the individual quits on the 22nd day of treatment.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof is administered Before the solvate or hydrate, the method further comprises the step of directing the individual to set a smoking cessation date. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine is administered about 7 days prior to the date of smoking cessation. Or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments, the administration of (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro -1 H -3- acceptable benzo on nitrogen or a pharmaceutically acceptable salt Boom After the solvate or hydrate, the method further comprises the step of directing the individual to set a smoking cessation date. In some embodiments, the date of smoking cessation is set to occur in the administration of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or A pharmaceutically acceptable salt, solvate or hydrate is at least 7 days later. In some embodiments, the date of smoking cessation is set to occur in the administration of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or A pharmaceutically acceptable salt, solvate or hydrate 36 days prior.

In some embodiments, the individual has previously attempted to quit but did not successfully quit. In some embodiments, the individual has previously attempted to quit but subsequently relapsed and resumed smoking.

In some embodiments, the administration produces statistically significant ability to withstand smoking cessation. Improvements, as measured by analyzing data from MPSS tests.

In some embodiments, the formulation and/or administration of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutical thereof The individual has withdrawn from nicotine for up to 12 weeks prior to the acceptable salt, solvate or hydrate.

In some embodiments, the formulation and/or administration of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutical thereof The individual has quit nicotine use for up to 24 weeks before the acceptable salt, solvate or hydrate.

In some embodiments, the formulation and/or administration of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutical thereof The individual has abstained from nicotine for up to 9 months prior to the acceptable salt, solvate or hydrate.

In some embodiments, the formulation and/or administration of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutical thereof The individual has withdrawn from nicotine for 52 weeks prior to the acceptable salt, solvate or hydrate.

In some embodiments, the forbidden is self-reported. In some embodiments, the self-report is based on a response to the questionnaire. In some embodiments, the questionnaire is a list of nicotine use. In some embodiments, the individual self reports that they did not smoke any cigarettes (or even smoked a cigarette). In some embodiments, the individual self-reports that no other nicotine-containing product is used. In some embodiments, the individual self reports that they did not smoke any cigarettes (even without a cigarette) and did not use any other nicotine-containing product.

In some embodiments, the duration of treatment is selected from the group consisting of: 12 weeks, 6 months, 9 months, 1 year, 18 months, 2 years, 3 years, 4 years, and 5 years.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof, The solvate or hydrate is at least about 2 weeks. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof, The solvate or hydrate is at least about 4 weeks. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof, The solvate or hydrate is at least about 8 weeks. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof, The solvate or hydrate is at least about 12 weeks. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof, The solvate or hydrate is at least about 6 months. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof, The solvate or hydrate is at least about 1 year. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof, The solvate or hydrate is at least about 2 years old. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof, The solvate or hydrate is from about 7 weeks to about 12 weeks. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof, The solvate or hydrate is from about 12 weeks to about 52 weeks. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof, The solvate or hydrate is from about 6 months to about 1 year.

In some embodiments, the individual receives treatment for a first treatment session. In some embodiments, the individual receives treatment for another treatment period, for example to increase the likelihood of long-term inconvenience. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzonitrile is administered to an individual who fails during the first treatment period The hydrazine or a pharmaceutically acceptable salt, solvate or hydrate thereof, optionally in combination with a supplement, continues for a second treatment period. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine is administered to an individual who relapses during the first treatment period. Or a pharmaceutically acceptable salt, solvate or hydrate thereof, optionally in combination with a supplement, for a second treatment period. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine is administered to an individual who relapses after the first treatment. Or a pharmaceutically acceptable salt, solvate or hydrate thereof, optionally in combination with a supplement, for a second treatment period. In some embodiments, the first treatment session is 12 weeks. In some embodiments, the second treatment period is 12 weeks or less. In some embodiments, the second treatment period is 12 weeks. In some embodiments, the second treatment period is greater than 12 weeks. In some embodiments, the first treatment period is one year. In some embodiments, the second treatment period is one year or less. In some embodiments, the second treatment period is one year. In some embodiments, the first treatment period is longer than the second treatment period. In some embodiments, the first treatment period is shorter than the second treatment period. In some embodiments, the first treatment period has the same length of time as the second period.

In some embodiments, the prevention or reduction of weight gain or the loss of weight loss is measured relative to the amount of weight gain or loss typically experienced when an individual attempts to quit. In some embodiments, the prevention or reduction of weight gain or the loss of weight loss is measured relative to the amount of weight gain or loss typically experienced when an individual attempts to quit using another drug.

In some embodiments, controlling weight gain comprises preventing weight gain. In some embodiments, controlling weight gain comprises causing weight loss. In some embodiments, controlling the weight gain comprises causing at least about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8 Weight loss of %, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%. In some embodiments, the weight loss is at least 1%. In some embodiments, the weight loss is at least 1.5%. In some embodiments, the weight loss is at least 2%. In some embodiments, the weight loss is at least about 3%. In some embodiments, the weight loss is at least 4%. In some embodiments, the weight loss is at least 5%. In some embodiments, controlling the weight gain comprises decreasing the BMI. In some embodiments, controlling weight gain comprises reducing body fat %. In some embodiments, controlling weight gain includes reducing waist circumference. In some embodiments, controlling the weight gain comprises reducing the BMI by at least about 0.25 kg/m ² , 0.5 kg/m ² , 1 kg/m ² , 1.5 kg/m ² , 2 kg/m ² , 2.5 kg/m ² , 3kg/m ² , 3.5kg/m ² , 4kg/m ² , 4.5kg/m ² , 5kg/m ² , 6kg/m ² , 7kg/m ² , 8kg/m ² , 9kg/m ² , 10kg/m ² , 11kg/m ² , 12kg/m ² , 13kg/m ² , 14kg/m ² , 15kg/m ² , 16kg/m ² , 17 kg/m ² , 18kg/m ² , 19kg/m ² or 20kg/ m ² . In some embodiments, the BMI is reduced by at least 1 kg/m ² . In some embodiments, the BMI is reduced by at least 1.5 kg/m ² . In some embodiments, the BMI is reduced by at least 2 kg/m ² . In some embodiments, the BMI is reduced by at least 2.5 kg/m ² . In some embodiments, BMI is reduced at least 5kg / m ^2. In some embodiments, the BMI is reduced by at least 10 kg/m ² . In some embodiments, controlling weight gain comprises reducing body fat % by at least about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6% 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%. In some embodiments, the % body fat reduction is at least 1%. In some embodiments, the % body fat reduction is at least 2.5%. In some embodiments, the % body fat reduction is at least 5%. In some embodiments, controlling the weight gain comprises reducing the waist circumference by at least about 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, or 10 cm. . In some embodiments, the reduction in waist circumference is at least 1 cm. In some embodiments, the reduction in waist circumference is at least 2.5 cm. In some embodiments, the reduction in waist circumference is at least 5 cm. In some embodiments, controlling the weight gain comprises reducing the body weight by at least about 0.5 kg, 1 kg, 1.5 kg, 2 kg, 2.5 kg, 3 kg, 3.5 kg, 4 kg, 4.5 kg, 5 kg, 6 kg, 7 kg, 8 kg, 9 kg, or 10 kg. In some embodiments, the reduction in body weight is at least 1 kg. In some embodiments, the reduction in body weight is at least 2.5 kg. In some embodiments, the reduction in body weight is at least 5 kg.

In some embodiments, the individual's low BMI is monitored. In some embodiments, during the administration, the individual's BMI becomes a BMI selected from one of the following: 18kg/m ² , 17.5kg/m ² , 17kg/m ² , 16kg/m ² and 15kg/m ² .

In some embodiments, the decrease in body weight is selected from one of: greater than about 1.5%, greater than about 2%, greater than about 2.5%, greater than about 3%, greater than about 3.5%, greater than about 4%, greater than about 4.5. % and greater than about 5%.

In some embodiments, the reduction in body weight is selected from one of: greater than about 1.5. Kg, greater than about 2 kg, greater than about 2.5 kg, greater than about 3 kg, greater than about 3.5 kg, greater than about 4 kg, greater than about 4.5 kg, and greater than about 5 kg.

In some embodiments, the BMI of the individual in need of treatment is selected from: 25kg/m ² , 24kg/m ² , 23kg / m ^2, 22kg/m ² , 21kg/m ² , 20kg/m ² , 19kg/m ² and 18.5kg/m ² . In some embodiments, the reduction in BMI does not exceed about 0.25 kg/m ² , 0.5 kg/m ² , 1 kg/m ² , 1.5 kg/m ² , 2 kg/m ² , 2.5 kg/m ² , 3 kg/m. ² , 3.5kg/m ² , 4kg/m ² , 4.5kg/m ² , 5kg/m ² , 6kg/m ² , 7kg/m ² , 8kg/m ² , 9kg/m ² , 10kg/m ² , 11kg /m ² , 12 kg/m ² , 13 kg/m ² , 14 kg/m ² , 15 kg/m ² , 16 kg/m ² , 17 kg/m ² , 18 kg/m ² , 19 kg/m ² or 20 kg/m ² . In some embodiments, the reduction in BMI does not exceed 1 kg/m ² . In some embodiments, BMI does not exceed the reduced 1.5kg / m ^2. In some embodiments, the reduction in BMI does not exceed 2 kg/m ² . In some embodiments, the reduction in BMI does not exceed 2.5 kg/m ² . In some embodiments, the reduction in BMI does not exceed 5 kg/m ² . In some embodiments, the reduction in BMI does not exceed 10 kg/m ² . In some embodiments, the reduction in body fat % does not exceed about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7% , 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%. In some embodiments, the % body fat reduction does not exceed 1%. In some embodiments, the % body fat reduction does not exceed 2.5%. In some embodiments, the % body fat reduction does not exceed 5%. In some embodiments, the reduction in waist circumference does not exceed about 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, or 10 cm. In some embodiments, the reduction in waist circumference does not exceed 1 cm. In some embodiments, the reduction in waist circumference does not exceed 2.5 cm. In some embodiments, the reduction in waist circumference does not exceed 5 cm. In some embodiments, the reduction in body weight does not exceed about 0.5 kg, 1 kg, 1.5 kg, 2 kg, 2.5 kg, 3 kg, 3.5 kg, 4 kg, 4.5 kg, 5 kg, 6 kg, 7 kg, 8 kg, 9 kg, or 10 kg. In some embodiments, the reduction in body weight does not exceed 1 kg. In some embodiments, the reduction in body weight does not exceed 2.5 kg. In some embodiments, the reduction in body weight does not exceed 5 kg.

In some embodiments, controlling the weight gain comprises maintaining at least a certain weight loss for at least about 12 weeks, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, or at least about 2 years. For example, in some embodiments, the individual loses 5 kg during the first treatment and maintains at least 1 kg of the weight loss during the second treatment period. In some embodiments, the individual loses 3 kg during the 12 weeks prior to treatment and loses a total of 5 kg after 1 year of treatment.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzoazepine or a pharmaceutically acceptable salt thereof, solvent Use of a compound or hydrate. For example, in some embodiments, if the individual's BMI becomes About 15kg/m ² , About 15.5kg/m ² , About 16kg/m ² , About 16.5kg/m ² , About 17kg/m ² , About 17.5kg/m ² , About 18kg/m ² , About 18.5kg/m ² , About 19kg/m ² , About 19.5kg/m ² About 20kg/m ² , About 20.5kg/m ² , About 21kg/m ² , About 21.5kg/m ² , About 22kg/m ² , About 22.5kg/m ² or At about 23 kg/m ² , the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzoazepine or a pharmaceutically acceptable salt thereof is interrupted. Use of solvates or hydrates.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or its medicinal agent is administered as described herein An acceptable salt, solvate or hydrate is optionally combined with at least one supplement and the individual experiences one or more additional beneficial effects.

In some embodiments, the one or more additional beneficial effects are selected from the group consisting of a reduction in body weight assessment, an improvement in cardiovascular indications, and/or improved glycemia. In some embodiments, the one or more additional beneficial effects are selected from the group consisting of a decrease in body weight assessment, an improvement in cardiovascular indications, and/or an improved lipidemia.

In some embodiments, one or more additional beneficial effects include a reduction in body weight assessment. In some embodiments, the reduction in body weight assessment includes weight loss. In some embodiments, one or more beneficial effects include a reduction in hunger, a reduction in food cravings, or an increase in the feeding interval.

In some embodiments, one or more additional beneficial effects comprise an improvement in one or more cardiovascular indications. In some embodiments, the improvement of one or more cardiovascular indications comprises one or more of the following: reduced systolic and diastolic blood pressure (SBP and DBP, respectively), decreased heart rate, decreased total cholesterol, LDL cholesterol Reduced, decreased HDL cholesterol and/or reduced triglyceride levels.

In some embodiments, one or more additional beneficial effects include SBP reduction. In some embodiments, the reduction in SBP in an individual without type 2 diabetes is at least about 2 mm Hg. In some embodiments, the reduction in SBP in an individual without type 2 diabetes is between 2 mm Hg and 5 mm Hg. In some embodiments, the reduction in SBP in an individual with type 2 diabetes is at least about 2 mm Hg. In some embodiments, the reduction in SBP in an individual with type 2 diabetes is between about 2 mm Hg and 5 mm Hg. In some embodiments, the decrease in SBP is at least about 1 mm Hg in an individual with fasting glucose impaired at baseline. In some embodiments, the decrease in SBP is between about 1 mm Hg and 5 mm Hg in an individual with fasting glucose impaired at baseline.

In some embodiments, one or more additional beneficial effects include a DBP reduction. In some embodiments, the reduction in DBP in an individual without type 2 diabetes is at least about 1 mm Hg. In some embodiments, the decrease in DBP in an individual without type 2 diabetes is at least between about 1 mm Hg and 5 mm Hg. In some embodiments, the reduction in DBP in an individual with type 2 diabetes is at least about 1 mm Hg. In some embodiments, the reduction in DBP in an individual with type 2 diabetes is between about 1 mm Hg and 5 mm Hg. In some embodiments, the decrease in DBP in an individual with fasting glucose impaired at baseline is at least about 1 mm Hg. In some embodiments, the decrease in DBP in an individual with fasting glucose impaired at baseline is between about 1 mm Hg and 5 mm Hg.

In some embodiments, one or more additional beneficial effects include a decrease in heart rate. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is at least about 2 BPM. In some embodiments, the heart rate is in an individual who does not have type 2 diabetes The reduction in rate is between about 2 BPM and 5 BPM. In some embodiments, the reduction in heart rate in an individual with type 2 diabetes is at least about 2 BPM. In some embodiments, the reduction in heart rate in an individual with type 2 diabetes is between about 2 BPM and 5 BPM. In some embodiments, the reduction in heart rate in an individual with a fasting glucose impaired at baseline is at least about 2 BPM. In some embodiments, the decrease in heart rate is between about 2 BPM and 5 BPM in individuals with baseline fasting glucose impairment.

In some embodiments, the improvement in lipemia comprises a decrease in total cholesterol content. In some embodiments, the reduction in total cholesterol content in an individual without type 2 diabetes is at least about 1 mg/dL. In some embodiments, the reduction in total cholesterol content in an individual without type 2 diabetes is between about 1.5 mg/dL and 2 mg/dL. In some embodiments, the reduction in total cholesterol content in an individual with type 2 diabetes is at least about 0.5 mg/dL. In some embodiments, the reduction in total cholesterol content in an individual with type 2 diabetes is between about 0.5 mg/dL and 1 mg/dL. In some embodiments, the reduction in total cholesterol content in an individual with a fasting glucose impaired at baseline is at least about 2 mg/dL. In some embodiments, the reduction in total cholesterol content in an individual with fasting glucose impaired at baseline is between about 2 mg/dL and 3 mg/dL.

In some embodiments, the improvement in lipemia comprises a decrease in LDL cholesterol content. In some embodiments, the reduction in LDL cholesterol content in an individual without type 2 diabetes is at least about 1 mg/dL. In some embodiments, the reduction in LDL cholesterol content in an individual without type 2 diabetes is between about 1 mg/dL and 2 mg/dL. In some embodiments, the reduction in LDL cholesterol content in an individual with type 2 diabetes is at least about 1 mg/dL. In some embodiments, the reduction in LDL cholesterol content in an individual with type 2 diabetes is between about 1 mg/dL and 1.5 mg/dL. In some embodiments, the reduction in LDL cholesterol content in an individual with a fasting glucose impaired at baseline is at least about 2 mg/dL. In some embodiments, the reduction in LDL cholesterol content in an individual with fasting glucose impaired at baseline is between about 2 mg/dL and 3 mg/dL.

In some embodiments, the improvement in lipemia comprises a decrease in HDL cholesterol content. In some embodiments, the reduction in HDL cholesterol content in an individual without type 2 diabetes is at least about 4 mg/dL. In some embodiments, the reduction in HDL cholesterol content in an individual without type 2 diabetes is between about 3 mg/dL and 6 mg/dL. In some embodiments, the reduction in HDL cholesterol content in an individual having type 2 diabetes is at least about 5 mg/dL. In some embodiments, the reduction in HDL cholesterol content in an individual with type 2 diabetes is between about 7 mg/dL and 10 mg/dL. In some embodiments, the reduction in HDL cholesterol content in an individual with fasting glucose impaired at baseline is at least about 2 mg/dL. In some embodiments, the reduction in HDL cholesterol content in an individual with fasting glucose impaired at baseline is between about 2 mg/dL and 3 mg/dL.

In some embodiments, one or more additional beneficial effects comprise an improvement in glycemia. In some embodiments, the improvement in glycemia comprises a reduction in fasting plasma glucose and/or a decrease in glycated hemoglobin (A1C) content. In some embodiments, the improvement in glycemia comprises a reduction in fasting plasma glucose. In some embodiments, the improvement in glycemia comprises a decrease in glycated hemoglobin (A1C) content. In some embodiments, the improvement in glycemia comprises a reduction in triglyceride content.

The compounds provided herein can be administered in a wide variety of dosage forms. It will be apparent to those skilled in the art that such dosage forms may comprise as active ingredient a pharmaceutically acceptable salt, solvate or hydrate of a compound provided herein or a compound provided herein.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvate The hydrate or hydrate is administered in a lozenge suitable for oral administration.

Conventional excipients (e.g., binders, fillers, acceptable wetting agents, tableting lubricants, and disintegrating agents) can be used for oral administration in the form of tablets and capsules. Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, the oral formulation can be in the form of a dry powder which can be reconstituted with water or another suitable liquid vehicle prior to use. Other additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavoring agents, and coloring agents may be added to the liquid formulation. Parenteral dosage forms can be prepared in an oily manner by dissolving the compound in a suitable liquid vehicle and sterile filtering the solution, followed by filling and sealing the appropriate vials or ampoules. These approaches are only a few examples of many suitable methods well known in the art for preparing dosage forms. Suitable pharmaceutically acceptable carriers other than the carriers mentioned herein are known in the art ; for example, see Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editor: Gennaro et al. People) .

While the compound may be administered as a raw or pure chemical for protection or treatment in an alternative use, it is preferred that the compound or active ingredient be presented as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.

Pharmaceutical formulations include the following: suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or presentation Suitable for administration by inhalation, insufflation or by transdermal patch. Transdermal patches dispense a drug at a controlled rate by delivering the drug for absorption in an efficient manner with minimal drug degradation. Typically, a transdermal patch comprises an impermeable backing layer, a single pressure sensitive adhesive, and a removable protective layer with a release liner. Those skilled in the art will understand and understand the techniques suitable for the manufacture of the desired effective transdermal patch based on the needs of the skilled artisan.

Accordingly, the compounds provided herein, as well as conventional adjuvants, carriers or diluents, may be in the form of a pharmaceutical formulation and unit dosage form thereof, and may be in the form of a solid (eg, a lozenge or a filled capsule) or a liquid (eg, a solution, Suspensions, emulsions, elixirs, gels or capsules filled therewith, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including Subcutaneous) use. The pharmaceutical compositions and unit dosage forms thereof may contain conventional ingredients in conventional proportions with or without additional active compounds or ingredients, and such unit dosage forms may contain any suitable effective amount equivalent to the intended daily dosage range to be used. Active ingredient.

In some embodiments, the active ingredient is formulated into an immediate release dosage form using techniques such as are known in the art. In some embodiments, the active ingredient is formulated into a modified release dosage form using techniques such as are known in the art. In some embodiments, the active ingredient is formulated into a sustained release dosage form using, for example, techniques known in the art. In some embodiments, the active ingredient is formulated into a delayed release dosage form using techniques such as are known in the art.

In some embodiments, the method comprises a plurality of administrations of a modified release dosage form having a frequency wherein the average interval between any two consecutive administrations is: at least about 24 hours or about 24 hours.

In some embodiments, the method comprises multiple administrations of a modified release dosage form, and the modified release dosage form is administered once daily.

In some embodiments, the plurality of administrations are: at least about 30 times, at least about 180 times; at least about 365 times, or at least about 730 times.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3 is administered to an individual administered a modified release dosage form as described herein. The _Cmax of the plasma concentration of the benzodiazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof is: less than about 60 ng/mL; less than about 40 ng/mL; less than about 20 ng/mL; or less than about 10 ng. /mL. In some embodiments, _Cmax divided by a therapeutically effective amount is equal to: less than about 1 x 10 ^-5 mL ^-1 ; less than about 5 x 10 ^-6 mL ^-1 ; less than about 1 x 10 ^-6 mL ^-1 ; or less than About 5 × 10 ^-7 mL ^-1 . In some embodiments, _Cmax occurs at: more than 30 minutes after administration; more than 1 hour after administration; or more than 2 hours after administration. In some embodiments, _Cmax occurs at: more than 3 hours after administration, more than 6 hours after administration, or more than 12 hours after administration.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3 is administered to an individual administered a modified release dosage form as described herein. The average peak-to-valley ratio of the plasma concentration of the benzoazepine or its pharmaceutically acceptable salt, solvate or hydrate is: less than about 3:1, less than about 2:1, less than about 1.5:1. Or less than about 1.1:1.

In some embodiments, the modified release dosage form further comprises (hydroxypropyl) methyl fiber Prime.

In some embodiments, the modified release dosage form further comprises one or more components selected from the group consisting of microcrystalline cellulose, mannitol, and magnesium stearate.

In some embodiments, the modified release dosage form further comprises a film coating.

In some embodiments, the film coating comprises a water soluble film coating.

In some embodiments, the film coating comprises ethylcellulose.

In some embodiments, the film coating further comprises (hydroxypropyl) methylcellulose.

In some embodiments, the ratio of ethylcellulose to (hydroxypropyl)methylcellulose is: about 75:25, about 80:20, or about 85:15.

In some embodiments, the modified release dosage form comprises a core lozenge and a film coating; wherein the core lozenge comprises: Form III ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydrogen -1 H -3-benzoazepine hydrochloride hemihydrate; mannitol; (hydroxypropyl) methylcellulose; microcrystalline cellulose; and magnesium stearate; and the film coating comprises a water-soluble film package clothes.

In some embodiments, the modified release dosage form comprises a core lozenge and a film coating, wherein the weight ratio of the core lozenge to the coating is about 20:1; and wherein the core lozenge comprises: about 7% Type III ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hydrochloride hemihydrate; about 22.5% mannitol; about 50% (hydroxyl Propyl)methylcellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium stearate; and the film coating comprises a water soluble film coating.

In some embodiments, the modified release dosage form comprises a core lozenge and a film coating; wherein the core lozenge comprises: Form III ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydrogen -1 H -3-benzoazepine hydrochloride hemihydrate; mannitol; (hydroxypropyl) methylcellulose; microcrystalline cellulose; and magnesium stearate; and the film coating comprises: ethylcellulose And (hydroxypropyl) methylcellulose.

In some embodiments, the modified release dosage form comprises a core lozenge and a film coating, wherein the weight ratio of the core lozenge to the coating is about 20:1; and wherein the core lozenge comprises: about 7% Type III ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hydrochloride hemihydrate; about 22.5% mannitol; about 50% (hydroxyl Propyl)methylcellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium stearate; and the film coating comprises: about 85% ethylcellulose; and about 15% (hydroxypropyl) methyl Cellulose; or about 75% ethylcellulose; and about 25% (hydroxypropyl) methylcellulose.

For oral administration, the pharmaceutical compositions may be in the form of, for example, a troche, a capsule, a suspension or a liquid. The pharmaceutical compositions are preferably in the form of dosage units containing the particular amount of active ingredient. Examples of such dosage units are capsules, troches, powders, granules or suspensions containing conventional additives such as lactose, mannitol, corn starch or potato starch; binders such as crystalline cellulose, cellulose derivatives, arab Acacia, corn starch or gelatin; a disintegrant such as corn starch, potato starch or sodium carboxymethylcellulose; and a lubricant such as talc or magnesium stearate. The active ingredient may also be administered in the form of a composition by injection, in which, for example, saline, dextrose or water may be employed as a suitable pharmaceutically acceptable carrier.

Dosages using the compounds provided herein can vary within wide limits and are conventionally known and known to the physician, and are adjusted for individual conditions in each individual case. It depends, for example, on the nature and severity of the condition to be treated, the condition of the individual, the compound employed, the treatment or protection against acute or chronic disease states, or the administration of other active compounds other than those provided herein. Representative dosages include, but are not limited to, from about 0.001 mg to about 5000 mg, from about 0.001 mg to about 2500 mg, from about 0.001 mg to about 1000 mg, from about 0.001 mg to about 500 mg, from about 0.001 mg to about 250 mg, from about 0.001 mg to 100 mg, From about 0.001 mg to about 50 mg and from about 0.001 mg to about 25 mg. Multiple doses, such as 2, 3 or 4 doses, can be administered during the day, especially when a relatively large amount is deemed necessary. Depending on the individual and as the health care provider deems appropriate, it may be necessary to deviate upward or downward from the dosages described herein.

All dosage amounts disclosed herein are calculated for the active moiety (i.e., the molecule or ion that confers the desired pharmacological or physiological effect). In addition, all doses of lorcaserin disclosed herein are directed to lorcaserin in the form of an anhydrous hydrochloride salt. Those skilled in the art will recognize that the dosage of other salts or crystalline forms of lorcaserin can be adjusted to be equal to the lorcaserin in the form of an anhydrous hydrochloride salt. For example, 10 mg of lorcaserin as disclosed herein encompasses a dosage form containing 10 mg of anhydrous lorcaserin hydrochloride and 10.4 mg of crystalline lorcaserin hydrochloride hemihydrate. In addition, 10 mg of lorcaserin as disclosed herein includes ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine Any salt or crystalline form of the same amount found in 10 mg of anhydrous lorcaserin hydrochloride.

Alternatively, the dosage of lorcaserin disclosed herein can be demonstrated by the indicated amount of anhydrous lorcaserin hydrochloride (including anhydrous chlorhexidine hydrochloride having a specified amount of 80% to 125%). or other crystalline salts, formulation and dosage amount of the equivalence of the AUC of the dosage regimen and / or in the form of C _max) of alternatively organisms, by the FDA, such as biological availability and bioequivalence of industry directories (Guidance Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations.USDepartment of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), March 2003, Rev. 1, www.fda.gov/cder/guidance/index.htm ). For example, the dosage of lorcaserin disclosed herein can be expressed as other salts or crystal forms, formulations, and dosages exhibiting bioequivalence with 10 mg of anhydrous lorcaserin hydrochloride in an immediate release oral dosage lozenge. The dosing amount of the protocol is replaced by the BELVIQ ^® FDA package insert ( BELVIQ (lorcaserin HCl) (package insert), revised in August 2012 ).

The amount of the active ingredient or active salt or derivative required for treatment will vary not only with the particular salt selected, but also with the route of administration, the nature of the condition being treated, and the age and condition of the individual, and will ultimately be The clinician decides. In general, those skilled in the art understand how to extrapolate in vivo data obtained in a model system, typically an animal model, to another model system (eg, a human). In some cases, such extrapolation may be based solely on motion The weight of the object model compared to another model (eg, a mammal, preferably a human), but more generally, such extrapolation is based not only on body weight but on multiple factors. Representative factors include the type of individual, age, weight, sex, diet and medical condition, severity of the disease, route of administration, pharmacological considerations (eg activity, efficacy, pharmacokinetics and toxicology profile of the particular compound used) Whether to utilize a drug delivery system, to treat or otherwise protect against acute or chronic disease states, or to administer other active compounds (eg, part of a pharmaceutical combination) other than the compounds provided herein. Dosage regimens for the treatment of disease conditions using the compounds and/or compositions provided herein are selected based on a number of factors as described above. Thus, the actual dosage regimen employed can vary widely, and thus can deviate from the preferred dosage regimen, and those skilled in the art will recognize that dosages and dosage regimens outside such typical ranges can be tested and, where appropriate, It can be used in the methods disclosed herein.

The desired dose may conveniently be presented in a single dose or divided doses (e.g., two, three, four or more sub-doses per day) administered at appropriate intervals. The sub-dose itself can be further divided into, for example, a plurality of discrete loosely spaced doses. In particular, when it is considered appropriate to administer a relatively large amount, the daily dose may be administered in divided portions, for example 2, 3 or 4 parts. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the indicated daily dose.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof Formulated and/or administered to an individual at a dose of greater than or equal to 20 mg/day, greater than or equal to 25 mg/day, greater than or equal to 30 mg/day, greater than or equal to 35 mg/day, or greater than or equal to 40 mg/day. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The individual is prescribed and/or administered to a dose equal to or less than 20 mg/day. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof Formulate and/or administer the individual at a dose of at least 20 mg/day. In some embodiments, (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro-benzo -1 H -3- nitrogen Boom hydrochloride or a solvate or hydrate Formulate and/or administer the individual at a dose equal to 20 mg/day.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The individual is prescribed and/or administered to a dose equal to at least 12.5 mg/day. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof Formulate and/or administer the individual at a dose equal to 12.5 mg to 20 mg/day. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The prescription is administered and/or administered to a dose equal to 12.5 mg/day.

In some embodiments, (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro-benzo -1 H -3- nitrogen Boom hydrochloride or a solvate or hydrate The individual is prescribed and/or administered to a dose equal to at least 15 mg/day. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof Formulate and/or administer the individual at a dose equal to 15 mg to 20 mg/day. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof Formulate and/or administer the individual at a dose equal to 15 mg/day.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The individual is prescribed and/or administered to a dose equal to at least 17.5 mg/day. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The individual is prescribed and/or administered to a dose equal to 17.5 mg to 20 mg/day. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The individual is prescribed and/or administered to a dose equal to 17.5 mg/day.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The individual is prescribed and/or administered to a dose equal to or less than 10 mg twice daily.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The individual is prescribed and/or administered to a dose equal to 10 mg twice daily.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The individual is prescribed and/or administered to a dose equal to at least 5 mg twice daily. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The individual is prescribed and/or administered to a dose equal to 5 mg twice daily.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The individual is prescribed and/or administered to a dose equal to at least 7.5 mg twice daily. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine hydrochloride or a solvate or hydrate thereof The individual is prescribed and/or administered to a dose equal to 7.5 mg twice daily.

In some embodiments, the individual may also prescribe and/or be administered a supplement.

The present invention also provides a composition comprising ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzoazepine or a pharmaceutically acceptable salt thereof a solvate or hydrate and at least one extender.

As used herein, "extenders" means herein added (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro-benzo -1 H -3- nitrogen or Boom Another therapeutic agent for the activity of a pharmaceutically acceptable salt, solvate or hydrate, as it relates to the method of reducing the frequency of smoking in an individual attempting to reduce the frequency of smoking; helping to try to terminate or reduce the use of tobacco products The individual terminates or reduces the use of tobacco products; helps to quit smoking and prevents related weight gain; controls the weight gain associated with smoking cessation in individuals who attempt to quit; reduces the weight gain associated with smoking cessation in individuals who attempt to quit; treatment attempts to treat nicotine dependence, addiction And/or nicotine dependence, addiction, and/or withdrawal from individuals who have abstained; or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine. In some embodiments, the "supplement" is not a stimulant.

Supplements include nicotine replacement therapy, antidepressants, and anxiolytics, such as selective serotonin reuptake inhibitors, such as citalopram, escitalopram, fluoxetine, Paroxetine, sertraline, and the like. Serotonin and norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, and the like can also be used. Norepinephrine and dopamine reuptake inhibitors such as bupropion may also be used. It is also possible to use tetracyclic antidepressants such as mirtazapine; combination reuptake inhibitors and receptor blockers such as trazodone, nefazodone, maprotiline (maprotiline); tricyclic antidepressants, such as amitriptyline, amoxapine, desipramine, doxepin, imipramine, go Nortriptyline, protriptyline, and trimipramine; monoamine oxidase inhibitors such as phenelzine, tranylcypromine, isocarboxazid, Selegiline; benzodiazepines, such as lorazepam, clonazepam, alprazolam, and diazepam; serotonin 1A Receptor agonists, such as buspirone, aripiprazole, quetiapine, tandospirone, and bifeprunox; and beta-adrenergic receptors Blockers, such as propranolol. Other supplements include other pharmacological agents such as UTP, amiloride, antibiotics, bronchodilators, anti-inflammatory agents, and mucolysis agents such as n-ethenyl-cysteine.

In some embodiments, the supplement is selected from the group consisting of nicotine replacement therapy. In some embodiments, the nicotine replacement therapy is selected from the group consisting of a nicotine chewable tablet, a nicotine transdermal system, a nicotine diamond lozenge, a nicotine sublingual tablet, and a nicotine spray or inhaler. In some embodiments, the supplement is an electronic cigarette.

In some embodiments, the composition comprises ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzenebenzazepine or a pharmaceutically acceptable salt thereof , solvates or hydrates and nicotine chewable tablets.

In some embodiments, the composition comprises ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof , solvates or hydrates and nicotine transdermal systems.

In some embodiments, the composition comprises ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof , solvates or hydrates and nicotine diamond tablets.

In some embodiments, the composition comprises ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof , solvates or hydrates and nicotine sublingual tablets.

In some embodiments, the composition comprises (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro -1 H -3- acceptable benzo on nitrogen or a pharmaceutically acceptable salt Boom , solvates or hydrates and nicotine sprays or inhalers.

In some embodiments, the composition comprises ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof , solvates or hydrates and electronic cigarettes.

In some embodiments, the supplement is selected from the group consisting of antidepressants.

In some embodiments, the composition comprises ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof , solvates or hydrates and antidepressants. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt thereof, solvate The hydrate or antidepressant is formulated into a fixed dose combination product. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt thereof, solvate Compounds or hydrates and antidepressants are formulated into co-packaged products. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt or solvate thereof Or hydrates and antidepressants are formulated for adjuvant therapy.

In some embodiments, the composition comprises ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof , solvates or hydrates and nortriptyline. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt thereof, solvate The compound or hydrate and nortriptyline are formulated into a fixed dose combination product. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt thereof, solvate The compound or hydrate and nortriptyline are formulated into a co-packaged product. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt or solvate thereof Or hydrate and nortriptyline are formulated for adjuvant therapy.

In some embodiments, the composition comprises ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof , solvates or hydrates and bupropion. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine\ or a pharmaceutically acceptable salt thereof, solvent The compound or hydrate and bupropion are formulated into a fixed dose combination product. In some embodiments, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt thereof, a solvent The substance or hydrate and bupropion are formulated into a co-packaged product. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt or solvate thereof Or hydrates and bupropion are formulated for adjuvant therapy.

In some embodiments, the composition comprises ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof A solvate or hydrate and clonidine or a pharmaceutically acceptable salt thereof. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt thereof, solvate The substance or hydrate and clonidine are formulated into a fixed dose combination product. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt thereof, solvate The product or hydrate and chlorination are formulated into a co-packaged product. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt or solvate thereof Or hydrates and clonidines are formulated for adjuvant therapy.

In some embodiments, the composition comprises ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt thereof , solvate or hydrate and varenicline or a pharmaceutically acceptable salt thereof. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt thereof, solvate The hydrate or valnicillin or a pharmaceutically acceptable salt thereof is formulated into a fixed dose combination product. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt thereof, solvate The product or hydrate and varenicline or a pharmaceutically acceptable salt thereof are formulated into a co-packaged product. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt or solvate thereof Or hydrates and varenicline or a pharmaceutically acceptable salt thereof are formulated for adjuvant therapy.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvate The hydrate or hydrate is a HCl salt of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzoazepine or a solvate or hydrate thereof.

In some embodiments, the individual has previously received treatment for the supplement. In some embodiments, the individual is refractory to prior treatment of the supplement.

In some embodiments, the individual has previously received treatment for nicotine replacement therapy. In some embodiments, the individual is refractory to prior treatment of nicotine replacement therapy.

The present invention also provides a ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt or solvate thereof. Or a composition of a hydrate and at least one supplement for reducing the frequency of smoking in an individual attempting to reduce the frequency of smoking; assisting an individual attempting to terminate or reduce the use of the tobacco product to terminate or reduce the use of the tobacco product; to help quit smoking and prevent related Weight gain; controlling the weight gain associated with smoking cessation in individuals attempting to quit; reducing the weight gain associated with smoking cessation in individuals attempting to quit; treating nicotine dependence, addiction in individuals attempting to treat nicotine dependence, addiction, and/or withdrawal And/or withdrawal; or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine.

The present invention also provides a ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt or solvate thereof. Or a composition of a hydrate and at least one supplement for use as an agent for reducing the frequency of smoking in an individual attempting to reduce the frequency of smoking; assisting an individual attempting to terminate or reduce the use of the tobacco product to terminate or reduce the use of the tobacco product; Smoking cessation and prevention of related weight gain; controlling the weight gain associated with smoking cessation in individuals attempting to quit; reducing the weight gain associated with smoking cessation in individuals attempting to quit; treating nicotine dependence in individuals attempting to treat nicotine dependence, addiction, and/or withdrawal Sex, addiction, and/or withdrawal; or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine.

The present invention also provides a ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt or solvate thereof. Or a composition of hydrate and at least one supplement for use in the manufacture of a medicament for reducing the frequency of smoking in an individual attempting to reduce the frequency of smoking; assisting an individual attempting to terminate or reduce the use of the tobacco product to terminate or reduce the use of the tobacco product Helps quit smoking and prevents related weight gain; controls the weight gain associated with smoking cessation in individuals who attempt to quit; reduces the weight gain associated with smoking cessation in individuals who attempt to quit; treatment attempts to treat individuals with nicotine dependence, addiction, and/or withdrawal Nicotine dependence, addiction, and/or withdrawal; or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine.

The present invention also provides a ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt or solvate thereof. Or a unit dosage form of a composition of the hydrate and at least one extender.

The invention also provides ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt, solvate thereof or Hydrate, which is used in combination with a supplement.

The invention also provides ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or its pharmaceutically acceptable use in combination with a supplement. a salt, solvate or hydrate that is used to: reduce the frequency of smoking in individuals who attempt to reduce the frequency of smoking; help individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products; help to quit smoking and prevent related weight gain; Controlling the weight gain associated with smoking cessation in individuals attempting to quit; reducing the weight gain associated with smoking cessation in individuals attempting to quit; treating nicotine dependence, addiction, and/or treatment of individuals attempting to treat nicotine dependence, addiction, and/or withdrawal Withdraw; or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine.

The present invention also provides a supplement selected from the group consisting of nicotine replacement therapy with ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or A pharmaceutically acceptable salt, solvate or hydrate combination is used.

The present invention also provides ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt or solvate thereof Or a combination of hydrates used to: reduce the frequency of smoking in individuals who attempt to reduce the frequency of smoking; help individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products; help to quit and prevent related weight gain; Controlling the weight gain associated with smoking cessation in individuals attempting to quit; reducing the weight gain associated with smoking cessation in individuals attempting to quit; treating nicotine dependence, addiction, and/or treatment of individuals attempting to treat nicotine dependence, addiction, and/or withdrawal Withdraw; or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine.

In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvent The hydrate or hydrate is formulated into an immediate release dosage form and the supplement is also formulated into an immediate release dosage form. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvent The hydrate or hydrate is formulated into an immediate release dosage form and the supplement is formulated into a modified release dosage form. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvent The hydrate or hydrate is formulated into a modified release dosage form and the supplement is formulated into an immediate release dosage form. In some embodiments, ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvent The compound or hydrate is formulated into a modified release dosage form, and the supplement is also formulated into a modified release dosage form.

( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof One or more other supplements identified herein are administered sequentially or simultaneously. The amount of the formulation and the pharmacological agent depends, for example, on the type of pharmacological agent used and the schedule and route of administration.

The supplement may be combined with ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt or solvate thereof The hydrate is delivered synchronously or can be administered separately. Supplemental delivery can be carried out by any suitable method known in the art including oral, inhalation, injection, and the like.

In some embodiments, the methods described herein further comprise the step of providing educational materials and/or counseling to the individual. In some embodiments, counseling is associated with smoking cessation. In some embodiments, counseling is related to weight management, including but not limited to counseling about diet and exercise. In some embodiments, counseling is associated with both smoking cessation and weight management, including but not limited to counseling about diet and exercise.

In some embodiments, the methods described herein further comprise the steps of: providing biochemical feedback to the individual; acupuncture; hypnosis; behavioral intervention; support services; and/or psychotherapy.

Instance Example 1 - Production of Stable Cell Lines

The plastid DNA encoding the receptor of interest is generated using standard molecular biology tools. The plastid usually contains a multi-colonization site for insertion of the coding sequence of the receptor of interest, a promoter that drives the expression of the receptor when introduced into the host cell, and a resistance gene sequence that causes the host cell to produce a protein that confers antibiotic resistance. The commonly used promoter is the cytomegalovirus promoter (CMV), and the commonly used resistance gene confers a neomycin-resistant neo gene. The plastid DNA is introduced into the parental cells (common cell lines including CHO-K1 and HEK293) using methods such as lipofection or electroporation. The cells are then allowed to recover in culture for 1-2 days. At this point, the selection agent (eg, if the plastid contains the neo gene is neomycin) is added to the cell culture medium at a concentration sufficient to kill any cells that have not taken up plastid DNA and thus are not yet resistant to neomycin. in.

Since transient transfection is an efficient method of introducing plastid DNA into cells, many cells in culture initially exhibit neomycin resistance. In the course of a few cell divisions, the performance of proteins encoded by plastids is usually lost and most cells are eventually killed by antibiotics. However, in a small number of cells, plastid DNA can be randomly integrated into chromosomal DNA. If the plastid DNA is integrated in a manner that allows for the phenotypic expression of the neo gene, then the cells are permanently resistant to neomycin. Typically, after two weeks of culture of the transfected cells, most of the remaining cell lines have integrated the plastids in this manner.

The resulting stable cell pool is highly heterogeneous and can significantly exhibit different amounts of receptor (or no receptor at all). While these types of cell populations may provide a functional response when stimulated with a suitable agonist for the receptor of interest, they are generally not suitable for cautious pharmacological studies based on receptor reserve effects caused by high throughput.

Therefore, the cell line is derived from this cell population. The cells were plated in a multiwell plate at a density of one cell/well. After the cells are tiled, the plates are examined and wells containing more than one cell are eliminated. The cells are then cultured for a certain period of time, and eventually they continue to divide in the presence of neomycin into larger culture dishes until sufficient cells are present for evaluation.

Cell evaluation

A variety of methods can be used to evaluate cells. Characterization of functional analysis reveals some cells Increasing the potency and efficacy of the agonist may indicate the presence of a receptor reserve. The preparation of cell membranes for evaluation in radioligand binding assays allows quantitative determination of membrane receptor density. Evaluation of cell surface receptor density can also be performed by flow cytometry using antibodies directed against the receptor or an epitope tag that can be engineered into the receptor, typically at the N-terminus of the GPCR. The flow cytometry method allows for determining whether the population of conserved cells express the receptor in a homogeneous manner (which is expected) and whether to quantify the relative amount of expression between each of the selected cell populations. However, it does not provide absolute receptor performance.

If the cell line is intended to have no receptor-retaining effect, the receptor performance should be low (relative to the other pure lines evaluated) and homogeneous (if flow cytometry is possible). In functional assays, the appropriate clonal produce than other inbred (i.e. higher EC ₅₀ value) of agonist potency. If a partial agonist is available, the absence of a receptor reserve will be reflected in a lower efficacy relative to the full agonist, while cells with a higher receptor expression will increase partial agonist efficacy. In cells that exhibit high receptor levels, some agonists may never exhibit efficacy below the full agonist.

If an agent that irreversibly binds to or interacts with the receptor of interest is available, the treatment of the cell line without the receptor reserve should reduce the available receptor density by radioligand binding assay, and Reduce the amount of functional response to the agonist. However, a decrease in receptor density should occur when no agonist potency or partial agonist efficacy is reduced.

Example 2 - Chloro-chrome to 5-HT ₂ Receptor efficacy and efficacy

Evaluate the efficacy and efficacy of lorcaserin in rat, monkey and human 5-HT _2A , 5-HT _2B and 5-HT _2C receptors. Chlorosylin-mediated signaling was observed in stable colonizing cell lines exhibiting low receptor density. Phenoxybenzamine (PBZ) was used as an irreversible 5-HT ₂ receptor antagonist to allow for a gradual reduction of the receptor binding site in each cell line to account for receptor effects (which may have been generated in previous studies) Inconsistent results) There is no observation performance and efficacy.

Cell line

The HEK293 cell line was generated using standard procedures to stably express human, rat and monkey 5-HT _2A , 5-HT _2B and 5-HT _2C receptors.

IP cumulative analysis

HEK293 cells expressing recombinant 5-HT _2A , 5-HT _2B and 5-HT _2C receptors were added to a sterile poly-D-lysine coated 96-well microtiter plate (35,000 cells/well), and with 0.6μCi / holes in inositol free DMEM muscle of the type of ^[3 H] inositol-labeled for 18 hours. PBZ prepared in DMEM without myositol was then added to the final specified concentration and incubated for 1 hour at room temperature. Removed by aspiration not included in ^[3 H] inositol and PBZ, replaced and supplemented with LiCl (final 10mM) and pargyline (pargyline, 10 M final) of the free inositol muscular fresh DMEM. Test compounds that were serially diluted were then added and incubated for 2 hours at 37 °C. The cells were then lysed by the addition of ice-cold 0.1 M formic acid followed by freezing at -80 °C. After thawing, total [ ³ H]inositol phosphate was analyzed according to [ ³ H]inositol using AG1-X8 ion exchange resin (Biorad), and [ ³ H] muscle was measured by scintillation counting using a Perkin Elmer TopCount scintillation counter. Alcohol phosphate. Embodiment EC ₅₀ measured at a minimum of a total of eight or 10 different concentrations, and was measured in triplicate at each concentration tested.

The raw count of the scintillation counter was output to GraphPad Prism for further analysis. Data were fit using a nonlinear regression to three S-parameter dose-response function to obtain the EC ₅₀ value and the height of the curve. Compound efficacy was calculated as the percentage of serotonin efficacy defined as 100% in each experiment. Since the IP accumulation experiment usually involves multiple assay plates and the serotonin dose response is for only one plate, each plate serum is determined from positive and negative control wells containing serotonin (usually 1 μM or 10 μM) and assay buffer. The magnitude of the prime reaction. The efficacy of each compound was calculated as a percentage of the serotonin positive control response on the assay plate.

Establish stable cell lines expressing recombinant human, rat and monkey 5-HT _2A , 5-HT _2B and 5-HT _2C receptors, and use them for the analysis of lorcaserin in IP accumulation and calcium analysis. Reference compound panel. Cell surface receptor densities as assessed by radioligand binding are extremely high in human and monkey cell lines and lower in rat cell lines. The receptor density in all three cell lines was regulated by PBZ.

Calcium analysis

The cells were harvested, counted, and resuspended in assay buffer [1 x HBSS (containing calcium and magnesium) containing 20 mM HEPES (pH 7.4)] and plated at 20,000 cells/well (25 μL/well) in black transparent Bottom standard tissue culture plate. A bottle of Molecular Devices Calcium 4 dye was diluted with 10 mL of assay buffer. The 1 mL aliquot was then diluted 10-fold with assay buffer supplemented with 2.5 mM probenecid. This dye stock solution was added to the assay plate at 25 μL/well and incubated at 37 ° C for 1 hour. Test compounds were serially diluted in DMSO and then further diluted in assay buffer. Control and test compounds (in 25 [mu]L assay buffer) were then added to the assay plates using a Molecular Devices FLIPR instrument. Plates were read every two seconds for 1.5 minutes and the peak height of each well was determined. The dose response curve included 10 compound concentrations, with triplicate assays performed at each test concentration.

Raw counts were exported to GraphPad Prism (v. 5) for further analysis. Data were fit using a nonlinear regression to three S-parameter dose-response function to obtain the EC ₅₀ value and the height of the curve. Compound efficacy was calculated as the percentage of serotonin efficacy defined as 100% in each experiment.

Radioligand binding assay

HEK293 cells expressing recombinant 5-HT _2A , 5-HT _2B and 5-HT _2C receptors were harvested, suspended in ice-cold phosphate buffered saline (pH 7.4) (PBS), and then at 48,000 g at 4 ° C. Centrifuge for 20 min. The resulting cell pellet was then resuspended in wash buffer containing 20 mM HEPES (pH 7.4) and 0.1 mM EDTA, homogenized on ice using Brinkman Polytron and centrifuged (48,000 g at 4 °C for 20 min). The pellet was then resuspended in 20 mM HEPES (pH 7.4), homogenized on ice and centrifuged (48,000 g at 4 °C for 20 min). The crude membrane pellet was stored at -80 °C until used for radioligand binding assays.

Commercially available 5-HT ₂ agonist ^[125 I] DOI as radioligand binding assays Radioligand embodiment, the determination of nonspecific binding at saturating concentrations of 10μM and the presence of unlabeled DOI. The competition experiment consisted of adding 95 μL of assay buffer (20 mM HEPES (pH 7.4), 10 mM MgCl ₂ ), 50 μL membrane, 50 μL radioligand stock solution and 5 μL of test compound diluted in assay buffer to 96 wells. The microtiter plate was then incubated for one hour at room temperature. Analytical incubation was terminated by rapid filtration through a Perkin Elmer F/C filter plate under vacuum pressure using a 96-well Packard filter unit, and then the filter plates were washed several times with ice-cold assay buffer. The plate was then dried at 45 ° C for a minimum of two hours. Finally, 25 [mu]L of BetaScint scintillation cocktail was added to each well and plates were counted in a Packard TopCount scintillation counter. In each competition study, test compounds were administered at 8 to 10 concentrations and triplicate assays were performed at each test concentration. Reference compounds (usually DOI) are included in each run set for quality control purposes.

Upload the raw data set of the scintillation counter for processing. The competition curves were fitted to a nonlinear least squares curve fitting program ₅₀ to obtain a value IC. The Ki value was determined from the IC ₅₀ value using the Cheng-Prusoff equation and the Kd value of each radioligand-receptor pair. The average Ki value is calculated from the average of the logKi values.

result

Figure 18 shows the efficacy and efficacy data generated by IP accumulation analysis for each combination of human, rat and monkey 5-HT _2A , 5-HT _2B and 5-HT _2C receptors. Chlorocycline displays high selectivity for the human 5-HT _2C receptor, and EC ₅₀ (39.2 nM) is about 1/14 of the EC ₅₀ (553 nM) of the 5-HT _2A receptor, and is 5-HT _2B The receptor has an EC ₅₀ (2380 nM) of about 1/60. Chlorcarberin also shows high efficacy (81%) against human 5-HT _2C receptors relative to serotonin. In contrast, lorcaserin exhibits a mixed potency of 5-HT _2A , 5-HT _2B and 5-HT _2C receptors in rats, and has the highest selectivity to 5-HT _2B receptors (195 nM, vs. 5). - HT _2C and 5-HT _2A receptors were 545 nM and 1110 nM, respectively). Chlorcarberin also showed high efficacy (94%) against rat 5-HT _2B receptor relative to serotonin.

Figure 19 (left) shows the comparison of drug concentrations in humans with 5-HT _2A , 5-HT _2B and 5-HT _2C receptor activation data. EC ₅₀ values (e.g., by analyzing the measured cumulative IP) for a horizontal line is displayed as a previous study lorcaserin chlorine concentration by the individual card mianserin 10mg BID treatment of the observed (expressed as plasma-free portion) drawn . Figure 19 (right) shows the comparison of drug concentrations in rats with 5-HT _2A , 5-HT _2B and 5-HT _2C receptor activation data. EC ₅₀ values of receptor activation (e.g. IP by the cumulant analysis measured) is displayed for over 10mg / kg / day, the rats were observed 30mg / kg / day and 100mg / kg / day lorcaserin to Healing The horizontal line drawn by the concentration of lorcaserin (expressed as no plasma fraction). In humans, the plasma drug concentration after administration lorcaserin approximately equal to 5-HT IP _2C receptor cumulative analysis of EC ₅₀ values, and is not close to the 5-HT _2A EC or 5-HT _2B receptor ₅₀ value. However, in rats, the plasma drug concentration for the lowest dose of lorcaserin (ie, 10 mg/kg/day) is greater than or equal to each of the 5-HT _2A , 5-HT _2B, and 5-HT _2C receptors. The EC ₅₀ value of one of the IP cumulative analyses. Given that full receptor activation is expected at low doses, providing a higher dose of lorcaserin to rats increases plasma drug concentration, but is less likely to improve efficacy. Therefore, low doses of lorcaserin may be sufficient for the efficacy observed in rats.

Example 3-2 study

A 12-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of lorcaserin as a potential adjuvant for smoking cessation. In this trial, 603 active smokers were randomized to receive lorcaserin 10 mg BID, 10 mg QD or placebo ( BELVIQ (lorcaserin HCl) (package insert) at a 1:1:1 ratio , revised in August 2012 ). Patients at baseline depend on nicotine and average 18 cigarettes per day. The patient was administered for two weeks on the 15th day of the trial, then attempted to quit, and was given a cessation counseling during the trial. The primary objective of the study was to evaluate smoking cessation efficacy, as measured by the continuous inhibition rate (CAR) of carbon monoxide confirmation during the last four weeks of the trial (week 9 to week 12). The CAR identified by carbon monoxide is defined as the unreported smoking or other nicotine use and the expiratory end expiratory carbon monoxide measurement of less than or equal to 10 million copies. Secondary goals of the study included evaluation of weight changes, safety, and tolerability. Other outcome measures included CAR from week 5 to week 8 of treatment, CAR from week 5 to week 12 of treatment, CAR from week 3 to week 12 of treatment, prevalence of prevalence (PP) for smoking at 7 days, and Questionnaire on smoking cravings, withdrawal, boosting effects, and eating behaviors. The end points of interest also include the number of cigarettes smoked each day, the ban with occasional loss (<5 cigarettes/day), the time of the ban (in weeks) and the time of relapse (if prohibited).

A schematic of the study design is provided in Figure 1. The baseline characteristics of the study individuals are provided in Figures 2 and 3. An overview of the configuration of the individual of the study is provided in Figure 4. The CAR data for the end-tidal carbon monoxide (CO) confirmation at weeks 5-8, 5-12, and 3-12 is provided in Figures 5-8.

At week 9 to week 12, individuals treated with lorcaserin 10 mg BID had a CAR that was statistically significantly greater than the expiratory terminal CO confirmed by clopidogrel 10 mg QD or placebo treated individuals. 5.64%, 8.72%, and 15.31% of individuals in placebo, lorcaserin 10 mg QD, and lorcaserin 10 mg BID, respectively, achieved a primary endpoint (p-value of 10 mg BID of lorcaserin compared to placebo = 0.0027 and odds ratio = 3.02). There was no significant difference in CAR confirmed by expiratory end CO between weeks 9 and 12 of individuals treated with lorcaserin 10 mg QD and placebo-treated individuals (Figure 5).

The percentage of individuals who were statistically significantly greater treated with chlorcalicillin 10 mg BID for the last 6 weeks of treatment compared to placebo-treated individuals showed persistence during the 7-day period prior to the clinical visit. Forbidden (eg by exhalation end CO content) 10 ppm verified) (Figure 9). In addition, the number of cigarettes smoked by clopidogrel 10 mg BID was significantly reduced in number at the 12th week compared to placebo-treated individuals (as measured by the nicotine use list). (Figure 10).

At week 12, individuals treated with lorcaserin 10 mg BID had significantly greater individuals treated with lorcaserin 10 mg QD or placebo (respectively, p = 0.0217 and 0.0004) Weight loss. There was no significant difference in body weight loss between individuals treated with lorcaserin 10 mg QD and placebo-treated individuals (Figures 11 and 13). At week 12, considerable body weight loss was observed for individuals treated with lorcaserin 10 mg BID over the entire BMI study and individuals treated with lorcaserin 10 mg QD over the entire BMI study ( Figures 14 and 15).

At 12 weeks, relative to baseline, responders treated with lorcaserin 10 mg BID (defined as individuals with a forbidden CO confirmation for 4 weeks from week 9 to week 12) lost 0.41 kg (SE 0.58 kg) At the 12th week, relative to baseline, they were treated with chlorcalicillin 10 mg QD or placebo, respectively, by 0.76 kg (SE 0.47 kg) and 0.73 kg (SE 1.14 kg) (Figures 12 and 13).

At week 12, the weight loss of non-smoking individuals (ie, non-responders) treated with lorcaserin 10 mg BID, lorcaserin 10 mg QD, or placebo was greater than the weight loss of each individual treated responder ( Figure 13). At 12 weeks, non-responders treated with lorcaserin 10 mg BID lost 1.02 kg (SE 0.21 kg) relative to baseline, while at week 12, clopidogrel 10 mg QD or placebo relative to baseline The treatments lost 0.50 kg (SE 0.21 kg) and 0.01 kg (SE 0.23 kg), respectively (Fig. 13).

An overview of the treatment of emergency adverse events is shown in Figure 17. In conclusion, treatment with lorcaserin was well tolerated. Adverse events were similar to those most commonly associated with lorcaserin in previous clinical trials (eg, headache, nausea, constipation, dizziness, and dry mouth). Serious adverse events (SAE) are not frequent and are not considered to be related to study treatment.

Example 4 - Salt

( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine, its related salts, mirror image isomers, crystal forms and intermediates </ RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; The entire disclosure of each of these patents is hereby incorporated by reference in its entirety in its entirety in the the the the the the the the the

Example 5 - Formulation

A variety of modified release dosage forms comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine salts and their crystalline forms have been reported in WO2012/030927 The entire disclosure of this patent is incorporated herein by reference.

Example 6 - Modified release ingot containing type III ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3 -benzoazepine hydrochloride hemihydrate Agent

Preparation of modified release ingot of type III (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate (compound 1) Formulations. As established by the pharmacokinetic simulation desired release profile of the upper limit is defined as C _max of no greater than C _max when administered BID immediate release tablets with the 10mg observed.

Reagents and materials Type III ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine hydrochloride hemihydrate

Hydroxypropyl methylcellulose K4M, Colorcon

Microcrystalline cellulose (Avicel PH102), FMC

Mannitol Pearlitol 200SD, Roquette

Mannomem EZ, SPI Pharma

Mannegol 2080, SPI Pharma

Plant-grade magnesium stearate Mallinckrodt

Surelease ^® (Ethyl Cellulose Dispersion), Colorcon

Opadry ^® (YS-1-7472), Colorcon

Opadry ^® II Blue (89F90951), Colorcon

Manufacturing

Make the following batches:

All modified release tablets were manufactured as follows using a direct compression process at a batch size of 300 g to 500 g. ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine hydrochloride hemihydrate, HPMC, mannitol and MCC in 2 boasts Blend in a de-V blender (Globe Pharma MaxiBlend ^® ) for 12 min. The mixture was screened through a sieve (No. 20). The sieved mixture was further blended for 5-10 min, magnesium stearate was added and blending was continued for another 5 min. Piccola PLC using rotary tableting machine (10-20rpm; 10kp) and the mixture was compressed into tablets, and having 11.5 "Vector diameter disk of cladding LDCS Hi-Coater ^® lozenges.

Dissolution test

Dissolution testing was performed using a USP Apparatus I (basket method) in 900 mL of 0.1 N HCl solution at 37 ° C and 100 rpm. The concentration of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzoazepine was analyzed using an HPLC method. The time required to achieve an 80% cumulative release (T80%) was estimated from the dissolution profile.

Establishment of the upper limit of the release curve

Use GastroPlus ^TM software (Simulations Plus Company, Lancaster, CA) to simulate a drug compound from the immediate release and modified release tablets of the kinetics 1. The release profile follows the first order release kinetics and T80% is about 8 hours. The lower limit is not defined. The pharmacokinetic parameters of Compound 1 were obtained from open-label, single-dose, cross-clinical studies in fed and fasted states. The input variables and preset values of the GastroPlus ^TM simulation are as follows

Compound 1 parameter

LogP: 2.56

pKa: 9.53

Dosage form: a) controlled release lozenge administered with 20 mg QD or b) immediate release lozenge administered with 10 mg BID

Solubility: 400mg/mL

Particle density: 1.2g/mL

Effective permeability: 3.54×10 ^-6 cm/s

Physiological parameters (default)

Gastric retention time: 0.25h

Dosage volume: 250mL

Small intestine transit time: 3.3h

Small intestine radius: 1.2cm

Small intestine length: 300cm

Colon volume: 1200mL

Pharmacokinetic parameters

Weight: 94kg

Blood to plasma concentration ratio: 1.3

Clearance rate: 19.56L/h

Apparent distribution volume: 307.36L

Surelease ^® /Opadry ^® Coating effect

Evaluate the Surelease ^® /Opadry ^® ratio of 85/15. Application of the Surelease ^® /Opadry ^® (85/15) coating will substantially reduce the release rate of the Compound 1 hydrochloride salt hemihydrate. The percent release decreased by 20% to 30% after 1 h lag time when the coating weight increased by 2.6% (batch 2) compared to the release of batch 1. The release was further delayed (batch 2) at a higher coating weight gain (4.6%). T80% of batch 2 is 9h, and T80% of batch 3 is 12h. A 2 hour lag time was observed for Batch 3. It can also be observed that the release kinetics migrate away from the first order to a more constant release, especially when the coating weight is increased by 4.6%.

Surelease ^® /Opadry ^® Rate effect

Compare the release profile of tablets coated with different Surelease®/Opadry® ratios when the coating weight is increased by about 5%. A batch of 1 tablet coated with Opadry ^® II blue was included as a control. All batches of core lozenges are formulated identically. As the ratio of Surelease ^® /Opadry ^® increases from 75/25 to 85/15, the release rate of Compound 1 is gradually reduced.

Effect of HPMC K4M content in core lozenges

To evaluate the effect of reducing the amount of HPMC K4M in the core lozenge on the release profile, a core lozenge containing 40% HPMC K4M was prepared. The amount of mannitol was increased to maintain a weight of 300 mg of tablet. Add about 3% (batch 6) and 5% (batch 7) coated tablets with Surelease ^® /Opadry ^® (85/15).

The release of API was 10% to 15% faster in batches 6 and 7 containing 40% HPMC K4M when compared to similarly coated tablets containing batches 2 and 3 of 50% HPMC K4M.

Surelease ^® /Opadry ^® Effect of coating content

Batches 8, 4 and 9 were coated with Surelease ^® /Opadry ^® (75/25) with different coating weight gains to evaluate the effect of coating weight on the release rate of the Compound 1 hydrochloride salt hemihydrate.

A higher coating weight increase will reduce the release rate. T80% is 7 hours, 8 hours and 10 The hours correspond to an increase in coating weight of 2.5%, 5.4%, and 9.9%, respectively.

API load effect

Batches 10 and 11 were developed to evaluate the effect of API loading in the tablet on the release rate. The increase in API is compensated by reducing the amount of mannitol by the same amount.

The increase in API loading in core lozenges from 6.93% to 10.4% shows a limited effect on the release profile. During dissolution, accelerated API release from batch 10 occurred during the first 6 hours and accelerated API release from batch 11 occurred during the first 8 hours. Thereafter, the release profile was essentially concentrated on tablets with a load of 6.63% (batch 2 and 3). The effect of the higher type III Compound 1 hydrochloride salt hemihydrate loading on its release was not as significant as a 5% increase in coating weight when the coating weight was increased by 3%.

In summary, the flexible and robust modified release formulation of Compound III hydrochloride salt hemihydrate was developed using two control mechanisms: HPMC swelling and ethylcellulose coating. Surelease ^® /Opadry ^® ratio, coating weight gain and HPMC content were identified as key formulation parameters.

Other uses of the disclosed methods will be apparent to those skilled in the art based on a review of this patent document.

Claims (107)

A method of assisting in terminating or reducing the use of a tobacco product to terminate or reduce the use of a tobacco product, comprising the steps of: prescribing and/or administering an effective amount of ( R )-8-chloro-1-methyl to the individual Base-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. A method of assisting in the use of a tobacco product and preventing a related weight gain, comprising the steps of prescribing and/or administering an effective amount of ( R )-8-chloro-1-methyl to an individual attempting to terminate the use of the tobacco product Base-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. The method of claim 1 or 2, wherein the use of the tobacco product is assisted in cessation of smoking, and wherein the attempt is made to terminate the individual in which the tobacco product is used to attempt to quit. A method of reducing the frequency of smoking in an individual attempting to reduce the frequency of smoking, comprising the steps of prescribing and/or administering an effective amount of ( R )-8-chloro-1-methyl-2,3 to the individual, 4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. A method of controlling the individual quitting attempt of weight gain associated with the method of smoking cessation, comprising the steps of: prescribing to the individual and / or an effective amount of (R) -8- chloro-l-methyl-2,3, 4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. The method of claim 5, wherein controlling the weight gain comprises preventing weight gain. The method of claim 6, wherein controlling the weight gain comprises inducing weight loss. The method of claim 7, wherein controlling the weight gain comprises inducing at least about 1% of body weight loss after 12 weeks of administration. The method of claim 7, wherein controlling the weight gain comprises inducing at least about 1.5% of body weight loss after 12 weeks of administration. The method of claim 7, wherein controlling the weight gain comprises inducing at least about 2% of body weight loss after 12 weeks of administration. The method of claim 7, wherein controlling the weight gain comprises decreasing the BMI. The method of claim 7, wherein controlling the weight gain comprises decreasing the percentage of body fat. The method of claim 7, wherein controlling the weight gain comprises reducing the waist circumference. A method of reducing weight gain associated with smoking cessation in an individual attempting to quit smoking, comprising the steps of: prescribing and/or administering an effective amount of ( R )-8-chloro-1-methyl-2,3 to the individual, 4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. The method of any one of claims 1 to 14, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzonitrile is administered Prior to hydrazine or a pharmaceutically acceptable salt, solvate or hydrate thereof, the method further comprises the step of directing the individual to set a smoking cessation date. The method of claim 15, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3- is administered about 7 days before the date of the smoking cessation is set. Benzodiazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. The method of any one of claims 1 to 14, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzonitrile is administered After hydrazine or a pharmaceutically acceptable salt, solvate or hydrate thereof, the method further comprises the step of directing the individual to set a smoking cessation date. The method of claim 17, wherein the date on which the smoking cessation is set occurs in the administration of the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzene Nitrogen or its pharmaceutically acceptable salt, solvate or hydrate after at least 7 days. The method of claim 17 or 18, wherein the date of smoking cessation is set to occur in the administration of the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3- Benzodiazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof 36 days before. The method of any one of claims 1 to 19, wherein the individual has previously attempted to quit but did not successfully quit. The method of any one of claims 1 to 19, wherein the individual has previously attempted to quit but subsequently relapses and resumes smoking. The method of any one of claims 1 to 21, wherein the administration produces a statistically significant improvement in the ability to withstand the cessation of smoking, as measured by analyzing data from the MPSS test. A method of treating nicotine dependence, addiction, and/or withdrawal in an individual attempting to treat nicotine dependence, addiction, and/or withdrawal, comprising the steps of: prescribing and/or administering an effective amount to the individual ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. A method of reducing the likelihood of attempting to terminate nicotine use by an individual to re-use nicotine, comprising the steps of prescribing and/or administering an effective amount of ( R )-8-chloro-1-methyl-2 to the individual , 3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. The method of claim 23 or 24, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzene is administered and/or administered The individual has quit nicotine use for up to 12 weeks prior to the nitrogen hydrazine or its pharmaceutically acceptable salt, solvate or hydrate. The method of claim 23 or 24, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzene is administered and/or administered The individual has quit nicotine use for up to 24 weeks prior to the nitrogen hydrazine or its pharmaceutically acceptable salt, solvate or hydrate. The method of claim 23 or 24, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzene is administered and/or administered The individual has quit nicotine use for up to 9 months prior to the nitrogen hydrazine or its pharmaceutically acceptable salt, solvate or hydrate. The method of claim 23 or 24, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzene is administered and/or administered The individual has quit nicotine use for 52 weeks prior to guanidine or a pharmaceutically acceptable salt, solvate or hydrate thereof. The method of any one of claims 1 to 28, wherein the individual has an initial body mass index <25 kg/m ² prior to administration. The method of any one of claims 1 to 28, wherein the initial body mass index of the individual prior to administration 25kg/m ² . The method of any one of claims 1 to 28, wherein the initial body mass index of the individual prior to administration 27kg/m ² . The method of claim 30 or 31, wherein the individual has at least one weight related comorbid condition prior to administration. The method of claim 32, wherein the weight-related comorbid condition is selected from the group consisting of hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea. The method of claim 32, wherein the weight-related comorbid condition is selected from the group consisting of hypertension, dyslipidemia, and type 2 diabetes. The method of any one of claims 1 to 28, wherein the initial body mass index of the individual prior to administration 30kg/m ² . An increase in the frequency of smoking in an individual who attempts to reduce the frequency of smoking, an attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control the weight gain associated with smoking cessation in individuals who attempt to quit smoking Reducing the weight gain associated with smoking cessation, the nicotine dependence, addiction and/or withdrawal of individuals attempting to treat nicotine dependence, addiction and/or withdrawal, or reducing the individual attempting to terminate nicotine use A method of re-using the possibility of nicotine, which includes: selecting the initial BMI An individual of 27 kg/m ² ; and prescribing and/or administering an effective amount of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3- to the individual Benzodiazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof for at least one year. The method of claim 36, wherein the individual is prescribed and/or the effective amount of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H - 3-benzoxazide or a pharmaceutically acceptable salt, solvate or hydrate thereof for one year. The method of claim 36 or 37, wherein the individual has at least one weight related comorbid condition prior to administration. The method of claim 38, wherein the weight-related comorbid condition is selected from the group consisting of hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea. The method of claim 38, wherein the weight-related comorbid condition is selected from the group consisting of hypertension, dyslipidemia, and type 2 diabetes. The method of any one of claims 36 to 40, wherein the initial body mass index of the individual prior to administration 30kg/m ² . An increase in the frequency of smoking in an individual who attempts to reduce the frequency of smoking, an attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control the weight gain associated with smoking cessation in individuals who attempt to quit smoking Reducing the weight gain associated with smoking cessation, the nicotine dependence, addiction and/or withdrawal of individuals attempting to treat nicotine dependence, addiction and/or withdrawal, or reducing the individual attempting to terminate nicotine use A method of re-using the possibility of nicotine comprising: administering to the individual ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine Or a pharmaceutically acceptable salt, solvate or hydrate thereof; monitoring the BMI of the individual during the administration; and if the BMI of the individual becomes <18.5 kg/m ² during the administration, interrupting Cast. The method of claim 42, wherein the individual has an initial BMI of from about 18.5 kg/m ² to about 25 kg/m ² prior to administration. The method of claim 43, wherein the individual has an initial BMI selected from one of: 24kg/m ² , 23kg / m ^2, 22.5kg/m ² , 22kg/m ² , 21kg/m ² , 20kg/m ² , 19kg/m ² and 18.5kg/m ² . The method of claim 43 or 44, wherein the BMI of the individual becomes a BMI selected from one of: 18kg/m ² , 17.5kg/m ² , 17kg/m ² , 16kg/m ² and 15kg/m ² . An increase in the frequency of smoking in an individual who attempts to reduce the frequency of smoking, an attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control the weight gain associated with smoking cessation in individuals who attempt to quit smoking Reducing the weight gain associated with smoking cessation, the nicotine dependence, addiction and/or withdrawal of individuals attempting to treat nicotine dependence, addiction and/or withdrawal, or reducing the individual attempting to terminate nicotine use A method of re-using the possibility of nicotine, which includes: to the initial BMI Individuals of 25 kg/m ² are administered ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt thereof, a solvate or hydrate; monitoring the body weight of the individual during the administration; and if the individual's weight is reduced by more than about 1% during the administration period, the administration is discontinued. The method of claim 46, wherein the initial BMI of the individual is between about 18.5 kg/m ² to about 25 kg/m ² prior to administration. The method of claim 47, wherein the individual has an initial BMI selected from one of: 24kg/m ² , 23kg / m ^2, 22.5kg/m ² , 22 kg/m ² , 21kg/m ² , 20kg/m ² , 19kg/m ² and 18.5kg/m ² . The method of any one of claims 46 to 48, wherein the reduction in body weight is selected from one of: greater than about 1.5%, greater than about 2%, greater than about 2.5%, greater than about 3%, greater than about 3.5% , greater than about 4%, greater than about 4.5%, and greater than about 5%. An increase in the frequency of smoking in an individual who attempts to reduce the frequency of smoking, an attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products, help to quit smoking and prevent related weight gain, and control the weight gain associated with smoking cessation in individuals who attempt to quit smoking Reducing the weight gain associated with smoking cessation, the nicotine dependence, addiction and/or withdrawal of individuals attempting to treat nicotine dependence, addiction and/or withdrawal, or reducing the individual attempting to terminate nicotine use A method of re-using the possibility of nicotine comprising: administering to the individual ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine Or a pharmaceutically acceptable salt, solvate or hydrate thereof; the body weight of the individual is monitored during the administration; and if the individual's body weight is reduced by more than about 1 kg during the administration period, the administration is discontinued. The method of claim 50, wherein the individual has an initial BMI of from about 18.5 kg/m ² to about 25 kg/m ² prior to administration. The method of claim 51, wherein the individual has an initial BMI selected from one of: 24kg/m ² , 23kg / m ^2, 22.5kg/m ² , 22kg/m ² , 21kg/m ² , 20kg/m ² , 19kg/m ² and 18.5kg/m ² . The method of claim 51 or 52, wherein the reduction in body weight is selected from one of: greater than about 1.5 kg, greater than about 2 kg, greater than about 2.5 kg, greater than about 3 kg, greater than about 3.5 kg, greater than about 4 kg, greater than About 4.5 kg and more than about 5 kg. The method of any one of claims 1 to 53, wherein the administration produces a statistically significant improvement in the ability to withstand the cessation of smoking, as measured by analyzing data from the MPSS test. The method of any one of claims 1 to 54, wherein the individual is administering the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzene Desire is preceded by azepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. The method of any one of claims 1 to 55, wherein the individual is administering the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzene Azeousin or a pharmaceutically acceptable salt, solvate or hydrate thereof is preceded by an existing psychiatric disorder. The method of claim 56, wherein the pre-existing mental illness is selected from the group consisting of schizophrenia, a two-way affective disorder, and major depression. The method of any one of claims 1 to 57, wherein the individual is also prescribed and/or administered with a supplement. The method of claim 58, wherein the supplement is varenicline or a pharmaceutically acceptable salt thereof. The method of claim 58, wherein the supplement is clonidine. The method of claim 58, wherein the supplement is a nicotine replacement therapy. The method of claim 61, wherein the nicotine replacement therapy is selected from the group consisting of a nicotine chewable tablet, a nicotine transdermal system, a nicotine diamond lozenge, a nicotine sublingual tablet, and a nicotine spray or inhaler. The method of claim 58, wherein the supplement is an antidepressant. The method of claim 63, wherein the antidepressant is selected from the group consisting of nortriptyline and bupropion. The method of any one of claims 1 to 64, wherein the individual has previously received treatment with a supplement. The method of claim 65, wherein the individual is refractory to the treatment of the supplement Sex. The method of any one of claims 1 to 64, wherein the individual has previously received treatment with nicotine replacement therapy. The method of claim 67, wherein the individual is refractory to the treatment of the nicotine replacement therapy. The method of any one of claims 1 to 68, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzonitrile is administered The individual smokes daily before hydrazine or a pharmaceutically acceptable salt, solvate or hydrate thereof 10 cigarettes. The method of any one of claims 1 to 69, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzonitrile is administered Prior to sputum or a pharmaceutically acceptable salt, solvate or hydrate thereof, the individual has moderate nicotine addiction as measured by a Nigerin-dependent Fagerström test. The method of any one of claims 1 to 69, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzonitrile is administered Prior to sputum or a pharmaceutically acceptable salt, solvate or hydrate thereof, the individual has a severe nicotine addiction as measured by the Fagerström test for nicotine dependent scores. The method of any one of claims 1 to 69, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzonitrile is administered Prior to sputum or a pharmaceutically acceptable salt, solvate or hydrate thereof, the individual has a very severe nicotine addiction as measured by the Fagerström test for nicotine dependent scores. The method of any one of claims 1 to 72, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or A pharmaceutically acceptable salt, solvate or hydrate is administered for at least about 2 weeks. The method of any one of claims 1 to 72, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or A pharmaceutically acceptable salt, solvate or hydrate is administered for at least about 4 weeks. The method of any one of claims 1 to 72, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or A pharmaceutically acceptable salt, solvate or hydrate is administered for at least about 8 weeks. The requested item A method according to any one of 1 to 72, wherein the (R) -8- chloro-l-methyl-2,3,4,5-tetrahydro-benzo -1 H -3- nitrogen or Boom A pharmaceutically acceptable salt, solvate or hydrate is administered for at least about 12 weeks. The method of any one of claims 1 to 72, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or A pharmaceutically acceptable salt, solvate or hydrate is administered for at least about 6 months. The method of any one of claims 1 to 72, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or A pharmaceutically acceptable salt, solvate or hydrate is administered for at least about one year. The method of any one of claims 1 to 72, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or A pharmaceutically acceptable salt, solvate or hydrate is administered for at least about 2 years. The method of any one of claims 1 to 72, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or Pharmaceutically acceptable salts, solvates or hydrates are administered for from about 12 weeks to about 52 weeks. The method of any one of claims 1 to 80, further comprising the step of providing educational material and/or counseling to the individual. The method of any one of claims 1 to 81, further comprising the step of providing biochemical feedback to the individual; acupuncture; hypnosis; behavioral intervention; support services; and/or psychotherapy. The method of any one of claims 1 to 82, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or A pharmaceutically acceptable salt, solvate or hydrate ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine hydrochloride Or a solvate or hydrate thereof. The method of any one of claims 1 to 83, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or A pharmaceutically acceptable salt, solvate or hydrate ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine hydrochloride Hemihydrate. The method of claim 83, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine hydrochloride or a solvate thereof Or the hydrate system prescribes and/or administers the individual at a dose equal to 20 mg/day. The method of claim 83, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine hydrochloride or a solvate thereof Or the hydrate system is prescribed and/or administered to the individual at a dose equal to 10 mg twice daily. The method of any one of claims 1 to 86, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or Pharmaceutically acceptable salts, solvates or hydrates are administered in lozenges suitable for oral administration. A composition comprising ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzodiazepine or a pharmaceutically acceptable salt thereof, solvate Or hydrate and at least one supplement. The composition of claim 88, wherein the supplement is selected from the group consisting of nicotine replacement therapy. The composition of claim 88, wherein the supplement is selected from the group consisting of an antidepressant. The composition of claim 88, wherein the supplement is selected from the group consisting of clonidine or a pharmaceutically acceptable salt thereof. The composition of claim 88, wherein the supplement is selected from the group consisting of varenicline or a pharmaceutically acceptable salt thereof. The composition of any one of claims 88 to 92, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or A pharmaceutically acceptable salt, solvate or hydrate thereof is selected from the group consisting of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl Salts and solvates or hydrates thereof. The composition of any one of claims 88 to 92, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof selected from the group consisting of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine And its pharmaceutically acceptable salts. The composition of any one of claims 88 to 92, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl salt Hydrate. The composition of any one of claims 88 to 92, wherein the ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride Hemihydrate. The composition of any one of claims 88 to 96 for use in the method of reducing the frequency of smoking in an individual attempting to reduce the frequency of smoking; assisting an individual attempting to terminate or reduce the use of the tobacco product to terminate or reduce the use of the tobacco product Helps quit smoking and prevents related weight gain; controls the weight gain associated with smoking cessation in individuals who attempt to quit; reduces the weight gain associated with smoking cessation in individuals who attempt to quit; treatment attempts to treat individuals with nicotine dependence, addiction, and/or withdrawal Nicotine dependence, addiction, and/or withdrawal; or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine. The compound of any one of claims 88 to 96 for use as an agent for reducing the frequency of smoking in an individual attempting to reduce the frequency of smoking; Helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products; help to quit smoking and prevent related weight gain; control the weight gain associated with smoking cessation in individuals who attempt to quit; reduce the weight gain associated with smoking cessation in individuals who attempt to quit; Treatment attempts to treat nicotine dependence, addiction, and/or withdrawal in individuals with nicotine dependence, addiction, and/or withdrawal; or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine. The composition of any one of claims 88 to 96 for use in the manufacture of a medicament for reducing the frequency of smoking in an individual attempting to reduce the frequency of smoking; assisting an individual attempting to terminate or reduce the use of tobacco products to terminate or reduce tobacco Use of the product; help to quit smoking and prevent related weight gain; control the weight gain associated with smoking cessation in individuals who attempt to quit; reduce the weight gain associated with smoking cessation in individuals who attempt to quit; treatment attempts to treat nicotine dependence, addiction and/or withdrawal The nicotine dependence, addiction, and/or withdrawal of the individual; or the likelihood of attempting to terminate the use of nicotine by the individual attempting to terminate nicotine use. A unit dosage form of the composition of any one of claims 88 to 96. ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof, It is used in the following methods: reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking; helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products; helping to quit smoking and preventing related weight gain; controlling individuals who attempt to quit smoking Weight gain associated with smoking cessation; reduction in weight gain associated with smoking cessation in individuals attempting to quit; treatment of nicotine dependence, addiction, and/or withdrawal in individuals attempting to treat nicotine dependence, addiction, and/or withdrawal; or reduction Try to stop the possibility of nicotine re-use of nicotine. ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof, It is used as an agent for reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking; helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products; to help quit smoking and prevent related weight gain; Weight gain associated with smoking cessation; reduction in weight gain associated with smoking cessation in individuals attempting to quit; treatment of nicotine dependence, addiction, and/or withdrawal in individuals attempting to treat nicotine dependence, addiction, and/or withdrawal; or Reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine. ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof, It is used to manufacture pharmaceuticals for reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking; to help individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products; to help quit smoking and to prevent related weight gain; Weight loss associated with smoking cessation; reduction in weight gain associated with smoking cessation in individuals attempting to quit; treatment of nicotine dependence, addiction, and/or withdrawal in individuals attempting to treat nicotine dependence, addiction, and/or withdrawal Or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine. ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof, It has at least one of the properties described herein and is used in combination with a supplement. ( R )-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzoazepine or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 104 Or hydrates, which are used in the following methods: reducing the frequency of smoking in individuals who attempt to reduce the frequency of smoking; helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products; helping to quit smoking and preventing related weight gain; Weight gain associated with smoking cessation in individuals attempting to quit; reducing weight gain associated with smoking cessation in individuals attempting to quit; treatment of nicotine dependence, addiction, and/or abstinence in individuals attempting to treat nicotine dependence, addiction, and/or withdrawal Broken; or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine. A supplement selected from the group consisting of nicotine replacement therapy and ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H- 3-benzene having at least one of the properties described herein Azepine or a pharmaceutically acceptable salt, solvate or hydrate thereof is used in combination. The supplement of claim 106, which is used in the method of reducing the frequency of smoking in an individual attempting to reduce the frequency of smoking; Helping individuals who attempt to terminate or reduce the use of tobacco products to terminate or reduce the use of tobacco products; help to quit smoking and prevent related weight gain; control the weight gain associated with smoking cessation in individuals who attempt to quit; reduce the weight gain associated with smoking cessation in individuals who attempt to quit; Treatment attempts to treat nicotine dependence, addiction, and/or withdrawal in individuals with nicotine dependence, addiction, and/or withdrawal; or reduce the likelihood that an individual attempting to terminate nicotine use will re-use nicotine.