WO2016069875A1 - Compositions et procédés permettant de renoncer au tabac - Google Patents

Compositions et procédés permettant de renoncer au tabac Download PDF

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Publication number
WO2016069875A1
WO2016069875A1 PCT/US2015/058016 US2015058016W WO2016069875A1 WO 2016069875 A1 WO2016069875 A1 WO 2016069875A1 US 2015058016 W US2015058016 W US 2015058016W WO 2016069875 A1 WO2016069875 A1 WO 2016069875A1
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WIPO (PCT)
Prior art keywords
individual
tetrahydro
chloro
benzazepine
methyl
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PCT/US2015/058016
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English (en)
Inventor
Dominic P. Behan
Alan GLICKLICH
Andrew J. Grottick
Maria Matilde Sanchez KAM
William R. Shanahan
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Arena Pharmaceuticals, Inc.
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Publication of WO2016069875A1 publication Critical patent/WO2016069875A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • Tobacco use is the leading cause of preventable illness and early death across the globe.
  • World Health Organization Fact Sheet July 2013
  • Tobacco use is directly related to cardiovascular disease, lung and other cancers, and chronic lower respiratory diseases (chronic bronchitis, emphysema, asthma, and other chronic lower respiratory diseases) ⁇ Health Effects of Cigarette Smoking. Centers for Disease Prevention website.
  • CHANTIX varienicline
  • ZYBAN bupropion SR
  • the prescribing information for both CHANTIX and ZYBAN include black box warnings.
  • the CHANTIX prescribing information carries a warning for serious neuropsychiatric events, to include symptoms of agitation, hostility, depressed mood changes, behavior or thinking that are not typical for the patient, and suicidal ideation or suicidal behavior (CHANTIX (varenicline) (package insert), New York, NY: Pfizer Labs, Division of Pfizer, Inc.; 2012).
  • the warning notes that a meta-analysis found cardiovascular events were infrequent, but some were reported more frequently in individuals treated with CHANTIX; the difference was not statistically significant (CHANTIX (varenicline) (package insert), New York, NY: Pfizer Labs, Division of Pfizer, Inc.; 2012).
  • the ZYBAN prescribing information includes a similar black box warning for serious neuropsychiatric events during treatment as well as after discontinuation of treatment (ZYBAN (bupropion hydrochloride) (package insert), Research Triangle Park, NC: GlaxoSmithKline; 2012).
  • Additional warnings include monitoring of individuals using antidepressants as there is an increased risk of suicidal thinking and behavior in children, adolescents and young adults, and other psychiatric disorders (ZYBAN (bupropion hydrochloride) (package insert), Research Triangle Park, NC: GlaxoSmithKline; 2012).
  • ZYBAN bupropion hydrochloride
  • weight gain is a well-recognized side effect of quitting smoking.
  • Smoking cessation leads to weight gain in about 80% of smokers.
  • the average weight gain in the first year after quitting is 4-5 kg, most of which is gained during the first 3 months. This amount of weight is typically viewed as a modest inconvenience compared with the health benefits of smoking cessation, but 10-20% of quitters gain more than 10 kg.
  • a method for reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of (/?)-8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Also provided is a method for 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 comprising the step of: prescribing and/or administering to the individual an effective amount of ( ?)-8-chloro- l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Also provided is a method for aiding in smoking cessation and preventing associated weight gain in an individual attempting to cease smoking and prevent weight gain comprising the step of: prescribing and/or administering to the individual an effective amount of (R)-8- chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Also provided is a method for controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of ( ?)-8-chloro-l- methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Also provided is a method of treatment for nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal comprising the step of: prescribing and/or administering to the individual an effective amount of (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Also provided is a method of reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use comprising the step of: prescribing and/or administering to the individual an effective amount of (/?)-8-chloro- l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Also provided is a method for reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of (/?)-8-chloro- l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • composition comprising (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and at least one supplemental agent.
  • a supplemental agent chosen from nicotine replacement therapies, for use in combination with (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • INDIVIDUAL As used herein, an "individual” is a human. An individual can be an adult or prepubertal (a child) and can be of any gender. The individual can be a patient or other individual seeking treatment. "Individual” is used herein interchangeably with “subject.” PLURALITY OF INDIVIDUALS: As used herein, a "plurality of individuals" means more than one individual.
  • ADMINISTERING means to provide a compound or other therapy, remedy or treatment.
  • a health care practitioner can directly provide a compound to an individual in the form of a sample, or can indirectly provide a compound to an individual by providing an oral or written prescription for the compound.
  • an individual can obtain a compound by themselves without the involvement of a health care practitioner.
  • Administration of the compound may or may not involve the individual actually internalizing the compound. In the case where an individual internalizes the compound, the body is transformed by the compound in some way.
  • PRESCRIBING means to order, authorize or recommend the use of a drug or other therapy, remedy or treatment.
  • a health care practitioner can orally advise, recommend or authorize the use of a compound, dosage regimen or other treatment to an individual.
  • the health care practitioner may or may not provide a prescription for the compound, dosage regimen or treatment.
  • the health care practitioner may or may not provide the recommended compound or treatment.
  • the health care practitioner can advise the individual where to obtain the compound without providing the compound.
  • a health care practitioner can provide a prescription for the compound, dosage regimen or treatment to the individual.
  • a health care practitioner can give a written or oral prescription to an individual.
  • a prescription can be written on paper or on electronic media such as a computer file, for example, on a handheld computer device.
  • a health care practitioner can transform a piece of paper or electronic media with a prescription for a compound, dosage regimen or treatment.
  • a prescription can be called in (oral) or faxed in (written) to a pharmacy or a dispensary.
  • a sample of the compound or treatment can be given to the individual.
  • giving a sample of a compound constitutes an implicit prescription for the compound.
  • Different health care systems around the world use different methods for prescribing and administering compounds or treatments and these methods are encompassed by the disclosure.
  • a prescription can include, for example, an individual's name and/or identifying information such as date of birth.
  • a prescription can include, the medication name, medication strength, dose, frequency of administration, route of administration, number or amount to be dispensed, number of refills, physician name, and/or physician signature.
  • a prescription can include a DEA number or state number.
  • a healthcare practitioner can include, for example, a physician, nurse, nurse practitioner or other related health care professional who can prescribe or administer compounds (drugs) for weight management, smoking cessation, or nicotine dependence.
  • a healthcare practitioner can include anyone who can recommend, prescribe, administer or prevent an individual from receiving a compound or drug including, for example, an insurance provider.
  • prevent such as prevention of weight gain associated with smoking cessation means prevention of the occurrence or onset of one or more symptoms associated with a particular disorder and does not necessarily mean the complete prevention of a disorder. For example, weight gain may be prevented even if the individual gains some amount of weight.
  • prevention refers to the administration of therapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one symptom of a disease or condition but who has not yet done so.
  • individuals can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease.
  • prevention therapy can be administered without prior identification of a risk factor, as a prophylactic measure. Delaying the onset of the at least one symptom can also be considered prevention or prophylaxis.
  • PHARMACEUTICALLY ACCEPTABLE SALTS, SOLVATES, AND HYDRATES It is understood that when the phrase “pharmaceutically acceptable salts, solvates, and hydrates" or the phrase “pharmaceutically acceptable salt, solvate, or hydrate” is used when referring to a compound/compounds as described herein, it embraces pharmaceutically acceptable solvates and/or hydrates of the compound/compounds, pharmaceutically acceptable salts of the compound/compounds, as well as pharmaceutically acceptable solvates and/or hydrates of pharmaceutically acceptable salts of the compound/compounds.
  • TREAT, TREATING, OR TREATMENT refers to the administration of therapy to an individual who already manifests, or who has previously manifested, at least one symptom of a disease, disorder, condition, dependence, or behavior.
  • “treating” can include any of the following with respect to a disease, disorder, condition, dependence, or behavior: alleviating, abating, ameliorating, inhibiting (e.g. , arresting the development), relieving, or causing regression.
  • Treating can also include treating the symptoms, preventing additional symptoms, preventing the underlying physiological causes of the symptoms, or stopping the symptoms (either prophylactically and/or therapeutically) of a disease, disorder, condition, dependence, or behavior.
  • treating a disorder in reference to a disorder means a reduction in severity of one or more symptoms associated with a particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.
  • a method for treatment of obesity can result in weight loss; however, the weight loss does not need to be enough such that the individual is no longer obese. It has been shown that even modest decreases in weight or related parameters such as BMI, waist circumference and percent body fat, can result in improvement of health, for example, lower blood pressure, improved blood lipid profiles, or a reduction in sleep apnea.
  • weight management refers to controlling weight (also called weight control) and/or controlling parameters related to weight, for example, BMI, percent body fat and/or waist circumference. In the context of the present disclosure, weight management is directed toward preventing weight gain, controlling weight gain, reducing weight gain, maintaining weight, or inducing weight loss.
  • weight management includes preventing an increase in BMI, reducing an increase in BMI, maintaining BMI, or reducing BMI; preventing an increase in percent body fat, reducing an increase in percent body fat, maintaining percent body fat, or reducing percent body fat; and preventing an increase in waist circumference, reducing an increase in waist circumference, maintaining waist circumference, or reducing waist circumference.
  • ADVERSE EVENT OR TOXIC EVENT is any untoward medical occurrence that may present itself during treatment.
  • Adverse events associated with treatment may include, for example, headache, nausea, constipation, fatigue, dry mouth, dizziness, abnormal dreams, insomnia, nasopharyngitis, toothache, sinusitis, back pain, somnolence, viral gastroenteritis, seasonal allergy, or pain in an extremity.
  • Additional possible adverse effects include, for example, gastrointestinal disorders (such as constipation, abdominal distension, and diarrhea), asthenia, chest pain, fatigue, drug hypersensitivity, fibromyalgia, temporomandibular joint syndrome, headache, dizziness, migraine, anxiety, depressed mood, irritability, suicidal ideation, bipolar disorder, depression, drug abuse, and dyspnea.
  • gastrointestinal disorders such as constipation, abdominal distension, and diarrhea
  • asthenia chest pain, fatigue, drug hypersensitivity, fibromyalgia, temporomandibular joint syndrome, headache, dizziness, migraine, anxiety, depressed mood, irritability, suicidal ideation, bipolar disorder, depression, drug abuse, and dyspnea.
  • gastrointestinal disorders such as constipation, abdominal distension, and diarrhea
  • asthenia chest pain, fatigue, drug hypersensitivity, fibromyalgia, temporomandibular joint syndrome, headache, dizziness, migraine, anxiety, depressed mood,
  • AGONIST As used herein, the term "agonist” refers to a moiety that interacts with and activates a receptor, such as the 5-HT 2 c serotonin receptor, and initiates a physiological or pharmacological response characteristic of that receptor.
  • immediate-release dosage form refers to a formulation which rapidly disintegrates upon oral administration to a human or other animal, releasing an active pharmaceutical ingredient (API) from the formulation.
  • API active pharmaceutical ingredient
  • 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 1 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% refers to the time needed to achieve 80% cumulative release of an API from a particular formulation comprising the API.
  • MODIFIED-RELEASE DOSAGE FORM The term "modified-release dosage form” refers to any formulation that, upon oral administration to a human or other animal, releases an API after a given time (i.e. , delayed release) or for a prolonged period of time (extended release), e.g. , at a slower rate over an extended period of time when compared to an immediate-release dosage-form of the API (e.g. , sustained release). Exemplary modified- release dosage forms are described in WO2012/030927.
  • the modified- release dosage form comprises: a core comprising about 20.8 mg lorcaserin HC1 hemihydrate, about 60 mg microcrystalline cellulose, about 65.5 mg mannitol, about 150 mg hydroxypropyl methylcellulose, about 0.75 mg colloidal silicon dioxide, and about 3 mg magnesium stearate; a functional coating comprising about 12.75 mg ethylcellulose dispersion type B, and about 2.25 mg OPADRY; and a film coating comprising about 13.5 mg OPADRY II.
  • nicotine replacement therapy refers to the remedial administration of nicotine to the body by means other than a tobacco product.
  • nicotine replacement therapy may include transdermal nicotine delivery systems, including patches and other systems that are described in the art, for example, in U.S. Pat. Nos. 4,597,961, 5,004,610, 4,946,853, and 4,920,989.
  • Inhaled nicotine e.g. , delivery of the nicotine through pulmonary routes
  • Transmucosal administration e.g., delivery of nicotine to the systemic circulation through oral drug dosage forms
  • Oral drug dosage forms e.g.
  • lozenge, capsule, gum, tablet, suppository, ointment, gel, pessary, membrane, and powder are typically held in contact with the mucosal membrane and disintegrate and/or dissolve rapidly to allow immediate systemic absorption.
  • the nicotine replacement therapy is chosen from nicotine gum (e.g. , NICORETTE), nicotine transdermal systems such as nicotine patches (e.g. , HABITROL and NICODERM), nicotine lozenges (e.g.
  • nicotine replacement therapy includes electronic cigarettes, personal vaporizers, and electronic nicotine delivery systems.
  • drug/device, biologic/device, drug/biologic, or drug/device/biologic that are physically, chemically, or otherwise combined or mixed and produced as a single entity; (2) two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products; (3) a drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g.
  • any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.
  • Combinations include without limitation a fixed-dose combination product (FDC) in which two or more separate drug components are combined in a single dosage form; a co-packaged product comprising two or more separate drug products in their final dosage forms, packaged together with appropriate labeling to support the combination use; and an adjunctive therapy in which a patient is maintained on a second drug product that is used together with (i.e.
  • Adjunctive therapy products may be co-packaged, and may or may not be labeled for concomitant use.
  • RESPONDER refers to an individual who experiences continuous abstinence from tobacco use during a specified period of administration of (R)-8- chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • responder refers to an individual who reports no smoking or other nicotine use from Week 9 to Week 12 of administration of lorcaserin hydrochloride hemihydrate and exhibits an end-expiratory exhaled carbon monoxide-confirmed measurement of ⁇ 10 ppm.
  • TOBACCO PRODUCT As used herein, "tobacco product” refers to a product that incorporates tobacco, i.e. , the agricultural product of the leaves of plants in the genus Nicotiana. Tobacco products can generally be divided into two types: smoked tobacco including without limitation pipe tobacco, cigarettes (including electronic cigarettes) and cigars, as well as Mu'assel, Dokha, shisha tobacco, hookah tobacco, or simply shisha; and smokeless tobacco including without limitation chewing tobacco, dipping tobacco (also known as dip), moist snuff (or snuff), American moist snuff, snus, Iqmik, Naswar, Gutka, Toombak, shammah, tobacco water, spit tobacco, creamy snuff or tobacco paste, dissolvable tobacco, and tobacco gum.
  • smoked tobacco including without limitation pipe tobacco, cigarettes (including electronic cigarettes) and cigars, as well as Mu'assel, Dokha, shisha tobacco, hookah tobacco, or simply shisha
  • FAGERSTROM TEST As used herein, "Fagerstrom test” refers to a standard test for nicotine dependence which is a test for assessing the intensity of nicotine addiction. See Heatherton, T. F., Kozlowski, L. T., Frecker, R. C, Fagerstrom, K. O. The Fagerstrom test for Nicotine Dependence: A revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 1991; 86:1119-27. The test consists of a brief, self-report survey that measures nicotine dependence on a scale of 0-10, with 10 being the highest level of dependence. A score of 0-2 corresponds to very low dependence. A score of 3-4 corresponds to low dependence. A score of 5 corresponds to moderate dependence. A score of 6-7 corresponds to high dependence. A score of 8-10 corresponds to very high dependence.
  • DSM-III-R Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition
  • MPSS Physical Symptoms Scale
  • the core elements of MPSS involve a 5-point rating of depressed mood, irritability, restlessness, difficulty concentrating and hunger and a 6-point rating of strength of urges to smoke and time spent with these urges.
  • lorcaserin refers to (/?)-8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine.
  • lorcaserin hydrochloride refers to the hydrochloric acid salt of (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine (see Statement on Nonproprietary Name Adopted by the USAN Council for Lorcaserin Hydrochloride).
  • the term “greater than” is used interchangeably with the symbol > and the term “less than” is used interchangeably with the symbol ⁇ .
  • the term less than or equal to is used interchangeably with the symbol ⁇ and the term greater than or equal to is used interchangeably with the symbol >.
  • the term “about” can be inserted before the integer.
  • the term “greater than 29 kg/m 2” can be substituted with “greater than about 29 kg/m 2 ".
  • composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i. e. , one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.
  • a method that recites prescribing or administering (R)- 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine can be separated into two methods— one reciting prescribing (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine and the other reciting administering (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine.
  • a method that recites prescribing (/?)-8-chloro- l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine and a separate method of the invention reciting administering (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine can be combined into a single method reciting prescribing and/or administering ( ?)-8-chloro-l-methyl-2,3,4,5- tetrahydro- lH-3-benzazepine.
  • 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 subjects in the Phase 2 clinical trial.
  • Figure 4 shows the disposition of subjects from the Phase 2 clinical trial.
  • Figure 5 shows CO-confirmed 4- week CARs for Weeks 9 to 12 in the MITT population from the Phase 2 clinical trial
  • "n" in Figures 5-8 is the number of subjects that reported not smoking (not even a puff or other nicotine use) and exhibited an end-expiratory CO level of ⁇ 10 ppm.
  • Figure 6 shows CO-confirmed 4- week CARs for Weeks 5 to 8 in the MITT population.
  • Figure 7 shows CO-confirmed 4-week CARs for Weeks 5 to 12 in the MITT population.
  • Figure 8 shows CO-confirmed 4-week CARs for Weeks 3 to 12 in the MITT population.
  • Figure 9 shows the 7-day point prevalence smoking abstinence at Week 12 in the MITT population
  • "n" in Figure 9 is the number of subjects who were continuously abstinent for the 7-day period preceding a clinical visit and exhibited an end-expiratory CO level of ⁇ 10 ppm.
  • Figure 10 shows the change from baseline in number of cigarettes smoked at Week 12 in the MITT population.
  • Figure 11 shows the change from baseline in body weight (in kg) at Week 12 in the MITT population.
  • Figure 12 shows the change from baseline in body weight (in kg) at Week 12 for responders in the MITT population.
  • "Responders" in Figure 12 are subjects who had 4 weeks of continuous abstinence from Week 9 to Week 12 and exhibited an end-expiratory CO level of ⁇ 10 ppm.
  • Figure 13 shows the change from baseline in body weight (in kg) at Week 12 by responder status in the MITT population.
  • "Responders" in Figure 13 are subjects who had 4 weeks of continuous abstinence from Week 9 to Week 12 and exhibited an end-expiratory CO level of ⁇ 10 ppm.
  • Figure 14 shows the change from baseline in body weight (in kg) at Week 12 by baseline BMI in the MITT population.
  • Figure 15 shows the change from baseline in body weight (in kg) at Week 12 by baseline BMI in the MITT population.
  • Figure 16 shows the change from baseline in body weight (in kg) at Week 12 by baseline BMI and responder status in the MITT population.
  • "Responders" in Figure 16 are subjects who had 4 weeks of continuous abstinence from Week 9 to Week 12 and exhibited an end-expiratory CO level of ⁇ 10 ppm.
  • Figure 17 shows a summary of treatment-emergent adverse events in the Phase 2 clinical trial.
  • Figure 18 shows potency and efficacy of lorcaserin in human, rat, and monkey 5-HT 2 A, 5-HT 2 B, and 5-HT 2 c receptors.
  • Figure 19 shows differences in exposure and 5-HT 2 receptor selectivity in humans and rats.
  • a method for 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 comprising the step of: prescribing and/or administering to the individual an effective amount of (/?)-8-chloro-l- methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • aiding in the cessation of use of a tobacco product is aiding smoking cessation, and the individual attempting to cease use of the tobacco product is an individual attempting to cease smoking.
  • Also provided is a method for aiding in the cessation of use of a tobacco product and the prevention of associated weight gain comprising the step of: prescribing and/or administering an effective amount of (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof to an individual attempting to cease use of the tobacco product.
  • aiding in the cessation of use of a tobacco product is aiding smoking cessation, and the individual attempting to cease use of the tobacco product is an individual attempting to cease smoking.
  • Also provided is a method for reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of (/?)-8-chloro-l- methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Also provided is a method for controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of ( ?)-8-chloro-l- methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Also provided is a method for reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of (/?)-8-chloro- l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Also provided is a method of treatment for nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal comprising the step of: prescribing and/or administering to the individual an effective amount of (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Also provided is a method of reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use comprising the step of:
  • administration is discontinued if the body weight of the individual decreases by more than about 1% during said administration. In some embodiments, administration is discontinued if the body weight of the individual decreases by more than about 2% during said administration. In some embodiments, administration is discontinued if the body weight of the individual decreases by more than about 3% during said administration. In some embodiments, administration is discontinued if the body weight of the individual decreases by more than about 4% during said administration. In some embodiments, administration is discontinued if the body weight of the individual decreases by more than about 5% during said administration.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is for use as an aid to smoking cessation treatment.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- 3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is for use as an aid for cessation of cigarette smoking.
  • the (R)-8-chloro- l-methyl- 2,3,4,5-tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is for use as an aid to smoking cessation treatment and the prevention of associated weight gain.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is for use as a weight-neutral intervention for smoking cessation.
  • the weight gain occurs during smoking cessation.
  • the weight gain occurs post-smoking cessation.
  • Any embodiment of the invention directed to smoking cessation or the cessation or lessening of use of a tobacco product can be adapted to the cessation or lessening of use of nicotine administration from any and all sources or any individual source, including tobacco products (or specific examples thereof), tobacco replacement therapy (or specific examples thereof), and/or any electronic nicotine delivery system (e.g. , electronic cigarettes or personal vaporizers).
  • the present invention specifically embraces all such embodiments.
  • selectivity refers to a relative comparison of the effects of an agonist on two or more receptors.
  • selectivity refers to the relative in vitro potency of an agonist for two receptors.
  • in vitro potency is quantified using a second messenger assay.
  • in vitro potency is quantified by EC5 0 .
  • selectivity refers to the relative binding affinity of an agonist for two receptors.
  • binding affinity is quantified by Ki.
  • selectivity is measured by comparing data generated from an IP accumulation assay.
  • selectivity is measured by comparing data generated from a calcium assay.
  • selectivity is measured by comparing data generated from a DOI assay.
  • selectivity values are determined using in vitro potency values generated in assays according to Example 2. For methodologies of ensuring the accuracy of in vitro potency values, see pages 155-157 of Cavero et al. (Cavero I and Guillon J-M. Safety Pharmacology assessment of drugs with biased 5-HT 2 B receptor agonism mediating cardiac valvulopathy. J Pharmacological and Toxicological Methods 69 (2014); 150-161).
  • (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine and pharmaceutically acceptable salts, solvates, and hydrates thereof encompass any one of the following salts, or a Markush group comprising any combination of the following salts as disclosed in WO2006/069363, WO2012/030927, WO2012/030938, WO2012/030951, and WO2012/030957:
  • (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine and pharmaceutically acceptable salts, solvates, and hydrates thereof encompass any one of the following salts, or a Markush group comprising any combination of the following salts as disclosed in WO2006/069363, WO2012/030927, WO2012/030938, WO2012/030951, and WO2012/030957:
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is selected from an HC1 salt of (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, and solvates or hydrates thereof.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is selected from a hydrate of (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, and pharmaceutically acceptable salts thereof.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is a hydrate of an HC1 salt of (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is (R)-8-chloro-l-methyl- 2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride hemihydrate.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is ( ?)-8-chloro-l-methyl- 2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride or a solvate or hydrate thereof.
  • the dosage forms described herein may comprise, as the active component, either 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 a compound described herein.
  • various hydrates and solvates of the compounds described herein and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K.J.
  • one aspect of the present disclosure pertains to methods of administering hydrates and solvates of compounds described herein and/or their pharmaceutical acceptable salts, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray diffraction, and the like.
  • TGA thermogravimetric analysis
  • TGA-mass spectroscopy TGA-mass spectroscopy
  • TGA-Infrared spectroscopy powder X-ray diffraction (PXRD)
  • Karl Fisher titration high resolution X-ray diffraction, and the like.
  • the present disclosure includes all isotopes of atoms occurring in the present salts and crystalline forms thereof.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • One aspect of the present invention includes every combination of one or more atoms in the present salts and crystalline forms thereof that is replaced with an atom having the same atomic number but a different mass number.
  • One such example is the replacement of an atom that is the most naturally abundant isotope, such as ] H or 12 C, found in one the present salts and crystalline forms thereof, with a different atom that is not the most
  • isotopes of hydrogen include 2 H (deuterium) and 3 H (tritium).
  • isotopes of carbon include n C, 13 C, and 14 C.
  • Isotopes of nitrogen include 13 N and 15 N.
  • compositions such as those prepared during synthesis, preformulation, and the like, and pharmaceutical compositions, such as those prepared with the intent of using in a mammal for the treatment of one or more of the disorders described herein, comprising one or more of the present salts and crystalline forms thereof, wherein the naturally occurring distribution of the isotopes in the composition is perturbed.
  • compositions and pharmaceutical compositions comprising salts and crystalline forms thereof as described herein wherein the salt is enriched at one or more positions with an isotope other than the most naturally abundant isotope.
  • Methods are readily available to measure such isotope perturbations or enrichments, such as mass spectrometry, and for isotopes that are radio-isotopes additional methods are available, such as radio- detectors used in connection with HPLC or GC.
  • additional methods are available, such as radio- detectors used in connection with HPLC or GC.
  • prior to administration of the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof the individual smokes 11-20 cigarettes per day.
  • prior to administration of the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof prior to administration of the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the individual smokes 21-30 cigarettes per day.
  • the individual has an initial BMI selected from one of the following: > 24 kg/m 2 , > 23 kg/m 2 , > 22.5 kg/m 2 , > 22 kg/m 2 , > 21 kg/m 2 , > 20 kg/m 2 , > 19 kg/m 2 , or > 18.5 kg/m 2 .
  • prior to administration the individual has an initial BMI > 23 kg/m 2 .
  • prior to administration the individual has an initial BMI > 22.5 kg/m 2 .
  • prior to administration the individual has an initial BMI > 22 kg/m 2 .
  • prior to administration the individual has an initial BMI > 18.5 kg/m 2 .
  • the individual prior to administration, has an initial BMI > 18 kg/m 2 . In some embodiments, prior to administration, the individual has an initial BMI > 17.5 kg/m 2 . In some embodiments, prior to administration, the individual has an initial body mass index > 25 kg/m 2 and at least one weight-related comorbid condition.
  • the individual prior to administration, has an initial body mass index > 27 kg/m 2 . In some embodiments, prior to administration, the individual has an initial body mass index > 27 kg/m 2 and at least one weight-related comorbid condition.
  • the weight-related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea. In some embodiments, the weight-related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.
  • the individual prior to administration, has an initial body mass index > 30 kg/m 2 .
  • the initial BMI of the individual prior to administration is 18.5 to 25 kg/m 2 .
  • the individual is suffering from depression prior to being administered the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the individual is suffering from a preexisting psychiatric disease prior to being administered the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the preexisting psychiatric disease is chosen from schizophrenia, bipolar disorder, or major depressive disorder.
  • individuals are assessed for nicotine dependence based on the Fagerstrom test.
  • the individual has a score of 0, 1, or 2.
  • the individual has a score of 3 or 4.
  • the individual has a score of 5.
  • the individual has a score of 6 or 7.
  • the individual has a score of 8, 9, or 10.
  • the individual has a score > 3.
  • the individual has a score > 5.
  • the individual has a score > 6.
  • the individual has a score > 8.
  • the individual has a Fagerstrom score of 0, 1, or 2 and a BMI ⁇ 25 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of 0, 1 , or 2 and a BMI > 25 kg/m 2 and ⁇ 30 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of 0, 1, or 2 and a BMI > 30 kg/m 2 .
  • the individual has a Fagerstrom score of 3 or 4 and a BMI ⁇ 25 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of 3 or 4 and a BMI > 25 kg/m 2 and ⁇ 30 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of 3 or 4 and a BMI > 30 kg/m 2 .
  • the individual has a Fagerstrom score of 5 and a BMI ⁇ 25 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of 5 and a BMI > 25 kg/m 2 and ⁇ 30 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of 5 and a BMI > 30 kg/m 2 .
  • the individual has a Fagerstrom score of 6 or 7 and a BMI ⁇ 25 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of 6 or 7 and a BMI > 25 kg/m 2 and ⁇ 30 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of 6 or 7 and a BMI > 30 kg/m 2 .
  • the individual has a Fagerstrom score of 8, 9, or 10 and a BMI ⁇ 25 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of 8, 9, or 10 and a BMI > 25 kg/m 2 and ⁇ 30 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of 8, 9, or 10 and a BMI > 30 kg/m 2 .
  • the individual has a Fagerstrom score of > 3 and a BMI ⁇ 25 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of > 3 and a BMI > 25 kg/m 2 and ⁇ 30 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of > 3 and a BMI > 30 kg/m 2 .
  • the individual has a Fagerstrom score of > 5 and a BMI ⁇ 25 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of > 5 and a BMI > 25 kg/m 2 and ⁇ 30 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of > 5 and a BMI > 30 kg/m 2 .
  • the individual has a Fagerstrom score of > 6 and a BMI ⁇ 25 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of > 6 and a BMI > 25 kg/m 2 and ⁇ 30 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of > 6 and a BMI > 30 kg/m 2 .
  • the individual has a Fagerstrom score of > 8 and a BMI ⁇ 25 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of > 8 and a BMI > 25 kg/m 2 and ⁇ 30 kg/m 2 . In some embodiments, the individual has a Fagerstrom score of > 8 and a BMI > 30 kg/m 2 .
  • a questionnaire is used to evaluate symptoms experienced during quit, such as the urge to smoke, withdrawal, or reinforcing effects.
  • the questionnaire is selected from: the Minnesota Nicotine Withdrawal Score (MNWS), Brief Questionnaire of Smoking Urges (QSU-Brief), McNett Coping Effectiveness Questionnaire (mCEQ), Three-Factor Eating Questionnaire (TFEQ), and Food Craving Inventory (FCI).
  • the nicotine dependency, addiction and/or withdrawal results from the use of tobacco products. In some embodiments, the nicotine dependency, addiction, and/or withdrawal results from cigarette smoking.
  • the nicotine dependency, addiction and/or withdrawal results from the use of nicotine replacement therapies.
  • the individual is first administered the (/?)-8-chloro- l-methyl- 2,3,4,5-tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof on the target quit day.
  • the individual is administered the (R)-8- chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, or 35 days prior to the target quit day.
  • the individual is administered the (/?)-8-chloro- l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof at least 7 days prior to the target quit day. In some embodiments, the individual is administered the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof about 7 to about 35 days prior to the target quit day.
  • the individual is administered the ( ?)-8-chloro- l- methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof 7 days prior to the target quit day. In some embodiments, the individual is administered the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof at least 14 days prior to the target quit day.
  • the individual is administered the (/?)-8-chloro- l-methyl- 2,3,4,5-tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof about 14 to about 35 days prior to the target quit day. In some embodiments, the individual is administered the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof 14 days prior to the target quit day.
  • the individual quits smoking between days 8 and 35 of treatment. In some embodiments, the individual quits smoking between days 15 and 35 of treatment. In some embodiments, the individual quits smoking between days 22 and 35 of treatment. In some embodiments, the individual quits smoking on day 8 of treatment. In some embodiments, the individual quits smoking on day 15 of treatment. In some embodiments, the individual quits smoking on day 22 of treatment.
  • the method prior to administering the (/?)-8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the method further comprises the step of: instructing the individual to set a date to cease smoking tobacco. In some embodiments, administration of the (/?)-8-chloro- l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof is initiated about 7 days prior to the date set to cease smoking tobacco.
  • the method further comprises the step of: instructing the individual to set a date to cease smoking tobacco.
  • the date set to cease smoking tobacco occurs after at least 7 days of administration of the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the date set to cease smoking tobacco occurs prior to 36 days of administration of the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the administration leads to a statistically significant improvement in the ability to tolerate the cessation of smoking as measured by analysis of data from the MPSS test.
  • the individual has abstained from nicotine use for 12 weeks prior to prescribing and/or administering the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the individual has abstained from nicotine use for 24 weeks prior to prescribing and/or administering the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the individual has abstained from nicotine use for 9 months prior to prescribing and/or administering the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the individual has abstained from nicotine use for 52 weeks prior to prescribing and/or administering the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • abstinence is self-reported.
  • the self- reporting is based on response to a questionnaire.
  • the questionnaire is a Nicotine Use Inventory.
  • the duration of treatment is selected from: 12 weeks, 6 months,
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for at least about 2 weeks. In some embodiments, the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3- benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for at least about 4 weeks. In some embodiments, the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for at least about 8 weeks.
  • the (/?)-8-chloro- l-methyl- 2,3,4,5-tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for at least about 12 weeks. In some embodiments, the (/?)-8-chloro- l- methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for at least about 6 months. In some embodiments, the (R)-8- chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for at least about 1 year.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for at least about 2 years. In some embodiments, the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for between about 7 weeks to about 12 weeks.
  • the (/?)-8-chloro- l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for between about 12 weeks to about 52 weeks.
  • the (R)-8- chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for between about 6 months to about 1 year.
  • the individual receives treatment for a first treatment period. In some embodiments, the individual receives treatment for an additional treatment period, e.g. , to increase the likelihood of long-term abstinence. In some embodiments, an individual who fails in a first treatment period is administered the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof optionally in combination with a supplemental agent for a second treatment period.
  • an individual who relapses during a first treatment is administered the (R)-8- chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof optionally in combination with a supplemental agent for a second treatment period.
  • an individual who relapses following a first treatment is administered the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof optionally in combination with a supplemental agent for a second treatment period.
  • the first treatment period is 12 weeks.
  • 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 more 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 and the second period are of the same length of time. In some embodiments, the prevention or reduction of weight gain, or inducement of weight loss, is measured relative to the amount of weight gain or loss typically experienced when an individual attempts smoking cessation. In some embodiments, the prevention or reduction of weight gain, or inducement of weight loss, is measured relative the amount of weight gain or loss typically experienced when an individual attempts smoking cessation with another drug.
  • controlling weight gain comprises preventing weight gain. In some embodiments, controlling weight gain comprises inducing weight loss. In some embodiments, controlling weight gain comprises inducing weight loss of 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 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%.
  • controlling weight gain comprises decreasing BMI. In some embodiments, controlling weight gain comprises decreasing percent body fat. In some embodiments, controlling weight gain comprises decreasing waist circumference. In some embodiments, controlling weight gain comprises decreasing BMI by at least about 0.25, 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 kg/m 2 . In some embodiments, BMI is decreased by at least 1 kg/m 2 . In some embodiments, BMI is decreased by at least 1.5 kg/m 2 . In some embodiments, BMI is decreased by at least 2 kg/m 2 . In some embodiments, BMI is decreased by at least 2.5 kg/m 2 .
  • controlling weight gain comprises decreasing percent 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%.
  • the decrease in percent body fat is at least 1%.
  • the decrease in percent body fat is at least 2.5%.
  • the decrease in percent body fat is at least 5%.
  • controlling weight gain comprises decreasing waist circumference by at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 cm. In some embodiments, the decrease in waist circumference is at least 1 cm. In some embodiments, the decrease in waist circumference is at least 2.5 cm. In some embodiments, the decrease in waist circumference is at least 5 cm. In some embodiments, controlling weight gain comprises decreasing body weight by at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 kg. In some embodiments, the decrease in body weight is at least 1 kg. In some embodiments, the decrease in body weight is at least 2.5 kg. In some embodiments, the decrease in body weight is at least 5 kg.
  • an individual is monitored for low BMI.
  • the BMI of the individual becomes a BMI selected from one of the following during administration: > 18 kg/m 2 , > 17.5 kg/m 2 , > 17 kg/m 2 , > 16 kg/m 2 , and > 15 kg/m 2 .
  • the decrease in body weight is selected from one of the following: more than about 1.5%, more than about 2%, more than about 2.5%, more than about 3%, more than about 3.5%, more than about 4%, more than about 4.5%, and more than about 5%.
  • the decrease in body weight is selected from one of the following: more than about 1.5 kg, more than about 2 kg, more than about 2.5 kg, more than about 3 kg, more than about 3.5 kg, more than about 4 kg, more than about 4.5 kg, and more than about 5 kg.
  • the individual in need of treatment has a BMI selected from: > 25 kg/m 2 , > 24 kg/m 2 , > 23 kg/m 2 , > 22 kg/m 2 , > 21 kg/m 2 , > 20 kg/m 2 , > 19 kg/m 2 , and > 18.5 kg/m 2 .
  • BMI is not decreased by more than about 0.25, 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 kg/m 2 .
  • BMI is not decreased by more than 1 kg/m 2 .
  • BMI is not decreased by more than 1.5 kg/m 2 .
  • BMI is not decreased by more than 2 kg/m 2 . In some embodiments, BMI is not decreased by more than 2.5 kg/m 2 . In some embodiments, BMI is not decreased by more than 5 kg/m 2 . In some embodiments, BMI is not decreased by more than 10 kg/m 2 . In some embodiments, percent body fat is not decreased by more than 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, percent body fat is not decreased by more than 1%.
  • percent body fat is not decreased by more than 2.5%. In some embodiments, percent body fat is not decreased by more than 5%. In some embodiments, waist circumference is not decreased by more than about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 cm. In some embodiments, waist circumference is not decreased by more than 1 cm. In some embodiments, waist circumference is not decreased by more than 2.5 cm. In some embodiments, waist circumference is not decreased by more than 5 cm. In some embodiments, body weight is not decreased by more than about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 kg. In some embodiments, the decrease in body weight is not more than 1 kg.
  • controlling weight gain comprises maintaining at least some weight loss for at least about 12 weeks, at least about 6 months, at least about 9 months, at least about one year, at least about 18 months, or at least about two years. For example, in some embodiments, an individual loses 5 kg during a first treatment and maintains at least 1 kg of that weight loss during a second treatment. In some embodiments, an individual loses 3 kg during the first 12 weeks of a treatment, and loses a total of 5 kg after one year of the treatment.
  • use of (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof is discontinued.
  • use of (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof is discontinued if the BMI of an individual becomes ⁇ about 15 kg/m 2 , ⁇ about 15.5 kg/m 2 , ⁇ about 16 kg/m 2 , ⁇ about 16.5 kg/m 2 , ⁇ about 17 kg/m 2 , ⁇ about 17.5 kg/m 2 , ⁇ about 18 kg/m 2 , ⁇ about 18.5 kg/m 2 , ⁇ about 19 kg/m 2 , ⁇ about 19.5 kg/m 2 ⁇ about 20 kg/m 2 , ⁇ about 20.5 kg/m 2 , ⁇
  • the individual experiences one or more additional beneficial effects as a result of the administration of (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof, optionally in combination with at least one supplemental agent, as described herein.
  • the one or more additional beneficial effects are chosen from a decrease in an assessment of weight, an improvement in cardiovascular indications, and/or an improved glycemia. In some embodiments, the one or more additional beneficial effects are chosen from a decrease in an assessment of weight, an improvement in cardiovascular indications, and/or an improved lipidemia.
  • the one or more additional beneficial effects comprise a decrease in an assessment of weight.
  • the decrease in an assessment of weight comprises weight loss.
  • the one or more beneficial effects comprises a decrease in hunger, a decrease in food cravings, or an increase in intermeal interval.
  • the one or more additional beneficial effects comprise an improvement in one or more cardiovascular indications.
  • the improvement in one or more cardiovascular indications comprises one or more of a reduction in systolic and diastolic blood pressure (SBP and DBP, respectively), a decrease in heart rate, a decrease in total cholesterol, a decrease in LDL cholesterol, a decrease in HDL cholesterol, and/or a decrease in triglyceride levels.
  • the one or more additional beneficial effects comprise a reduction in SBP.
  • the reduction in SBP in an individual without type 2 diabetes is at least about 2 mmHg. In some embodiments, the reduction in SBP in an individual without type 2 diabetes is between 2 and 5 mmHg. In some embodiments, the reduction in SBP in an individual with type 2 diabetes is at least about 2 mmHg. In some embodiments, the reduction in SBP in an individual with type 2 diabetes is between about 2 and 5 mmHg. In some embodiments, the reduction in SBP in an individual with baseline impaired fasting glucose is at least about 1 mmHg. In some embodiments, the reduction in SBP in an individual with baseline impaired fasting glucose is between about 1 and 5 mmHg.
  • the one or more additional beneficial effects comprise a reduction in DBP.
  • the reduction in DBP in an individual without type 2 diabetes is at least about 1 mmHg. In some embodiments, the reduction in DBP in an individual without type 2 diabetes is at least between about 1 and 5 mmHg. In some embodiments, the reduction in DBP in an individual with type 2 diabetes is at least about 1 mmHg. In some embodiments, the reduction in DBP in an individual with type 2 diabetes is between about 1 and 5 mmHg. In some embodiments, the reduction in DBP in an individual with baseline impaired fasting glucose is at least about 1 mmHg. In some embodiments, the reduction in DBP in an individual with baseline impaired fasting glucose is between about 1 and 5 mmHg.
  • the one or more additional beneficial effects comprise a reduction in heart rate.
  • the reduction in heart rate in an individual without type 2 diabetes is at least about 2 BPM. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is between about 2 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 and 5 BPM. In some embodiments, the reduction in heart rate in an individual with baseline impaired fasting glucose is at least about 2 BPM. In some embodiments, the reduction in heart rate in an individual with baseline impaired fasting glucose is between about 2 and 5 BPM.
  • the improvement in lipidemia comprises a decrease in total cholesterol level.
  • the decrease in total cholesterol level in individuals without type 2 diabetes is at least about 1 mg/dL. In some embodiments, the decrease in total cholesterol level in individuals without type 2 diabetes is between about 1.5 and 2 mg/dL. In some embodiments, the decrease in total cholesterol level in individuals with type 2 diabetes is at least about 0.5 mg/dL. In some embodiments, the decrease in total cholesterol level in individuals with type 2 diabetes is between about 0.5 and 1 mg/dL. In some embodiments, the decrease in total cholesterol level in individuals with baseline impaired fasting glucose is at least about 2 mg/dL. In some embodiments, the decrease in total cholesterol level in individuals with baseline impaired fasting glucose is between about 2 and 3 mg/dL.
  • the improvement in lipidemia comprises a decrease in LDL cholesterol level.
  • the decrease in LDL cholesterol level in individuals without type 2 diabetes is at least about 1 mg/dL. In some embodiments, the decrease in LDL cholesterol level in individuals without type 2 diabetes is between about 1 and 2 mg/dL. In some embodiments, the decrease in LDL cholesterol level in individuals with type 2 diabetes is at least about 1 mg/dL. In some embodiments, the decrease in LDL cholesterol level in individuals with type 2 diabetes is between about 1 and 1.5 mg/dL. In some embodiments, the decrease in LDL cholesterol level in individuals with baseline impaired fasting glucose is at least about 2 mg/dL. In some embodiments, the decrease in LDL cholesterol level in individuals with baseline impaired fasting glucose is between about 2 and 3 mg/dL.
  • the improvement in lipidemia comprises a decrease in HDL cholesterol level.
  • the decrease in HDL cholesterol level in individuals without type 2 diabetes is at least about 4 mg/dL.
  • the decrease in HDL cholesterol level in individuals without type 2 diabetes is between about 3 and 6 mg/dL.
  • the decrease in HDL cholesterol level in individuals with type 2 diabetes is at least about 5 mg/dL.
  • the decrease in HDL cholesterol level in individuals with type 2 diabetes is between about 7 and 10 mg/dL.
  • the decrease in HDL cholesterol level in individuals with baseline impaired fasting glucose is at least about 2 mg/dL.
  • the decrease in HDL cholesterol level in individuals with baseline impaired fasting glucose is between about 2 and 3 mg/dL.
  • the one or more additional beneficial effects comprise an improvement in glycemia.
  • the improvement in glycemia comprises a reduction in fasting plasma glucose and/or a reduction in glycated hemoglobin (AIC) levels.
  • the improvement in glycemia comprises a reduction in fasting plasma glucose.
  • the improvement in glycemia comprises a reduction in glycated hemoglobin (AIC) levels.
  • the improvement in glycemia comprises a decrease in triglyceride levels.
  • the compounds provided herein can be administered in a wide variety of dosage forms. It will be obvious to those skilled in the art that the dosage forms may comprise, as the active component, either a compound provided herein or a pharmaceutically acceptable salt, solvate, or hydrate of a compound provided herein. In some embodiments, the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered in a tablet suitable for oral administration.
  • Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions and syrups.
  • the oral preparations can be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non- aqueous vehicles (including edible oils), preservatives and flavorings and colorants can be added to the liquid preparations.
  • Parenteral dosage forms can be prepared by dissolving the compound in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms. Suitable pharmaceutically- acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20 th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.).
  • a compound for use in the prophylaxis or treatment, can, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
  • Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with minimal degradation of the drug.
  • transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner.
  • compositions and unit dosage forms thereof can thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof can comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the active ingredient is formulated as an immediate-release dosage form using, e.g. , techniques known in the art. In some embodiments, the active ingredient is formulated as a modified-release dosage form using, e.g. , techniques known in the art. In some embodiments, the active ingredient is formulated as a sustained-release dosage form using, e.g. , techniques known in the art. In some embodiments, the active ingredient is formulated as a delayed-release dosage form using, e.g. , techniques known in the art.
  • the method comprises a plurality of administrations of the modified-release dosage form, with a frequency wherein the average interval between any two sequential administrations is: at least about 24 hours, or about 24 hours.
  • the method comprises a plurality of administrations of the modified-release dosage form, and the modified-release dosage form is administered once a day.
  • the plurality of administrations is: at least about 30, at least about 180; at least about 365, or at least about 730.
  • the plasma concentration of the (/?)-8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof in the individual administered a modified-release dosage form, as described herein, has a Cm aX of: 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.
  • the C max divided by the 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 x 10 "7 mL “1 .
  • the C max occurs: more than 30 minutes after administration; more than 1 hour after administration; or more than 2 hours after administration. In some embodiments, the C max occurs: more than 3 hours after administration, more than 6 hours after administration, or more than 12 hours after administration.
  • the average peak to trough ratio of the plasma concentration of the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof in the individual administered a modified-release dosage form as described herein is: less than about 3: 1, less than about 2: 1, less than about 1.5: 1, or less than about 1.1 : 1.
  • the modified-release dosage form further comprises (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form further comprises one or more ingredients selected from: microcrystalline cellulose, mannitol, and magnesium stearate.
  • the modified-release dosage form further comprises a film coating.
  • the film coating comprises a water-soluble film coating.
  • the film coating comprises ethyl cellulose.
  • the film coating further comprises (hydroxypropyl)methyl cellulose.
  • the ratio of the ethyl cellulose to the (hydroxypropyl)methyl cellulose is: about 75 :25, about 80:20, or about 85: 15.
  • the modified-release dosage form comprises a core tablet and a film coating; wherein the core tablet comprises: (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- 3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium stearate; and the film coating comprises a water-soluble film coating.
  • the modified-release dosage form comprises a core tablet and a film coating, wherein the weight to weight ratio of the core tablet to the coating is about 20: 1 ; and wherein the core tablet comprises: about 7% (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- 3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium stearate; and the film coating comprises a water-soluble film coating.
  • the modified-release dosage form comprises a core tablet and a film coating; wherein the core tablet comprises: (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- 3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium stearate; and the film coating comprises: ethyl cellulose; and (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form comprises a core tablet and a film coating, wherein the weight to weight ratio of the core tablet to the coating is about 20: 1 ; and wherein the core tablet comprises: about 7% (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- 3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium stearate; and the film coating comprises: about 85% ethyl cellulose; and about 15% (hydroxypropyl)methyl cellulose; or about 75% ethyl cellulose; and about 25% (hydroxypropyl)methyl cellulose.
  • the pharmaceutical composition can be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
  • the dose when using the compounds provided herein can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the individual, on the compound employed, on whether an acute or chronic disease state is treated or prophylaxis conducted or on whether further active compounds are administered in addition to the compounds provided herein.
  • Representative doses include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg.
  • Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate from the healthcare provider it may be necessary to deviate upward or downward from the doses described herein.
  • All dosage amounts disclosed herein are calculated with respect to the active moiety, i. e. , the molecule or ion that gives the intended pharmacologic or physiologic action. Further, all dosage amounts of lorcaserin disclosed herein are for lorcaserin in the anhydrous hydrochloride form.
  • dosage amounts for other salt or crystalline forms of lorcaserin can be adjusted to equate lorcaserin in the anhydrous hydrochloride form.
  • 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.
  • 10 mg of lorcaserin as disclosed herein includes any salt or crystalline form with the same amount of ( ?)-8-chloro-l-methyl- 2,3,4,5-tetrahydro-lH-3-benzazepine as found in 10 mg of the anhydrous lorcaserin hydrochloride.
  • the dosage amounts of lorcaserin disclosed herein can be replaced with dosage amounts for other salt or crystalline forms, formulations, and dosage regimens that exhibit bioequivalence to the specified amount of anhydrous lorcaserin hydrochloride, including forms with 80-125% of the AUC and/or C max for the specified amount of anhydrous lorcaserin hydrochloride as measured by method disclosed in the FDA's Guidance for Industry for Bioavailability and Bioequivalence (Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products— General Considerations. U.S.
  • lorcaserin disclosed herein can be replaced with dosage amounts for other salt or crystalline forms, formulations, and dosage regimens that exhibit bioequivalence to 10 mg of anhydrous lorcaserin hydrochloride in an immediate -release orally administered tablet as described in the FDA package insert for BELVIQ ® (BELVIQ (lorcaserin HCl) (package insert), revised August 2012).
  • the amount of active ingredient, or an active salt or derivative thereof, required for use in 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 at the discretion of the attendant physician or clinician.
  • a model system typically an animal model
  • these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors.
  • compositions and/or compositions provided herein are selected in accordance with a variety factors as cited above.
  • the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods disclosed herein.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g. , into a number of discrete loosely spaced administrations.
  • the daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4 part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose greater than or equal to 20 mg per day, greater than or equal to 25 mg per day, greater than or equal to 30 mg per day, greater than or equal to 35 mg per day, or greater than or equal to 40 mg per day.
  • the (/?)-8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to or less than 20 mg per day.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose of at least 20 mg per day. In some embodiments, the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to 20 mg per day.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to at least 12.5 mg per day. In some embodiments, the ( ?)-8-chloro- l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to between 12.5 mg and 20 per day.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to 12.5 mg per day.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to at least 15 mg per day. In some embodiments, the ( ?)-8-chloro- l- methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to between 15 and 20 mg per day.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to 15 mg per day.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to at least 17.5 mg per day. In some embodiments, the ( ?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to between 17.5 and 20 mg per day.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to 17.5 mg per day.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to or less than 10 mg twice per day.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to 10 mg twice per day.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to at least 5 mg twice per day.
  • the (R)-8- chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to 5 mg twice per day.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to at least 7.5 mg twice per day.
  • the (R)-8- chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to 7.5 mg twice per day.
  • the individual is also being prescribed and/or administered a supplemental agent.
  • a composition comprising (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and at least one supplemental agent.
  • supplemental agent refers to an additional therapeutic agent which complements the activity of the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof described herein as it relates to 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.
  • the "supplemental agent" is not phentermine.
  • Supplemental agents include nicotine replacement therapies, antidepressants and anxiolytics such as selective serotonin reuptake inhibitors, e.g. , citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and the like. Serotonin and norepinephrine reuptake inhibitors, such as duloxetine, venlafaxine, and the like may also be used. Norepinephrine and dopamine reuptake inhibitors such as bupropion may also be used.
  • selective serotonin reuptake inhibitors e.g. , citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and the like.
  • Serotonin and norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, and the like may also be used.
  • Norepinephrine and dopamine reuptake inhibitors such as bupropion may also be used
  • Tetracyclic antidepressants such as mirtazapine; combined reuptake inhibitors and receptor blockers such as trazodone, nefazodone, maprotiline; tricyclic antidepressants, such as amitriptyline, amoxapine, desipramine, doxepin, imipramine, 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 receptor blockers, such as propranolol may also be used.
  • the supplemental agent is chosen from nicotine replacement therapies.
  • the nicotine replacement therapy is chosen from nicotine gum, nicotine transdermal systems, nicotine lozenges, nicotine microtabs, and nicotine sprays or inhalers.
  • the supplemental agent is an electronic cigarette.
  • the composition comprises (/?)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and nicotine gum.
  • the composition comprises (/?)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and a nicotine transdermal system.
  • the composition comprises (/?)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and a nicotine lozenge.
  • the composition comprises (/?)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and a nicotine microtab.
  • the composition comprises (/?)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and a nicotine spray or inhaler.
  • the composition comprises (/?)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and an electronic cigarette.
  • the supplemental agent is chosen from antidepressants.
  • the composition comprises (/?)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and an antidepressant.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- ⁇ -3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the antidepressant are formulated as a fixed dose combination product.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the antidepressant are formulated as a co-packaged product.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the antidepressant are formulated for adjunctive therapy.
  • the composition comprises (/?)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and nortriptyline.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the nortriptyline are formulated as a fixed dose combination product.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the nortriptyline are formulated as a co-packaged product.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the nortriptyline are formulated for adjunctive therapy.
  • the composition comprises (/?)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and bupropion.
  • (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3- benzazepine ⁇ or pharmaceutically acceptable salt, solvate, or hydrate thereof and the bupropion are formulated as a fixed dose combination product.
  • the (R)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the bupropion are formulated as a co-packaged product.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the bupropion are formulated for adjunctive therapy.
  • the composition comprises (/?)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and clonidine or a pharmaceutically acceptable salt thereof.
  • the (R)-8- chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the clonidine are formulated as a fixed dose combination product.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the clonidine are formulated as a co-packaged product.
  • the (/?)-8-chloro- l-methyl- 2,3,4,5-tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the clonidine are formulated for adjunctive therapy.
  • the composition comprises (/?)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and varenicline or a pharmaceutically acceptable salt thereof.
  • the (R)- 8-chloro-l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the varenicline or a pharmaceutically acceptable salt thereof are formulated as a fixed dose combination product.
  • the ( ?)-8-chloro- l- methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the varenicline or a pharmaceutically acceptable salt thereof are formulated as a co-packaged product.
  • the (/?)-8-chloro- l-methyl-2, 3,4,5- tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof and the varenicline or a pharmaceutically acceptable salt thereof are formulated for adjunctive therapy.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is an HQ salt of ( ?)-8-chloro- 1 -methyl-2,3 ,4,5-tetrahydro- lH-3-benzazepine or solvate or hydrate thereof.
  • the individual has previously undergone treatment with a supplemental agent. In some embodiments, the individual was refractory to the previous treatment with the supplemental agent.
  • the individual has previously undergone treatment with a nicotine replacement therapy. In some embodiments, the individual was refractory to the previous treatment with the nicotine replacement therapy.
  • composition comprising (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and at least one supplemental agent for:
  • composition comprising (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and at least one supplemental agent for use as a medicament for:
  • composition comprising (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and at least one supplemental agent in the manufacture of a medicament 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.
  • a unit dosage form of a composition comprising ( ?)-8-chloro-l- methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof and at least one supplemental agent.
  • a supplemental agent chosen from nicotine replacement therapies, for use in combination with (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • a supplemental agent for use in combination with ( ?)-8-chloro- l- methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof 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.
  • the (/?)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is formulated as an immediate- release dosage form and the supplemental agent is also formulated as an immediate-release dosage form.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is formulated as an immediate-release dosage form and the supplemental agent is formulated as a modified-release dosage form.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is formulated as a modified-release dosage form and the supplemental agent is formulated as an immediate- release dosage form.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- 3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof is formulated as a modified-release dosage form and the supplemental agent is also formulated as a modified- release dosage form.
  • the (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine or pharmaceutically acceptable salt, solvate, or hydrate thereof may be administered sequentially or concurrently with the one or more other supplemental agents identified herein.
  • the amounts of formulation and pharmacologic agent depend, for example, on what type of pharmacologic agent(s) are used, and the scheduling and routes of administration.
  • Supplemental agents may be delivered concomitantly with (/?)-8-chloro-l-methyl- 2,3,4,5-tetrahydro-lH-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or may be administered independently. Supplemental agent delivery may be via any suitable method known in the art including orally, inhalation, injection, etc.
  • the methods described herein further comprise the step of: providing the individual with educational materials and/or counseling.
  • the counseling relates to smoking cessation.
  • the counseling relates to weight management, including without limitation counseling regarding diet and exercise.
  • the counseling relates to both smoking cessation and weight management, including without limitation counseling regarding diet and exercise.
  • the methods described herein further comprise the step of: providing the individual with biochemical feedback; acupuncture; hypnosis; behavioral intervention; support services; and/or psychosocial treatment.
  • Plasmid DNA coding for a receptor of interest is produced using standard molecular biology tools.
  • the plasmid typically contains a multi-cloning site where the coding sequence for the receptor of interest is inserted, a promoter to drive expression of the receptor when introduced into a host cell, and a resistance gene sequence that causes the host cell to produce a protein that confers antibiotic resistance.
  • a commonly used promoter is the cytomegalovirus promoter (CMV), and a commonly used resistance gene is the neo gene that confers resistance to neomycin.
  • CMV cytomegalovirus promoter
  • the plasmid DNA is introduced into parental cells (commonly used cell lines include CHO-K1 and HEK293) using methods such as lipofection or electroporation. Cells are then allowed to recover in culture for 1-2 days.
  • a selection agent ⁇ e.g. , neomycin if the expression plasmid contained the neo gene
  • neomycin if the expression plasmid contained the neo gene
  • transient transfection is an efficient method to introduce plasmid DNA into cells
  • many cells in the culture will initially display neomycin resistance. Over the course of a few cell divisions, expression of proteins encoded by the plasmid is typically lost and most cells will eventually be killed by the antibiotic.
  • the plasmid DNA may become randomly integrated into the chromosomal DNA. If the plasmid DNA becomes integrated in a way that allows continued expression of the neo gene, these cells become permanently resistant to neomycin. Typically, after culturing the transfected cells for two weeks, most of the remaining cells are those that have integrated the plasmid in this manner.
  • the resulting stable pool of cells is highly heterogeneous, and may express vastly different levels of receptor (or no receptor at all). While these types of cell populations may provide functional responses when stimulated with appropriate agonists to the receptor of interest, they are typically not suitable for careful pharmacological studies in view of receptor reserve effects caused by high expression levels.
  • Clonal cell lines are therefore derived from this cell population.
  • the cells are plated in multi-well plates at a density of one cell per well. After cell plating, the plates are inspected and wells containing more than one cell are rejected. The cells are then cultured for a period of time and those that continue to divide in the presence of neomycin are eventually expanded into larger culture vessels until there are sufficient cells for evaluation.
  • Characterization in functional assays may reveal that some cells exaggerate the potencies and efficacies of agonists, likely indicating the presence of a receptor reserve.
  • the preparation of cell membranes for evaluation in radioligand binding assays allows for quantitative determination of membrane receptor densities.
  • Evaluation of cell surface receptor density may also be performed by flow cytometry using antibodies to the receptor or an epitope tag that can be engineered into the receptor, typically at the N-terminus for GPCRs. The flow cytometry method allows one to determine if the clonal cell population expresses the receptor in a homogenous manner (which would be expected) and quantitate relative expression levels between each clonal cell population. However, it does not provide absolute receptor expression levels.
  • receptor expression should be low (relative to other clones evaluated) and homogeneous (if flow cytometry evaluation is possible).
  • a suitable clone will produce agonist potencies that are lower than other clones (i.e. , higher EC 50 values). If partial agonists are available, the absence of receptor reserve will be reflected in low efficacies relative to full agonists, whereas cells with higher receptor expression levels will exaggerate partial agonist efficacies. In cells expressing high receptor levels, partial agonists may no longer display efficacies lower than full agonists.
  • treatment of cell lines that contain no receptor reserve should reduce the available receptor density measured by radioligand binding and may reduce the magnitude of functional responses to agonists. However, the reduction of receptor density should occur without producing reductions in agonist potencies or partial agonist efficacies.
  • HT 2B HT 2B
  • 5-HT 2 c receptors Lorcaserin-mediated signaling was observed in stable clonal cell lines expressing low receptor densities.
  • Phenoxybenzamine (PBZ) was used as an irreversible 5-HT 2 receptor antagonist to allow for progressive reductions of receptor binding sites in each cell line in order to observe potency and efficacy in the absence of receptor reserve effects (which may have generated inconsistent results in previous studies).
  • HEK293 cell lines were generated to stably express human, rat, and monkey 5-HT 2A , 5- HT 2B , and 5-HT 2 c receptors using standard procedures.
  • HEK293 cells expressing recombinant 5-HT 2A , 5-HT 2B , and 5-HT 2 c receptors were added to sterile poly-D-lysine-coated 96- well microtiter plates (35,000 cells/well) and labeled with 0.6 ⁇ of [ 3 H]inositol in myo-inositol-free DMEM for 18 hours.
  • PBZ prepared in myo-inositol-free DMEM was then added to a final specified concentration and incubation was conducted for 1 hour at room temperature.
  • Stable, clonal cell lines expressing recombinant human, rat, and monkey 5-HT 2A , 5- HT 2B , and 5-HT 2 c receptors were established and used to profile lorcaserin and a panel of reference compounds in IP accumulation and calcium assays.
  • Cell surface receptor densities, as assessed by radioligand binding, were very high in the human and monkey cell lines and were lower in the rat cell line. Receptor densities in all three cell lines were modulated by PBZ.
  • Controls and test compounds (in 25 ⁇ assay buffer) were then added to assay plates using a Molecular Devices FLIPR instrument. Plates were read every two seconds for 1.5 minutes and the peak height was determined for each well. Dose response curves included ten compound concentrations in which triplicate determinations were made at each test concentration.
  • HEK293 cells expressing the recombinant 5-HT 2A , 5-HT 2B , and 5-HT 2 c receptors were harvested, suspended in ice-cold phosphate buffered saline, pH 7.4 (PBS), and then centrifuged at 48,000 g for 20 min at 4°C. The resulting cell pellet was then re-suspended in wash buffer containing 20 mM HEPES, pH 7.4 and 0.1 mM EDTA, homogenized on ice using a Brinkman Polytron, and centrifuged (48,000 g for 20 min at 4°C).
  • the pellet was then resuspended in 20 mM HEPES, pH 7.4, homogenized on ice, and centrifuged (48,000 g for 20 min at 4°C). Crude membrane pellets were stored at -80°C until used for radioligand binding assays.
  • Radioligand binding assays were performed using the commercially available 5-HT 2 receptor agonist [ 125 I]DOI as the radioligand and nonspecific binding was determined in the presence of unlabeled DOI at a saturating concentration of 10 ⁇ .
  • Competition experiments consisted of addition of 95 ⁇ of Assay Buffer (20 mM HEPES, pH 7.4, 10 mM MgC12), 50 ⁇ L ⁇ of membranes, 50 ⁇ L ⁇ of radioligand stock, and 5 ⁇ L ⁇ of test compound diluted in assay buffer to 96-well microtiter plates, which were then incubated for one hour at room temperature.
  • Assay incubations were terminated by rapid filtration through Perkin Elmer F/C filtration plates under vacuum pressure using a 96-well Packard filtration apparatus, followed by washing filter plates several times with ice-cold Assay Buffer. Plates were then dried at 45 °C for a minimum of two hours. Finally, 25 ⁇ L ⁇ of BetaScint scintillation cocktail was added to each well and the plates were counted in a Packard TopCount scintillation counter. In each competition study, test compounds were dosed at eight to ten concentrations with triplicate determinations at each test concentration. A reference compound, typically DOI, was included in every runset for quality control purposes.
  • Ki values were determined from IC 50 values using the Cheng-Prusoff equation and the Kd value for each radioligand-receptor pair. Mean Ki values were calculated from the mean of the logKi values.
  • Figure 18 shows potency and efficacy data generated using the IP accumulation assay for each combination of the human, rat, and monkey 5-HT 2A , 5-HT 2B , and 5-HT 2 c receptors.
  • Lorcaserin demonstrated high selectivity for the human 5-HT 2C receptor, with an EC 50 (39.2 nM) approximately 14 times lower than the EC 50 for the 5-HT 2A receptor (553 nM) and approximately 60 times lower than the EC 50 for the 5-HT 2B receptor (2380 nM).
  • Lorcaserin also demonstrated high efficacy (81 ) at the human 5-HT 2 c receptor relative to serotonin.
  • lorcaserin demonstrated mixed potency for the rat 5-HT 2A , 5-HT 2B , and 5-HT 2 c receptors, with greatest selectivity for the 5-HT 2B receptor (195 nM, compared to 545 nM and 1110 nM for the 5-HT 2 c and 5-HT 2A receptors, respectively).
  • Lorcaserin also demonstrated high efficacy (94%) at the rat 5-HT 2B receptor relative to serotonin.
  • Figure 19 shows a comparison of drug concentration in humans to the 5- HT 2A , 5-HT 2B , and 5-HT 2 c receptor activation data.
  • EC 50 values are shown as horizontal lines plotted against observed lorcaserin concentrations (expressed as plasma free fractions) for subjects treated with lorcaserin 10 mg BID in a previous study.
  • Figure 19 shows a comparison of drug concentration in rats to the 5-HT 2A , 5-HT 2B , and 5-HT 2 c receptor activation data.
  • EC 50 values for receptor activation are shown as horizontal lines plotted against the observed lorcaserin concentrations (expressed as plasma free fractions) for rats treated with 10 mg/kg/day, 30 mg/kg/day, and 100 mg/kg/day of lorcaserin.
  • the plasma drug concentration following the administration of lorcaserin was approximately equal to the EC 50 value from the IP accumulation assay for the 5-HT 2 c receptor, and did not approach the EC 50 value for the 5-HT 2 A or 5-HT 2 B receptors.
  • the plasma drug concentration for the lowest dose of lorcaserin administered i.e.
  • a 12- week, randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of lorcaserin as a potential aid to smoking cessation.
  • 603 active smokers were randomized to receive lorcaserin 10 mg BID, 10 mg QD, or placebo in a 1 : 1: 1 ratio (BELVIQ (lorcaserin HCl) (package insert), revised August 2012).
  • BELVIQ lorcaserin HCl
  • Patients at baseline were dependent on nicotine and averaged 18 cigarettes per day.
  • Patients were dosed for two weeks before attempting to quit around day 15 of the trial, and received smoking cessation counseling during the trial.
  • the primary objective of the study was to assess smoking cessation efficacy, as measured by the carbon monoxide-confirmed continuous abstinence rate (CAR) during the last four weeks of the trial (Weeks 9 to 12).
  • CAR carbon monoxide-confirmed continuous abstinence rate
  • the carbon monoxide-confirmed CAR is defined as no reported smoking or other nicotine use and an end-expiratory exhaled carbon monoxide measurement of less than or equal to ten parts per million.
  • Secondary objectives for the study included assessment of body weight change, safety, and tolerability.
  • Additional outcome measures included CAR for Weeks 5 to 8 of treatment, CAR for Weeks 5 to 12 of treatment, CAR for Weeks 3 to 12 of treatment, 7-day point prevalence (PP) smoking abstinence, and questionnaires regarding the urge to smoke, withdrawal, reinforcing effects, and eating behavior. Endpoints of interest also included the number of cigarettes smoked per day, abstinence with occasional slips ( ⁇ 5 cigarettes per day), time to abstinence (in weeks), and time to relapse (if abstinent).
  • FIG. 1 A schematic of the study design is provided in Figure 1. Baseline characteristics for the study subjects are provided in Figures 2 and 3. A summary of the disposition of subjects from the study is provided in Figure 4. Data for end-expiratory carbon monoxide (CO)-confirmed CARs for Weeks 5-8, 5-12, and 3-12 is provided in Figures 5-8.
  • CO carbon monoxide
  • Subjects treated with lorcaserin 10 mg BID had statistically significantly greater end- expiratory CO-confirmed CARs for Weeks 9 to 12 than subjects treated with lorcaserin 10 mg QD or placebo.
  • End-expiratory CO- confirmed CARs for Weeks 9 to 12 were not significantly different for subjects treated with lorcaserin 10 mg QD versus subjects treated with placebo (Figure 5).
  • Non-responders treated with lorcaserin 10 mg BID, lorcaserin 10 mg QD, or placebo who did not quit smoking had greater weight loss than responders for each respective treatment at Week 12 (Figure 13).
  • Non-responders who were treated with lorcaserin 10 mg BID lost 1.02 kg (SE 0.21 kg) at Week 12 relative to baseline, while those treated with lorcaserin 10 mg QD or placebo lost 0.50 kg (SE 0.21 kg) and 0.01 kg (SE 0.23 kg), respectively, at Week 12 relative to baseline (Figure 13).
  • Example 6 Modified-Release Tablets Comprising (/f)-8-Chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine Hydrochloride Salt Hemihydrate, Form III
  • Modified-release tablet formulations of (R)-8-chloro- l-methyl-2,3,4,5-tetrahydro- lH- 3-benzazepine hydrochloride salt hemihydrate, Form III (Compound 1) were prepared.
  • the upper limit of the desired release profile as established by pharmacokinetics simulation was defined as a Cmax not more than the C max observed when dosing 10 mg immediate-release tablets BID.
  • All modified-release tablets were manufactured with a direct compression process at a batch size of 300 g to 500 g as follows. (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine hydrochloride salt hemihydrate, HPMC, mannitol and MCC were blended in a 2- quart V blender (Globe Pharma MaxiBlend ® ) for 12 min. The mixture was screened through a sieve (#20). The sieved mixture was blended for a further 5- 10 min, magnesium stearate was added and blending was continued for a further 5 min. The mixture was compressed into tablets using a Piccola PLC rotary tablet press (10-20 rpm; 10 kp) and the tablets were coated using a Vector LDCS Hi-Coater ® with an 11.5 "-diameter pan. Dissolution Testing
  • Dissolution testing was performed using USP apparatus I (basket method) in 900 mL 0.1 N HC1 solution at 37 °C and 100 rpm.
  • concentration of (#)-8-chloro-l-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine was analyzed using an HPLC method.
  • the time needed to achieve 80% cumulative release (T80%) was estimated from the dissolution profiles.
  • the GastroPlusTM software (Simulations Plus, Inc., Lancaster, CA) was used to simulate the pharmacokinetics of Compound 1 from immediate-release and modified-release tablets.
  • the release profile follows first order release kinetics and T80% is approximately 8 hours. The lower limit was not defined.
  • Pharmacokinetics parameters of Compound 1 were obtained from an open-label, single-dose, cross-over clinical study in the fed and fasted state. Input variables and default values for GastroPlusTM simulation were as follows
  • Dosage form a) controlled release tablet with 20-mg QD dosing or b) immediate -release tablet of 10-mg BID dosing
  • Surelease ® /Opadry ® (85/15) coating decreases the release rate of Compound 1 hydrochloride salt hemihydrate, Form III substantially.
  • the percentage of release was reduced by 20% to 30% after a 1-h lag time, compared to the release from Batch 1. Release was further delayed at a higher coating weight gain (4.6%) (Batch 2).
  • T80% of Batch 2 was 9 h and T80% of Batch 3 was 12 h.
  • a lag time of 2 hours was observed for Batch 3. It can be also observed that the release kinetics shifted away from first order towards more constant release, especially at a coating weight gain of 4.6%.
  • core tablets were prepared containing 40% HPMC K4M.
  • the amount of mannitol was increased to maintain the 300 mg tablet weight.
  • the tablets were coated with Surelease ® /Opadry ® (85/15) at a coating weight gain of approximately 3% (Batch 6) and 5% (Batch 7).
  • T80 is 7 hours, 8 hours, and

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Abstract

L'invention concerne des compositions comprenant de la (R)-8-chloro-1-méthyl-2,3,4,5-tétrahydro-1H-3-benzazépine ou un sel, solvate ou hydrate pharmaceutiquement acceptable de celle-ci, éventuellement en association avec un agent supplémentaire, et des procédés pour : réduire la fréquence de consommation de tabac chez un individu essayant de diminuer sa consommation de tabac ; aider à cesser ou réduire la consommation d'un produit du tabac chez un individu essayant de cesser ou de diminuer sa consommation d'un produit du tabac ; aider au renoncement au tabac et prévenir la prise de poids associée ; lutter contre la prise de poids associée au renoncement au tabac par un individu essayant de renoncer au tabac ; réduire la prise de poids associée au renoncement au tabac par un individu essayant de renoncer au tabac ; traiter la dépendance, l'addiction et/ou le sevrage à la nicotine chez un individu essayant de traiter sa dépendance, son addiction et/ou son sevrage à la nicotine ; ou réduire le risque d'une reprise de la consommation de nicotine par un individu essayant de renoncer à la consommation de nicotine, comprenant l'administration de la (R)-8-chloro-1-méthyl-2,3,4,5-tétrahydro-1H-3-benzazépine ou d'un sel, solvate ou hydrate pharmaceutiquement acceptable de celle-ci, éventuellement en association avec un agent supplémentaire.
PCT/US2015/058016 2014-10-30 2015-10-29 Compositions et procédés permettant de renoncer au tabac WO2016069875A1 (fr)

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