Methods and compositions comprising at least one alpha3 beta4 nAChR antagonist or pharmaceutically acceptable salt thereof

Abstract

The present invention is directed to methods and formulations for treating, modifying, and/or managing gastrointestinal secretion, and intestinal conditions that cause the same. Methods of using at least one α3 β4 nAChR antagonist and formulations comprising at least one α3 β4 nAChR antagonist, or pharmaceutically acceptable salt thereof, are included.

1 . A method for treating at least one gastrointestinal condition in a subject in need thereof comprising administering to the subject a composition comprising a therapeutically effective amount of at least one α3 β4 nAChR antagonist or pharmaceutically acceptable salt thereof, wherein the at least one α3 β4 nAChR antagonist exhibits an IC 50  value for the α3 β4 sub-type of nAChR ranging from 1.0×10 −6  to 1×10 −9  or exhibits a potency for the α3 β4 nAChR sub-type at least two-times greater in comparison to at least one other nAChR sub-type.  
     
     
         2 . The method according to  claim 1 , wherein the at least one antagonist acts as a competitive or noncompetitive/allosteric inhibitor.  
     
     
         3 . The method according to  claim 1 , wherein the at least one gastrointestinal condition is an abnormal increase in gastrointestinal secretion.  
     
     
         4 . The method according to  claim 1 , wherein the at least one gastrointestinal condition is an abnormal increase in gastrointestinal secretion and motility.  
     
     
         5 . The method according to  claim 1 , wherein the at least one gastrointestinal condition is chosen from diarrhea-related or linked symptoms, chronic diarrhea, functional diarrhea, cancer-related diarrhea, carcinoid syndrome, diarrhea related symptoms of inflammatory bowel disease and microscopic colitis, chemotherapy and radiotherapy linked diarrhea, AIDS related diarrhea, infectious diarrhea, food intolerance and malabsorption related diarrhea, medicine linked diarrhea, celiac disease, and endocrine diseases, functional bowel disorders, ulcerative colitis, granulomatous enteritis, Crohn's disease, infectious diseases of the small and large intestine, pyloric spasm, abdominal cramps, mild dysenteries, diverticulitis, acute enterocolitis, neurogenic bowel disorders, spastic colitis, and any diarrhea-related or linked symptom of any of the foregoing conditions.  
     
     
         6 . The method according  claim 5 , wherein the condition is a diarrhea related condition.  
     
     
         7 . The method according to  claim 5  wherein the condition is chemotherapy-related diarrhea.  
     
     
         8 . The method according to  claim 1 , wherein the at least one α3 β4 antagonist is N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof.  
     
     
         9 . The method according to  claim 8 , wherein the at least one gastrointestinal condition is an abnormal increase in gastrointestinal secretion and wherein the abnormal increase is gastrointestinal secretion is reduced, while at least one side effect associated with the administration of a conventional formulation of N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof is minimized.  
     
     
         10 . The method according to  claim 9 , wherein the at least one side effect is chosen from effects on the subject's heart rate, blood pressure, vision, and bladder function.  
     
     
         11 . The method according to  claim 8 , wherein the therapeutically effective amount of N,-2,2,3-tetramethylbicyclo-[2.1.1]heptan-2-amine or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 0.2 mg to about 40 mg.  
     
     
         12 . The method according to  claim 11 , wherein the N,-2,2,3-tetramethylbicyclo-[2.1.1]heptan-2-amine or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 0.5 mg to about 20 mg.  
     
     
         13 . The method according to  claim 12 , wherein the N,-2,2,3-tetramethylbicyclo-[2.1.1]heptan-2-amine or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 1 mg to about 15 mg.  
     
     
         14 . The method according to  claim 13 , wherein the N,-2,2,3-tetramethylbicyclo-[2.1.1]heptan-2-amine or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 2 mg to about 12 mg.  
     
     
         15 . The method according to  claim 8 , wherein the N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine comprises racemic N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, enriched (R)—N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, enriched (S)—N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, substantially pure (R)—N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, substantially pure (S)—N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or pharmaceutically acceptable salts of any of the foregoing  
     
     
         16 . The method according to  claim 15 , wherein the N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine comprises racemic N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof.  
     
     
         17 . The method according to  claim 15 , wherein the N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine comprises enriched N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof.  
     
     
         18 . The method according to  claim 15 , wherein the N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine comprises substantially pure N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof.  
     
     
         19 . The method according to  claim 1 , wherein the composition is suitable for oral, intra-nasal, or transdermal administration.  
     
     
         20 . The method according to  claim 19 , wherein the composition is suitable for buccal or sublingual administration.  
     
     
         21 . The method according to  claim 1 , wherein the composition is a modified-release formulation.  
     
     
         22 . The method according to  claim 1 , wherein the composition comprises a modified-release formulation in combination with an immediate-release formulation.  
     
     
         23 . The method according to  claim 1 , wherein the administration of the at least one antagonist, or a pharmaceutically acceptable salt thereof, provides a maximum plasma concentration of the at least one antagonist at about 3.5 hours, or later, following a first administration.  
     
     
         24 . The method according to  claim 23 , wherein the maximum plasma concentration of the at least one antagonist is achieved at about 6 hours, or later, following a first administration.  
     
     
         25 . The method according to  claim 1 , wherein the at least one antagonist, or a pharmaceutically acceptable salt thereof, is administered once-daily.  
     
     
         26 . The method according to  claim 1 , wherein the at least one antagonist, or a pharmaceutically acceptable salt thereof, is administered in combination with at least one other pharmaceutically active compound.  
     
     
         27 . The method according to  claim 26 , wherein the at least one other pharmaceutically active compound is chosen from ganglionic blockers, nicotinic-receptor antagonists, gastrointestinal motility altering agents, antispasmodics, antimuscarinic agents, opiates, 5-HT receptor agonists, 5-HT receptor antagonists, calcium channel blockers, beta adrenergic receptor blockers, agents that alter fluid transport across the gut, agents that alter fluid transport into or out of gastrointestinal cells, diuretics, anti-diarrheals, H 2 -antihistamines, proton pump inhibitors, antacids, anti-inflammatory agents, steroids, mineralocorticoids, corticosteroids, anti-infective agents, immunomodulators, and fish oil.  
     
     
         28 . The method according to  claim 27 , wherein the at least one other pharmaceutically active compound is chosen from hexamethonium, trimethaphan, chloroisondamine, erysodine, β-dihydroerythrodine, amantidine, perpidine, succinylcholine, decamethonium, tubocurarine, atracurium, doxacurium, mivicurium, pancuronium, rocuronium, vencuronium, glycopyrrolate, atropine, hyscomine, scopolamine, loperamide, difenoxine, codeine, morphine, oxymorphone, oxycontin, dihydrocodeine, fentanyl, alosetron hydrochloride, verapamil, amiloride, furosemide, bismuth, sandostatin, sulfasalazine, estrogens, prednisone, prednisolone, cortisol, cortisone, fluticasone, dexamethasone, betamethasone, 5-aminosalicylic acid, metronidazole, ciprofloxacin, azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, fish oil, remicade, heparin, and nicotine.  
     
     
         29 . The method according to  claim 1 , wherein the composition comprises extended-release components, or delayed-release components, or both extended-release and delayed-release components.  
     
     
         30 . The method according to  claim 1 , wherein the composition further comprises at least one immediate-release component.  
     
     
         31 . The method according to  claim 1 , wherein the composition produces a peak:trough plasma level ratio of the at least one antagonist of less than about 4:1.  
     
     
         32 . The method according to  claim 31 , wherein the peak:trough plasma level ratio is less than about 3:1.  
     
     
         33 . The method according to  claim 32 , wherein the peak:trough plasma level ratio is less than about 2:1.  
     
     
         34 . The method according to  claim 1 , wherein administration of the composition provides a plasma concentration of the at least one antagonist, at least about 24 hours following a first administration, that is greater than or equal to about 25% of the peak plasma concentration achieved following the administration.  
     
     
         35 . The method according to  claim 34 , wherein the plasma concentration of at least one antagonist, at least about 24 hours following a first administration, is greater than or equal to about 50% of the peak plasma concentration achieved following the administration.  
     
     
         36 . The method according to  claim 1 , wherein administration of the composition provides a plasma concentration of the at least one antagonist that is greater than or equal to about 50% of the peak plasma concentration, for greater than or equal to about 14 hours, following a first administration.  
     
     
         37 . The method according to  claim 36 , wherein the plasma concentration of the at least one antagonist is greater than or equal to about 50% of the peak plasma concentration, for greater than or equal to about 16 hours, following a first administration.  
     
     
         38 . The method according to  claim 37 , wherein the plasma concentration of the at least one antagonist is greater than or equal to about 50% of the peak plasma concentration, for greater than or equal to about 18 hours, following a first administration.  
     
     
         39 . The method according to  claim 38 , wherein said plasma concentration of the at least one antagonist is greater than or equal to about 50% of the peak plasma concentration, for greater than or equal to about 24 hours, following a first administration.  
     
     
         40 . The method according to  claim 1 , wherein the composition, when tested in a U.S. Pharmacopeia (USP) Type 2 Apparatus, at 37° C., stirred at 50 rpm, and in pH 6.8 phosphate buffer, releases less than about 60% of the at least one antagonist in less than about 2 hours, greater than or equal to about 40% in about 12 or more hours, and about 70% or more in about 24 or more hours.  
     
     
         41 . The method according to  claim 40 , wherein less than or equal to about 60% of the at least one antagonist is released in about 2 hours, less than or equal to about 70% is released in about 4 hours, greater than or equal to about 50% is released in about 8 hours, greater than or equal to about 65% is released in about 12 hours, and greater than or equal to about 80% is released in about 24 hours.  
     
     
         42 . The method according to  claim 41 , wherein less than or equal to about 50% of the at least one antagonist is released in about 2 hours, less than or equal to about 65% is released in about 4 hours, greater than or equal to about 60% is released in about 8 hours, greater than or equal to about 70% is released in about 12 hours, and greater than or equal to about 80% is released in about 24 hours.  
     
     
         43 . The method according to  claim 42 , wherein less than or equal to about 40% of the at least one antagonist is released in about 2 hours, about 20% to about 60% is released in about 4 hours, greater than or equal to about 70% is released in about 8 hours, greater than or equal to about 75% is released in about 12 hours, and greater than or equal to about 80% is released in about 24 hours.  
     
     
         44 . A method for modifying and/or managing gut secretion in a subject in need thereof comprising administering to the subject a composition comprising a therapeutically effective amount of at least one α3 β4 nAChR antagonist or pharmaceutically acceptable salt thereof, wherein the at least one α3 β4 nAChR antagonist exhibits an IC 50  value for the α3 β4 sub-type of nAChR ranging from 1.0×10 −6  to 1×10 −9  or exhibits a potency for the α3 β4 nAChR sub-type at least two-times greater in comparison to at least one other nAChR sub-type.  
     
     
         45 . The method according to  claim 44 , wherein the at least one antagonist acts as a competitive or noncompetitive/allosteric inhibitor.  
     
     
         46 . The method according to  claim 44 , wherein the at least one gastrointestinal disorder is an abnormal increase in gastrointestinal secretion.  
     
     
         47 . The method according to  claim 44 , wherein the at least one gastrointestinal condition is chosen from diarrhea-related or linked symptoms, chronic diarrhea, functional diarrhea, cancer-related diarrhea, carcinoid syndrome, diarrhea related symptoms of inflammatory bowel disease and microscopic colitis, chemotherapy and radiotherapy linked diarrhea, AIDS related diarrhea, infectious diarrhea, food intolerance and malabsorption related diarrhea, medicine linked diarrhea, celiac disease, and endocrine diseases, and any diarrhea-related or linked symptom of any of the foregoing conditions.  
     
     
         48 . The method according  claim 47 , wherein the condition is a diarrhea related condition.  
     
     
         49 . The method according to  claim 47 , wherein the condition is chemotherapy-related diarrhea.  
     
     
         50 . The method according to  claim 44 , wherein the at least one antagonist is N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof.  
     
     
         51 . The method according to  claim 44 , wherein the composition is a modified-release formulation.  
     
     
         52 . A method for reducing gastrointestinal motility in a subject suffering from an abnormal increase in gastrointestinal motility comprising administering a composition comprising a therapeutically effective amount of N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine or pharmaceutically acceptable salt thereof, wherein the N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine exhibits an IC 50  value for the α3 β4 sub-type of nAChR ranging from 1.0×10 −6  to 1×10 −9  or exhibits a potency for the α3 β4 nAChR sub-type at least two-times greater when compared to at least one other nAChR sub-type.  
     
     
         53 . The method according to  claim 52 , wherein the N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine acts as a competitive or noncompetitive/allosteric inhibitor.  
     
     
         54 . The method according to  claim 52 , wherein the at least one gastrointestinal disorder is an abnormal increase in gastrointestinal secretion  
     
     
         55 . The method according to  claim 52 , wherein the at least one gastrointestinal condition is chosen from functional bowel disorders, inflammatory bowel disease, ulcerative colitis, granulomatous enteritis, Crohn's disease, infectious diseases of the small and large intestine, pyloric spasm, abdominal cramps, mild dysenteries, diverticulitis, acute enterocolitis, neurogenic bowel disorders, spastic colitis, and diarrhea-related or linked symptom of any of the foregoing conditions.  
     
     
         56 . The method according  claim 55 , wherein the condition is a diarrhea related condition.  
     
     
         57 . The method according to  claim 52 , wherein at least one gastrointestinal condition is chemotherapy-related diarrhea.  
     
     
         58 . The method according to  claim 52 , wherein the composition is a modified-release formulation.  
     
     
         59 . A method of reducing gastrointestinal secretion in a subject suffering from an abnormal increase in gastrointestinal secretion comprising administering to the subject a gastrointestinal secretion reducing amount of N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof, wherein the N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof is administered in the form of a modified-release formulation.  
     
     
         60 . The method according to  claim 59 , wherein the abnormal increase in gastrointestinal secretion is reduced, while minimizing at least one side effect associated with the administration of a conventional formulation of N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof.  
     
     
         61 . The method according to  claim 60 , wherein the at least one effect is chosen from effects on the subject's heart rate, blood pressure, vision, and bladder function.  
     
     
         62 . The method according to  claim 59 , wherein the modified-release formulation is suitable for oral, intra-nasal, or transdermal administration.  
     
     
         63 . The method according to  claim 59 , wherein the modified-release formulation is in combination with an immediate-release formulation.  
     
     
         64 . The method according to  claim 59 , wherein the gastrointestinal secretion reducing amount of N,-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine or a pharmaceutically acceptable salt thereof ranges from about 0.2 mg to about 40 mg.  
     
     
         65 . The method according to  claim 64 , wherein said gastrointestinal secretion reducing amount ranges from about 0.5 mg to about 20 mg.  
     
     
         66 . The method according to  claim 65 , wherein the gastrointestinal secretion reducing amount ranges from about 1 mg to about 15 mg.  
     
     
         67 . The method according to  claim 66 , wherein the gastrointestinal secretion reducing amount ranges from about 2 mg to about 12 mg.  
     
     
         68 . The method according to  claim 59 , wherein the administration of N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof, provides a maximum plasma concentration of N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine at about 3.5 hours, or later, following a first administration.  
     
     
         69 . The method according to  claim 68 , wherein the maximum plasma concentration of N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine is achieved at about 6 hours, or later, following a first administration.  
     
     
         70 . The method according to  claim 59 , wherein said N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof, is administered once-daily.  
     
     
         71 . The method according to  claim 59 , wherein the N-2,32,3-tetramethylbicyclo-[2.1.1]heptan-2-amine comprises racemic N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, enriched (R)—N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, enriched (S)—N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, substantially pure (R)—N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, substantially pure (S)—N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or pharmaceutically acceptable salts thereof.  
     
     
         72 . The method according to  claim 71 , wherein the N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine comprises racemic N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof.  
     
     
         73 . The method according to  claim 71 , wherein the N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine comprises enriched N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof.  
     
     
         74 . The method according to  claim 71 , wherein said N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine comprises substantially pure N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof.  
     
     
         75 . The method according to  claim 59 , wherein the N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof, is administered in combination with at least one other pharmaceutically active compound.  
     
     
         76 . The method according to  claim 75 , wherein the at least one other pharmaceutically active compound is chosen from ganglionic blockers, nicotinic-receptor antagonists, gastrointestinal motility altering agents, antispasmodics, antimuscarinic agents, opiates, 5-HT receptor agonists, 5-HT receptor antagonists, calcium channel blockers, beta adrenergic receptor blockers, agents that alter fluid transport across the gut, agents that alter fluid transport into or out of gastrointestinal cells, diuretics, anti-diarrheals, H 2 -antihistamines, proton pump inhibitors, antacids, anti-inflammatory agents, steroids, mineralocorticoids, corticosteroids and glucocorticosteriods, anti-infective agents, immunomodulators, fish oil, and combinations thereof.  
     
     
         77 . The method according to  claim 28 , wherein said at least one other pharmaceutically active compound is chosen from hexamethonium, trimethaphan, chloroisondamine, erysodine, β-dihydroerythrodine, amantidine, perpidine, succinylcholine, decamethonium, tubocurarine, atracurium, doxacurium, mivicurium, pancuronium, rocuronium, vencuronium, glycopyrrolate, atropine, hyscomine, scopolamine, loperamide, difenoxine, codeine, morphine, oxymorphone, oxycontin, dihydrocodeine, fentanyl, alosetron hydrochloride, verapamil, amiloride, furosemide, bismuth, sandostatin, sulfasalazine, estrogens, prednisone, prednisolone, cortisol, cortisone, fluticasone, dexamethasone, betamethasone, 5-aminosalicylic acid, metronidazole, ciprofloxacin, azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, fish oil, remicade, heparin, nicotine, octreoyide, diphenoxylate, and combinations thereof.  
     
     
         78 . The method according to  claim 59 , wherein the modified-release formulation provides an in vitro release profile when measured by a U.S. Pharmacopoeia (USP) Type 1 Apparatus (baskets) or U.S. Pharmacopeia (USP) Type 2 Apparatus (paddles) at 37° C. and 50 rpm or higher in phosphate buffer at pH 6.8 or higher for the measuring period: 
 2 hours: less than or equal to about 60%;  
 4 hours: less than or equal to about 70%;  
 8 hours: greater than or equal to about 50%;  
 12 hours: greater than or equal to about 65%; and  
 24 hours: greater than or equal to about 80%.  
 
     
     
         79 . A method of reducing gastrointestinal secretion and motility in a subject suffering from an abnormal increase in gastrointestinal secretion and motility comprising administering to the subject a therapeutically effective amount of N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof, wherein the N-2,3,3-tetramethylbicyclo-[2.1.1]heptan-2-amine, or a pharmaceutically acceptable salt thereof is administered in the form of a modified-release formulation.