Compositions comprising nicotinic agonists and methods of using same

Abstract

The disclosure is directed at least in part to compositions and methods comprising nicotinic agonists for treating e.g., nervous system disorders, in particular, to combination therapies that include a nicotinic agonist (for example, nicotine) and a nicotinic acetylcholine receptor desensitization inhibitor (for example, opipramol).

1 . A method for treatment of a central nervous system (CNS) or a peripheral nervous system disorder, comprising co-administering to a patient in need thereof a therapeutically effective amount of a nicotinic agonist and a nicotinic acetylcholine receptor (nAChR) desensitization inhibitor. 
     
     
         2 . The method of  claim 1 , wherein said CNS disorder is a cognitive disorder. 
     
     
         3 . The method of  claim 1  or  2 , wherein said CNS disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), vascular dementia, Lewy body disease, post-traumatic dementia, Pick's disease, multiple sclerosis, Jakob-Creutzfeldt disease, nicotine addiction, alcohol addiction, cannabis addiction, cocaine addiction, neurological conditions associated with acquired immune deficiency syndrome (AIDS), and Huntington's disease. 
     
     
         4 . A method of treating anxiety or depression, comprising co-administering to a patient in need thereof a therapeutically effective amount of a nicotinic agonist and a nicotinic acetylcholine receptor (nAChR) desensitization inhibitor. 
     
     
         5 . A method of treating or suppressing tobacco or nicotine dependence or usage, comprising co-administering to a patient in need thereof a therapeutically effective amount of a nicotinic agonist and a nicotinic acetylcholine receptor (nAChR) desensitization inhibitor. 
     
     
         6 . The method of any one of  claims 1 - 5 , wherein the effect of a subsequent administration of the nicotinic agonist to said patient is substantially more therapeutically effective as compared to a subsequent administration of a nicotinic agonist using a method for treatment consisting of first administering to said patient a nicotinic agonist alone. 
     
     
         7 . The methods of any one of  claims 1 - 6 , wherein the effect of the nicotinic agonist is substantially prolonged following said co-administering in said patient as compared to administering to said patient a nicotinic agonist alone. 
     
     
         8 . The method of any one of  claims 1 - 7 , wherein the effect of nicotinic agonist after co-administration is about twice as effective as compared to administering to the patient the nicotinic agonist alone. 
     
     
         9 . The method of any one of  claims 1 - 8 , wherein the nAChR desensitization inhibitor reduces the desensitization of said nicotinic agonist for at least about 3 hours. 
     
     
         10 . The method of any one of  claims 1 - 9 , wherein the nAChR desensitization inhibitor reduces the desensitization of said nicotinic agonist for at least about 12 hours. 
     
     
         11 . The method of any one of  claims 1 - 10 , wherein the nAChR desensitization inhibitor reduces the desensitization of said nicotinic agonist for at least about 1 day. 
     
     
         12 . The method of any one of  claims 1 - 10 , wherein the nAChR desensitization inhibitor reduces the desensitization of said nicotinic agonist for at least about 3 days. 
     
     
         13 . The method of any one of  claims 1 - 11 , wherein the nicotinic agonist and the nAChR desensitization inhibitor are administered together in the same dosage form. 
     
     
         14 . The method of any one of  claims 1 - 13 , wherein the nicotinic agonist and the nAChR desensitization inhibitor are administered in separate dosage forms. 
     
     
         15 . The method of  claim 14 , wherein the nicotinic agonist and the nAChR desensitization inhibitor are administered in different dosage forms. 
     
     
         16 . The method of  claim 14  or  15 , wherein the nicotinic agonist and the nAChR desensitization inhibitor are administered sequentially. 
     
     
         17 . The method of any one of  claims 14 - 16 , wherein the nicotinic agonist and the nAChR desensitization inhibitor are administered successively separated by about 10 minutes to about 12 hours. 
     
     
         18 . The method of any one of  claims 1 - 17 , wherein said nicotinic agonist and said nAChR desensitization inhibitor, are each administered via a formulation chosen from: oral, parenteral, mucosal, inhalation and transdermal formulations, or a combination thereof. 
     
     
         19 . The method of any one of  claims 1 - 18 , wherein said nicotinic agonist and said nAChR desensitization inhibitor are co-administered in the form of chewing gum, sachets, thin film, transdermal patches, capsules, tablets, lozenges, or nasal sprays. 
     
     
         20 . The method of any one of  claims 1 - 19 , wherein the nicotinic agonist is administered transdermally. 
     
     
         21 . The method of any one of  claims 1 - 18 , wherein the nAChR desensitization inhibitor is administered orally. 
     
     
         22 . The method of any one of  claims 1 - 21 , wherein said nicotinic agonist and said nAChR desensitization inhibitor are each administered in a substantially continuous manner over at least 12 hours. 
     
     
         23 . The method of any one of  claims 1 - 22 , wherein said nicotinic agonist and said nAChR desensitization inhibitor are each administered in a substantially continuous manner over at least 1 day. 
     
     
         24 . The method of any one of  claims 1 - 23 , wherein said nicotinic agonist and said nAChR desensitization inhibitor are each administered in a substantially continuous manner over at least 3 days. 
     
     
         25 . The method of any one of  claims 1 - 24 , wherein said nicotinic agonist and said nAChR desensitization inhibitor are each administered in a substantially continuous manner over at least one week. 
     
     
         26 . The method of any one of  claims 1 - 25 , wherein said nicotinic agonist and said nAChR desensitization inhibitor are administered in one transdermal patch. 
     
     
         27 . The method of any one of  claims 1 - 25 , wherein said nicotinic agonist in a first transdermal patch and said nAChR desensitization inhibitor is administered in a second transdermal patch. 
     
     
         28 . The method of any one of  claims 1 - 27 , further comprising re-administering a therapeutically effective amount of a nicotinic agonist and a nAChR desensitization inhibitor. 
     
     
         29 . The method of  claim 28 , wherein the re-administering occurs within about 1 day of the previous administration. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein the nicotinic agonist is chosen from:
 nicotine, decamethonium bromide, epibatidine, lobeline, varenicline, epiboxidine, epiquinamide, ABT-418, ABT-594, DMXB-A, altinicline and metanicotine, and combinations thereof.   
     
     
         31 . The method of any one of  claims 1 - 30 , wherein the nicotinic agonist is nicotine or a pharmaceutically acceptable salt or N-oxide thereof 
     
     
         32 . The method of any one of  claims 1 - 31 , wherein the nAChR desensitization inhibitor is chosen from: ion channel inhibitors, sigma receptor antagonists, tricyclic or tetracyclic antidepressants, beta blockers, muscarinic agonists, and nicotinic aceltycholine agonists. 
     
     
         33 . The method of any one of  claims 1 - 32 , wherein the nAChR desensitization inhibitor is chosen from: opipramol, galantamine, clomipramine, mirtazapine, maprotiline and lidocaine, and pharmaceutically acceptable salts, esters, and prodrugs thereof. 
     
     
         34 . The method of any one of  claims 1 - 33 , wherein the nicotinic agonist is nicotine and the nAChR densitization inhibitor is opipramol or a pharmaceutically acceptable salt or ester thereof. 
     
     
         35 . The method of  claim 34 , wherein about 5 mg/day to about 21 mg/day of the nicotine is administered. 
     
     
         36 . The method of  claim 34  or  35 , wherein about 50 mg/day to about 250 mg/day of opipramol is administered. 
     
     
         37 . The method of any one of  claims 1 - 36 , wherein the nicotinic agonist is effective for at least about 1 day. 
     
     
         38 . The method of any one of  claims 1 - 37 , wherein the nicotinic agonist is effective for at least about 3 days. 
     
     
         39 . A method of reducing nAchR desensitization caused by administering a nicotinic agonist, comprising co-administering to a patient an nicotinic agonist and nAChR desensitization inhibitor chosen from ion channel inhibitors, tricyclic antidepressants, beta blockers, muscarinic agonists, and nicotinic aceltycholine agonists. 
     
     
         40 . The method of  claim 39 , wherein the nicotinic agonist is nicotine. 
     
     
         41 . The method of  claim 39  or  40 , wherein the nAChR desensitization inhibitor is chosen from: opipramol, galantamine, lidocaine or clomipramine, or pharmaceutically acceptable salts, esters, and prodrugs thereof. 
     
     
         42 . A pharmaceutical composition comprising a nicotinic agonist and a nAChR desensitization inhibitor. 
     
     
         43 . The pharmaceutical composition of  claim 42 , wherein the nicotinic agonist is chosen from: nicotine, decamethonium bromide, epibatidine, lobeline, varenicline, epiboxidine, epiquinamide, ABT-418, ABT-594, DMXB-A, altinicline and metanicotine, and combinations or N-oxides thereof. 
     
     
         44 . The pharmaceutical composition of  claim 42  or  43 , wherein the nicotinic agonist is nicotine. 
     
     
         45 . The pharmaceutical composition of any one of  claims 42 - 44 , wherein the nAChR desensitization inhibitor is chosen from opipramol, galantamine, and lidocaine and pharmaceutically acceptable salts, esters, and prodrugs thereof. 
     
     
         46 . The pharmaceutical composition of any one of  claims 42 - 45 , wherein the nAChR desensitization inhibitor is opipramol, or a pharmaceutically acceptable salt, ester, or prodrug thereof. 
     
     
         47 . The pharmaceutical composition of any one of  claims 42 - 46 , wherein the nicotinic agonist and nAChR desensitization inhibitor is present in a weight ratio of nicotinic agonist:nAChR desensitization inhibitor of about 1:2 to about 1:100. 
     
     
         48 . The pharmaceutical composition of any one of  claims 42 - 47 , wherein the nicotinic agonist and nAChR desensitization inhibitor is present in a weight ratio of nicotinic agonist:nAChR desensitization inhibitor of about 1:5 to about 1:20. 
     
     
         49 . The pharmaceutical composition of any one of  claims 42 - 48 , wherein the nicotinic agonist and nAChR desensitization inhibitor is present in a weight ratio of nicotinic agonist:nAChR desensitization inhibitor of about 1:14. 
     
     
         50 . The pharmaceutical composition of any one of  claims 42 - 49 , further comprising a pharmaceutically acceptable carrier. 
     
     
         51 . The pharmaceutical composition of  claim 50 , wherein the pharmaceutically acceptable carrier is suitable for transdermal or topical administration to a patient. 
     
     
         52 . The pharmaceutical composition of any one of  claims 42 - 51 , comprising: a) nicotine or pharmaceutically acceptable salts or N-oxides thereof, and b) opipramol or pharmaceutically acceptable salts, esters, and prodrugs thereof. 
     
     
         53 . The pharmaceutical composition of any one of  claims 42 - 52 , wherein the amounts of each of nicotinic agonist and the nAchR desensitization inhibitor are such that the combination provides an effective amount of nicotinic agonist for the treatment of a central nervous system disorder upon adminstration after one or more doses are administered to a patient. 
     
     
         54 . The pharmaceutical composition of any one of  claims 42 - 53 , wherein said composition is suitable for any one of: oral, parenteral, transcutaneous, mucosal, transdermal or inhalation administration. 
     
     
         55 . The pharmaceutical composition any one of  claims 42 - 54 , wherein the composition is a chewing gum, thin film, sachet, transdermal patch, capsule, tablet, or nasal spray. 
     
     
         56 . A transdermal patch comprising the pharmaceutical composition of any one of  claims 42 - 55 . 
     
     
         57 . A transdermal patch for administration of a co-therapy to a patient, wherein said patch comprises a) nicotine, b) opipramol or pharmaceutically acceptable salts, esters, and prodrugs thereof, and c) a pharmaceutically acceptable carrier suitable for transdermal or topical administration to a patient. 
     
     
         58 . The transdermal patch of  claim 57 , wherein the patch is formulated to provide substantially continuous delivery of the nicotine and the opipramol to a patient. 
     
     
         59 . A method of treating Parkinson's disease, comprising administering to a patient in need thereof the transdermal patch of  claim 57  or  58 . 
     
     
         60 . A method of treating Alzheimer's disease, comprising administering to a patient in need thereof the transdermal patch of  claim 57  or  58 . 
     
     
         61 . A method of treating schizophrenia, comprising administering to a patient in need thereof the transdermal patch of  claim 57  or  58 . 
     
     
         62 . A controlled release medical device for delivery of a composition comprising a) nicotine, b) opipramol or a pharmaceutically acceptable salt, ester, or a prodrug thereof; which is capable of delivering the composition in a pre-determined delivery rate to a patient. 
     
     
         63 . The controlled release medical device of  claim 61 , wherein the pre-determined delivery rate is substantially continuously over at least 1 day. 
     
     
         64 . The controlled release medical device of  claim 63 , wherein the pre-determined delivery rate is substantially continuously over at least 1 day. 
     
     
         65 . A kit comprising: a first pharmaceutical composition comprising a nicotinic agonist, and a second pharmaceutical composition comprising a nAChR desensitization inhibitor, and instructions for administration of the first and second composition. 
     
     
         66 . The kit of  claim 65 , wherein the first and second composition forms a transdermal patch.