WO2005049043A1 - Therapie combinee comprenant de la metformine et des agents anticonvulsivants - Google Patents

Therapie combinee comprenant de la metformine et des agents anticonvulsivants Download PDF

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Publication number
WO2005049043A1
WO2005049043A1 PCT/US2004/038508 US2004038508W WO2005049043A1 WO 2005049043 A1 WO2005049043 A1 WO 2005049043A1 US 2004038508 W US2004038508 W US 2004038508W WO 2005049043 A1 WO2005049043 A1 WO 2005049043A1
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formula
subjects
topiramate
compound
metformin
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PCT/US2004/038508
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English (en)
Inventor
Martin Q. Fitchet
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Ortho-Mcneil Pharmaceutical, Inc.
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Publication of WO2005049043A1 publication Critical patent/WO2005049043A1/fr

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    • 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

Definitions

  • the present invention is directed to a method for promoting weight loss and / or treating obesity comprising combination therapy with a therapeutically effective amount of metformin and an anticonvulsant agent, preferably topiramate.
  • Obesity is a state of excess adipose tissue mass. Although often viewed as equivalent to increased body weight, this need not be the case-lean but very muscular individuals may be overweight by arbitrary standards without having increased adiposity. Body weights are distributed continuously in populations, so that a medically meaningful distinction between lean and obese is somewhat arbitrary. Obesity is therefore more effectively defined by assessing its linkage to morbidity or mortality. Although not a direct measure of adiposity, the most widely used method to gauge obesity is the body mass index (BMI), which is equal to weight/height 2 (in kg/m 2 ).
  • BMIs for the midpoint of all heights and frames among both men and women range from 19 to 26 kg/m 2 ; at a similar BMI, women have more body fat than men. Based on unequivocal data of substantial morbidity, a BMI of 30 is most commonly used as a threshold for obesity in both men and women. Large-scale epidemiologic studies suggest that all-cause, metabolic, and cardiovascular morbidity begin to rise (albeit at a slow rate) when BMIs are ⁇ 25, suggesting that the cut-off for obesity should be lowered.
  • BMI weighted mass index
  • adiposity such as hypertension and glucose intolerance
  • Obesity has major adverse effects on health. Morbidly obese individuals (>200% ideal body weight) have as much as a twelvefold increase in mortality. Morality rates rise as obesity increases, particularly when obesity is associated with increased intraabdominal fat (see above). It is also apparent that the degree to which obesity affects particular organ systems is influenced by susceptibility genes that vary in the population. Hyperinsulinemia and insulin resistance are pervasive features of obesity, increasing with weight gain and diminishing with weight loss. Further, obesity is a major risk factor for diabetes, and as many as 80% of patients with type 2 diabetes mellitus are obese. Weight loss, even of modest degree, is associated with increased insulin sensitivity and often improves glucose control in diabetes.
  • the effect of obesity on cardiovascular mortality in women may be seen at BMIs as low as 25.
  • Obesity especially abdominal obesity, is associated with an atherogenic lipid profile, with increased low-density lipoprotein (LDL) cholesterol, very low density lipoprotein and triglyceride, and decreased high- density lipoprotein cholesterol.
  • Obesity is also associated with hypertension.
  • Obesity-induced hypertension is associated with increased peripheral resistance and cardiac output, increased sympathetic nervous system tone, increased salt sensitivity, and insulin-mediated salt retention; it is often responsive to modest weight loss.
  • Obesity may be associated with a number of pulmonary abnormalities. These include reduced chest wall compliance, increased work of breathing, increased minute ventilation due to increased metabolic rate, and decreased total lung capacity and functional residual capacity. Severe obesity may be associated with obstructive sleep apnea and the "obesity hypoventilation syndrome". Sleep apnea can be obstructive (most common), central, or mixed. Weight loss (10 to 20 kg) can bring substantial improvement, as can major weight loss following gastric bypass or restrictive surgery. Continuous positive airway pressure has been used with some success. Obesity is associated with enhanced biliary secretion of cholesterol, supersaturation of bile, and a higher incidence of gallstones, particularly cholesterol gallstones.
  • a person 50% above ideal body weight has about a sixfold increased incidence of symptomatic gallstones.
  • Fasting-induced cholecystitis is a complication of extreme diets.
  • Obesity in males is associated with higher mortality from cancer of the colon, rectum, and prostate; obesity in females is associated with higher mortality from cancer of the gallbladder, bile ducts, breasts, endometrium, cervix, and ovaries. Some of the latter may be due to increased rates of conversion of androstenedione to estrone in adipose tissue of obese individuals.
  • Obesity is associated with an increased risk of osteoarthritis, no doubt partly due to the trauma of added weight bearing. The prevalence of gout may also be increased.
  • acanthosis nigricans manifested by darkening and thickening of the skin folds on the neck, elbows, and dorsal interphalangeal spaces.
  • Acanthosis reflects the severity of underlying insulin resistance and diminishes with weight loss. Friability of skin may be increased, especially in skin folds, enhancing the risk of fungal and yeast infections.
  • venous stasis is increased in the obese. (www.harrisons.accessmedicine.com Harrison's Online, Chapter 77: Obesity, Oct. 2004)
  • R 1 is hydrogen or alkyl
  • R 2 , R 3 , R 4 and R 5 are independently hydrogen or lower alkyl and, when X is CH2, R 4 and R 5 may be alkene groups joined to form a benzene ring and, when X is oxygen, R 2 and R 3 and/or R 4 and R 5 together may be a methylenedioxy group of the following formula II:
  • R 6 and R 7 are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring; and metformin.
  • R 1 is hydrogen or alkyl
  • R 2 , R 3 , R 4 and R 5 are independently hydrogen or lower alkyl and, when X is CH2, R 4 and R 5 may be alkene groups joined to form a benzene ring and, when X is oxygen, R 2 and R 3 and/or R 4 and R 5 together may be a methylenedioxy group of the following formula II:
  • R 6 and R 7 are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring; and metformin.
  • the present invention is directed to a method for promoting weight loss and / or treating obesity comprising combination therapy with a therapeutically effective amount of metformin and an anticonvulsant agent, a compound of formula I
  • R 1 , R 2 , R 3 , R 4 and R 5 are as herein defined.
  • the mammals are preferably humans.
  • the compound of formula I is topiramate. In an embodiment of the present invention, the compound of formula I is administered in an amount in the range of from about 25 to 600 mg. In another embodiment of the present invention, the compound of formula I is administered in an amount in the range of from about 50 to 200 mg once or twice daily.
  • the metformin is administered in an amount in the range of from about 500 to about 2500 mg daily. In another embodiment of the present invention, the metformin is administered in an amount in the range of from about 1000 to about 2000 mg daily.
  • the present invention to methods of treatment comprising combination therapy wherein the amount of topiramate is therapeutically effective and wherein the amount of metformin is therapeutically effective.
  • R 1 is hydrogen or alkyl
  • R 2 , R 3 , R 4 and R 5 are independently hydrogen or lower alkyl and, when X is CH2, R 4 and R 5 may be alkene groups joined to form a benzene ring and, when X is oxygen, R 2 and R 3 and/or R 4 and R 5 together may be a I methylenedioxy group of the following formula II:
  • R 6 and R 7 are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring.
  • Rl in particular is hydrogen or alkyl of about 1 to 4 carbons, such as methyl, ethyl and iso-propyl.
  • Alkyl throughout this specification includes straight and branched chain alkyl.
  • Alkyl groups for R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are of about 1 to 3 carbons and include methyl, ethyl, iso-propyl and n-propyl.
  • a particular group of compounds of formula I is that wherein X is oxygen and both R 2 and R 3 and R 4 and R 5 together are methylenedioxy groups of the formula II, wherein R 6 and R 7 are both hydrogen both alkyl or combine to form a spiro cyclopentyl or cyclohexyl ring, in particular where R 6 and R 7 are both alkyl such as methyl.
  • a second group of compounds is that wherein X is CH2 and R 4 and R 5 are joined to form a benzene ring.
  • a third group of compounds of formula I is that wherein both R 2 and R 3 are hydrogen.
  • the compounds of formula I may be synthesized by the following methods: (a) Reaction of an alcohol of the formula RCH2OH with a chlorosulfamate of the formula CISO2NH2 or CISO2NHR 1 in the presence of a base such as potassium f-butoxide or sodium hydride at a temperature of about -20° to 25° C and in a solvent such as toluene, THF, or dimethylformamide wherein R is a moiety of the following formula (III):
  • the chlorosulfate of the formula RCH2OSO2CI may then be reacted with an amine of the formula R 1 NH 2 at a temperature of abut 40° to 25° C in a solvent such as methylene chloride or acetonitrile to produce a compound of formula I.
  • a solvent such as methylene chloride or acetonitrile.
  • the starting materials of the formula RCH2OH may be obtained commercially or as known in the art.
  • starting materials of the formula RCH2OH wherein both R 2 and R 3 and R 4 and R 5 are identical and are of the formula II may be obtained by the method of R. F. Brady in Carbohydr. Res. 1970, 14, 35 or by reaction of the trimethylsilyl enol ether of a R 6 COR 7 ketone or aldehyde with fructose at a temperature of about 25° C, in a solvent such a halocarbon, e.g. methylene chloride in the presence of a protic acid such as hydrochloric acid or a Lewis Acid such as zinc chloride.
  • the trimethylsilyl enol ether reaction is described by G. L. Larson et al. in J. Org. Chem. 1973, 38, 3935.
  • carboxylic acids and aldehydes of the formulae RCOOH and RCHO may be reduced to compounds of the formula RCH 2 OH by standard reduction techniques, e.g. reaction with lithium aluminum hydride, sodium borohydride or borane-THF complex in an inert solvent such a diglyme, THF or toluene at a temperature of about 0° to 100° C, e.g. as described by H.O. House in "Modern Synthetic Reactions", 2nd Ed., pages 45 to 144 (1972).
  • the compounds of formula I may also be made by the process disclosed US Patents: No.4,513,006, No.5,242,942, and No.5,384,327, which are incorporated by reference herein.
  • the compounds of formula I include the various individual isomers as well as the racemates thereof, e.g., the various alpha and beta attachments, i.e., below and above the plane of the drawing, of R 2 , R 3 , R 4 and R 5 on the 6- membered ring.
  • the oxygen of the methylenedioxy group II are attached on the same side of the 6-membered ring.
  • Metformin also known as N,N-dimethylimidodicarbonimidic diamide, is an agent useful in the treatment of type II diabetes. Metformin is typically administered in the form of its hydrochloride salt and is currently available in the United States in Extended-Release Tablets. Metformin is a biguanide oral antidiabetic agent that can be used in monotherapy or in combination with other classes of antidiabetic agents to lower blood glucose with additional therapeutic benefits, many believed to be related to a reduction in insulin resistance. Metformin, unlike many antidiabetic agents, does not cause weight gain and may lead to a small sustained reduction in weight. This is believed to be secondary to a decrease in energy intake. For this reason, metformin is often the agent of choice in overweight and obese subjects with type 2 diabetes.
  • the term “therapeutically effective amount” means that amount of active compounds or pharmaceutical agents that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • therapeutically effective amount shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response.
  • the therapeutically effective amount of combination therapy comprising administration of a compound of formula I and metformin would be the amount of the compound of formula I and the amount metformin that when taken together or sequentially have a combined effect that is therapeutically effective.
  • the amount of the compound of formula I and/or the amount of metformin individually may or may not be therapeutically effective.
  • the compounds may be co-administered by any suitable means, simultaneously, sequentially or in a single pharmaceutical composition.
  • the number of dosages of each compound given per day may not necessarily be the same, e.g. where one compound may have a greater duration of activity, and will therefore, be administered less frequently.
  • the compound(s) of formula I and metformin may be administered via the same or different routes of administration.
  • the compound(s) of formula I and metformin may be administered via the same or different routes of administration. Suitable examples of methods of administration are orally, intravenous (iv), intramuscular (im), and subcutaneous (sc).
  • Compounds may also be administrated directly to the nervous system including, but not limited to the intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal and/or peri-spinal routes of administration by delivery via intracranial or intravertebral needles and/or catheters with or without pump devices.
  • the compound(s) of formula I and metformin may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient's sex, age, weight, diet, time of administration and concomitant diseases, will result in the need to adjust dosages.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • one or more sulfamate compounds of formula I are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., i.v. sterile injectable formulations will be prepared using appropriate solubilizing agents.
  • a unit dose would contain about 15 to 200 mg of the active ingredient.
  • Topiramate is currently available for oral administration in round tablets containing 25 mg, 100 mg or 200 mg of active agent.
  • the tablets contain some or all of the following inactive ingredients: lactose hydrous, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide, and polysorbate 80.
  • Example 1 A Multicenter, Randomized. Double-Blind, Placebo-Controlled, Parallel-Group Study of the Efficacy and Safety of Topiramate in the Treatment of Obese Type 2 Diabetic Subjects Treated With Metformin
  • Subjects must have been taking metformin monotherapy for at least 4 months and have had a stable dose, not to exceed 2.1 g per day, for at least 2 months prior to enrollment. Subjects may have had an established diagnosis of controlled hypertension or dyslipidemia, with their antihypertensive and hypolipidemic medication stable for at least 2 months prior to enrollment.
  • non-pharmacologic therapy which consisted of an individual diet, a behavioral modification program, and a physical activity program, was provided to each subject.
  • the energy level of the prescribed diet was 600 kcal (2500 kJ) less than the individual subject's calculated total energy expenditure.
  • Non-pharmacologic therapy began at enrollment and continued through to Week 66, with assessments and advice concerning diet, exercise, and behavior at each visit.
  • the dosage was increased (titrated) until the assigned (target) daily dosage or the maximum tolerated dosage, if less, was achieved; (c) 52 week Maintenance Phase during which subjects continued to receive placebo or topiramate at their assigned dosage or their maximum tolerated dosage for a period of 1 year; (d) 6 week Follow-Up Phase during which the subjects' dosage of study medication was decreased (tapered) by approximately 50% per week over a 2 week period and then was discontinued. A final visit was conducted 4 weeks after discontinuation of study treatment.
  • Efficacy was evaluated on the basis of data regarding body weight, HbA-ic, BMI, FPG, waist and hip circumference and waist/hip ratio, fasting lipid profile, fasting insulin, C-peptide, uric acid, urinary albumin excretion, blood pressure, and health-related quality of life (HRQOL) assessments.
  • HRQOL health-related quality of life
  • the following analysis populations were defined prior to unblinding: (1 ) The Intent-to-treat (ITT) population for efficacy analysis included all randomized subjects who received at least 1 dose of study medication and had at least 1 on-treatment primary or secondary efficacy evaluation. (2) The Modified Intent-to-treat (MITT) population was the primary population for efficacy analysis and consisted of all randomized subjects who received at least 1 dose of study medication and had at least 1 on-treatment primary or secondary efficacy evaluation AND who had the opportunity to complete at least 24 weeks of double-blind (8-week titration and 16-week maintenance) treatment before announcement of early termination of the study. (3) The Safety population was the primary population for safety analysis and included all randomized subjects who received at least 1 dose of study drug and for whom any safety information after the beginning of treatment was available.
  • the planned sample size for the study was 540 subjects (180 subjects per treatment group). This sample size was planned based on the condition that the study would be declared positive if there was a statistically significant positive effect on either of the 2 primary endpoints, and was the maximum of the sample sizes computed for the 2 primary efficacy variables with 95% power at a 0.025 two-sided significance level.
  • the assumption was that it was important to detect a difference of 5% in percent weight change between active treatment and placebo groups after 1 year of therapy and that the standard deviation (SD) of the percent change was 11.0%.
  • SD standard deviation
  • the assumption also was that it was important to detect a difference of 0.5% in mean HbA- ⁇ c change between active treatment and placebo groups after 1 year of therapy and that the standard deviation of the change was 1.2%.
  • a power of 95% could be achieved for the HbA- ⁇ c analysis and a power of 98% could be achieved for the percent weight change analysis, each with a 2-sided significance level of 0.025.
  • the Intent-to-treat population included 637 subjects.
  • the Modified Intent-to-treat population included 307 subjects. Of the 646 subjects randomly assigned to trial treatment, 640 (99%) subjects comprised the Safety population.
  • Subjects receiving topiramate were more likely to discontinue due to adverse events than were subjects receiving placebo. Additional reasons for discontinuation were subject choice (7% placebo-treated subjects vs. 5% topiramate-treated subjects), lack of efficacy (5% vs. 2%), and lost to follow-up (1 % vs. 2%).
  • Median by-subject average dosages were 87.8 mg/day in the topiramate 96 mg/day group and 160.5 mg/day in the topiramate 192 mg/day group across the titration and maintenance periods.
  • the median average dosages during the maintenance period approached the target daily dosages (95.5 mg/day in the 96 mg/day group and 190.4 mg/day in the 192 mg/day group).
  • the planned duration of the treatment period, including the titration phase and the maintenance phase as stated in the protocol was 60 weeks (420 days), followed by a 2-week tapering period.
  • the median duration of therapy, including the tapering period was 196 days for the placebo group, 202 days for the topiramate 96 mg/day group, and 206 days for the topiramate 192 mg/day group.
  • the primary efficacy variables in the study were mean percent change in weight and mean absolute change in HbA ⁇ c from randomization (baseline) to the Week 24 value. Due to the correlation between these 2 variables, the nominal significance level ⁇ * for the primary efficacy analyses was adjusted from 0.05 to 0.035.
  • Table 4 Mean Percent Change from Baseline Body Weight Over Time (ITT Population
  • Body Weight Responders For the MITT population, fourteen percent of subjects in the placebo group, 42% of subjects in the topiramate 96 mg/day group, and 53% of subjects in the topiramate 192 mg/day group lost at least 5% of their baseline body weight, i.e., were '5% body weight responders.' Two percent of subjects in the placebo group, 11% in the topiramate 96 mg/day group, and 27% in the topiramate 192 mg/day group lost at least 10% of their baseline body weight, i.e., were '10% body weight responders.' All differences between topiramate and placebo were statistically significant (p ⁇ 0.019). Results for the ITT population were similar to those of the MITT population. Results for the MITT and ITT populations were as listed in Tables 5 and 6 below.
  • Subjects who lost at least 5% or at least 10% of their weight from baseline to the Week 24 LOCF value were classified as 5% or 10% body weight responders.
  • 5% body weight responders In the MITT population, 42% of subjects in the topiramate 96 mg/day group and 53% of subjects in the topiramate 192 mg/day group were 5% body weight responders. In contrast, 14% of subjects in the placebo group were 5% body weight responders. Similarly, a greater percentage of I subjects were 10% body weight responders in the topiramate groups than in the placebo group. Eleven percent of subjects in the topiramate 96 mg/day group and 27% of subjects in the topiramate 192 mg/day group were 10% body weight responders compared with 2% of subjects in the placebo group.

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Abstract

L'invention concerne une thérapie combinée comprenant de la metformine et des dérivés anticonvulsivants, qui permet de traiter l'obésité et d'activer une perte de poids.
PCT/US2004/038508 2003-11-18 2004-11-17 Therapie combinee comprenant de la metformine et des agents anticonvulsivants WO2005049043A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005110405A1 (fr) * 2004-05-03 2005-11-24 Duke University Compositions influant sur la perte de poids
US7425571B2 (en) 2002-05-17 2008-09-16 Orexigen Therapeutics, Inc. Method for treating obesity
US7462626B2 (en) 2003-04-29 2008-12-09 Orexigen Therapeutics, Inc. Compositions for affecting weight loss
US7713959B2 (en) 2004-01-13 2010-05-11 Duke University Compositions of an anticonvulsant and mirtazapine to prevent weight gain
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US8916195B2 (en) 2006-06-05 2014-12-23 Orexigen Therapeutics, Inc. Sustained release formulation of naltrexone
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9125868B2 (en) 2006-11-09 2015-09-08 Orexigen Therapeutics, Inc. Methods for administering weight loss medications
US9248123B2 (en) 2010-01-11 2016-02-02 Orexigen Therapeutics, Inc. Methods of providing weight loss therapy in patients with major depression
US9457005B2 (en) 2005-11-22 2016-10-04 Orexigen Therapeutics, Inc. Compositions and methods for increasing insulin sensitivity
US9633575B2 (en) 2012-06-06 2017-04-25 Orexigen Therapeutics, Inc. Methods of treating overweight and obesity
US11324741B2 (en) 2008-05-30 2022-05-10 Nalpropion Pharmaceuticals Llc Methods for treating visceral fat conditions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BAPTISTA ET AL.: "Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives", PHARMACOPSYCHIATRY, vol. 35, no. 6, 2002, pages 205 - 219, XP008045948 *
WERNEKE ET AL.: "Options for pharmacological management of obesity in patients treated with atypical antipsychotics", INT'L CLINICAL PSYCHOPHARMACOLOGY, vol. 17, no. 4, 2002, pages 145 - 160, XP009035036 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7425571B2 (en) 2002-05-17 2008-09-16 Orexigen Therapeutics, Inc. Method for treating obesity
US7754748B2 (en) 2002-05-17 2010-07-13 Duke University Method for treating obesity
US10238647B2 (en) 2003-04-29 2019-03-26 Nalpropion Pharmaceuticals, Inc. Compositions for affecting weight loss
US7462626B2 (en) 2003-04-29 2008-12-09 Orexigen Therapeutics, Inc. Compositions for affecting weight loss
US7713959B2 (en) 2004-01-13 2010-05-11 Duke University Compositions of an anticonvulsant and mirtazapine to prevent weight gain
WO2005110405A1 (fr) * 2004-05-03 2005-11-24 Duke University Compositions influant sur la perte de poids
US9457005B2 (en) 2005-11-22 2016-10-04 Orexigen Therapeutics, Inc. Compositions and methods for increasing insulin sensitivity
US9107837B2 (en) 2006-06-05 2015-08-18 Orexigen Therapeutics, Inc. Sustained release formulation of naltrexone
US8916195B2 (en) 2006-06-05 2014-12-23 Orexigen Therapeutics, Inc. Sustained release formulation of naltrexone
US9125868B2 (en) 2006-11-09 2015-09-08 Orexigen Therapeutics, Inc. Methods for administering weight loss medications
US11324741B2 (en) 2008-05-30 2022-05-10 Nalpropion Pharmaceuticals Llc Methods for treating visceral fat conditions
US9248123B2 (en) 2010-01-11 2016-02-02 Orexigen Therapeutics, Inc. Methods of providing weight loss therapy in patients with major depression
US10322121B2 (en) 2010-01-11 2019-06-18 Nalpropion Pharmaceuticals, Inc. Methods of providing weight loss therapy in patients with major depression
US10403170B2 (en) 2012-06-06 2019-09-03 Nalpropion Pharmaceuticals, Inc. Methods of treating overweight and obesity
US9633575B2 (en) 2012-06-06 2017-04-25 Orexigen Therapeutics, Inc. Methods of treating overweight and obesity
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US10363224B2 (en) 2013-03-13 2019-07-30 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules
US8889190B2 (en) 2013-03-13 2014-11-18 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10172878B2 (en) 2013-03-15 2019-01-08 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules
US9555005B2 (en) 2013-03-15 2017-01-31 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules

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