Modified-release dosage forms of 5-ht2c agonists useful for weight management

Abstract

The present invention relates to methods for weight management that utilize modified-release dosage forms comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine salts and crystalline forms thereof. The present invention further relates to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine salts, crystalline forms thereof and modified-release dosage forms comprising them.

1 . A modified-release dosage form comprising a therapeutically effective amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof. 
     
     
         2 . The modified-release dosage form according to  claim 1 , wherein said modified-release dosage form is a tablet. 
     
     
         3 . A method for weight management, comprising administering to an individual in need thereof, the modified-release dosage form according to  claim 1 . 
     
     
         4 . The method according to  claim 3 , wherein said method comprises a plurality of administrations of said modified-release dosage form, with a frequency wherein the average interval between any two sequential said administrations is:
 at least about 24 hours; or   about 24 hours.   
     
     
         5 . The method according to  claim 3 , wherein said method comprises a plurality of administrations of said modified-release dosage form, and wherein said modified-release dosage form is administered once-a-day. 
     
     
         6 . The method according to  claim 3 , wherein said plurality of administrations is:
 at least about 30;   at least about 180;   at least about 365; or   at least about 730.   
     
     
         7 . The method according to  claim 4 , wherein said method is more efficacious than an immediate-release method for weight management; wherein said immediate-release method for weight management comprises administering to an individual in need thereof, at said frequency, said plurality of administrations of an immediate-release dosage form comprising said therapeutically effective amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof. 
     
     
         8 . The method according to  claim 4 , wherein said method is more efficacious than an immediate-release method for weight management; wherein said immediate-release method for weight management comprises administering to an individual in need thereof, an immediate-release dosage form comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and wherein the total plasma exposure of said individual to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine over the course of said immediate-release method is equal to or greater than the total plasma exposure of said individual to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine over the course of said method. 
     
     
         9 . The method according to  claim 3 , wherein the plasma concentration of said (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in said individual has a C max  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.   
     
     
         10 . The method according to  claim 3 , wherein the C max  divided by the therapeutically effective amount is equal to:
 less than about 1×10 −5  mL −1 ;   less than about 5×10 −6  mL −1 ;   less than about 1×10 −6  mL −1 ; or   less than about 5×10 −7  mL −1 .   
     
     
         11 . The method according to  claim 3 , wherein said C max  occurs:
 more than 30 minutes after said administering;   more than 1 hour after said administering;   more than 2 hours after said administering.   more than 3 hours after said administering;   more than 6 hours after said administering; or   more than 12 hours after said administering.   
     
     
         12 . The method according to  claim 3 , wherein the average peak to trough ratio of said plasma concentration of said (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in said individual is:
 less than about 3:1;   less than about 2:1;   less than about 1.5:1; or   less than about 1.1:1.   
     
     
         13 . The method according to  claim 3 , wherein said modified-release dosage form comprises a salt selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride and pharmaceutically acceptable solvates and hydrates thereof. 
     
     
         14 . The method according to  claim 13 , wherein said salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate. 
     
     
         15 . The method according to  claim 3 , wherein said modified-release dosage form further comprises (hydroxypropyl)methyl cellulose. 
     
     
         16 . The method according to  claim 15 , wherein said modified-release dosage form further comprises one or more ingredients selected from: microcrystalline cellulose, mannitol, and magnesium stearate. 
     
     
         17 . The method according to  claim 3 , wherein said modified-release dosage form further comprises a film coating. 
     
     
         18 . The method according to  claim 17 , wherein said film coating comprises a water-soluble film coating. 
     
     
         19 . The method according to  claim 17 , wherein said film coating comprises ethyl cellulose. 
     
     
         20 . The method according to  claim 19 , wherein said film coating further comprises (hydroxypropyl)methyl cellulose. 
     
     
         21 . The method according to  claim 20 , wherein the ratio of said ethyl cellulose to said (hydroxypropyl)methyl cellulose is:
 about 75:25;   about 80:20; or   about 85:15.   
     
     
         22 . The method according to  claim 13 , wherein said modified-release dosage form comprises a core tablet and a film coating; wherein said core tablet comprises: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium sterate; and said film coating comprises a water-soluble film coating. 
     
     
         23 . The method according to  claim 13 , wherein said modified-release dosage form comprises a core tablet and a film coating, wherein the weight to weight ratio of said core tablet to said coating is about 20:1; and wherein said core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-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 sterate; and said film coating comprises a water-soluble film coating. 
     
     
         24 . The method according to  claim 13 , wherein said modified-release dosage form comprises a core tablet and a film coating; wherein said core tablet comprises: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium sterate; and said film coating comprises: ethyl cellulose; and (hydroxypropyl)methyl cellulose. 
     
     
         25 . The method according to  claim 13 , wherein said modified-release dosage form comprises a core tablet and a film coating, wherein the weight to weight ratio of said core tablet to said coating is about 20:1; and wherein said core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-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 sterate; and said film coating comprises:
 about 85% ethyl cellulose; and about 15% (hydroxypropyl)methyl cellulose; or   about 75% ethyl cellulose; and about 25% (hydroxypropyl)methyl cellulose.   
     
     
         26 . The method according to  claim 3 , wherein said modified-release dosage form has a T80% of:
 at least 3 h;   at least 6 h;   at least 9 h; or   at least 12 h.   
     
     
         27 . The method according to  claim 3 , wherein said modified-release dosage form comprises a salt selected from: a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and pharmaceutically acceptable solvates and hydrates thereof, and wherein said salt has an aqueous solubility of:
 less than about 200 mg/mL at about room temperature;   less than about 100 mg/mL at about room temperature;   less than about 50 mg/mL at about room temperature;   less than about 25 mg/mL at about room temperature;   less than about 10 mg/mL at about room temperature; or   less than about 5 mg/mL at about room temperature.   
     
     
         28 . The method according to  claim 3 , wherein said modified-release dosage form comprises a salt selected from:
 (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; and   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-acetamidobenzoate salt-cocrystal;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans-cinnamate salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(±)-mandelate salt; and   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemipamoate salt;   and pharmaceutically acceptable solvates and hydrates thereof.   
     
     
         29 . A salt selected from:
 (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-acetamidobenzoate salt-cocrystal;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans-cinnamate salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt;   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(±)-mandelate salt; and   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemipamoate salt;   and pharmaceutically acceptable solvates and hydrates thereof.   
     
     
         30 . A pharmaceutical composition comprising a salt according to  claim 29 , and a pharmaceutically acceptable carrier. 
     
     
         31 . A process for preparing a pharmaceutical composition comprising admixing a salt according to  claim 29 , and a pharmaceutically acceptable carrier. 
     
     
         32 . A method for weight management, comprising administering to an individual in need thereof, a therapeutically effective amount of a salt according to  claim 29 . 
     
     
         33 . The method according to  claim 3 , wherein said weight management comprises one or more of: weight loss, maintenance of weight loss, decreased food consumption, increasing meal-related satiety, reducing pre-meal hunger, and reducing intra-meal food intake. 
     
     
         34 . The method according to  claim 3 , as an adjunct to diet and exercise. 
     
     
         35 . The method according to  claim 3 , wherein said individual in need of weight management is selected from:
 an obese patient with an initial body mass index ≧30 kg/m 2 ;   an overweight patient with an initial body mass index ≧27 kg/m 2  in the presence of at least one weight related comorbid condition;   an overweight patient with an initial body mass index ≧27 kg/m 2  in the presence of at least one weight related comorbid condition; wherein said weight related co-morbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.   
     
     
         36 . The method according to  claim 3 , further comprising administering a second anti-obesity agent to said individual. 
     
     
         37 . The method according to  claim 36 , wherein said second anti-obesity agent is selected from: chlorphentermine, clortermine, phenpentermine, and phentermine, and pharmaceutically acceptable salts, solvates, and hydrates thereof. 
     
     
         38 . The method according to  claim 3 , further comprising administering an anti-diabetes agent to said individual. 
     
     
         39 . The method according to  claim 38 , wherein said anti-diabetes agent is metformin. 
     
     
         40 .- 56 . (canceled) 
     
     
         57 . The modified-release dosage form according to  claim 1 , wherein said anti-diabetes agent is metformin. 
     
     
         58 . A method of manufacturing a pharmaceutical composition comprising admixing a compound selected from: a salt according to  claim 29  and pharmaceutically acceptable solvates and hydrates thereof, with a pharmaceutically acceptable excipient. 
     
     
         59 . A method of manufacturing a modified-release dosage form comprising:
 a. providing a compound selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable salts, solvates, and hydrates thereof; and   b. formulating said compound into a modified-release dosage form.