US 20180303818A1 (19 ) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0303818 A1 Heldman (43 ) Pub . Date: Oct. 25 , 2018 (54 ) COMPOSITIONS COMPRISING NICOTINIC Publication Classification AND METHODS OF USING (51 ) Int. Cl. SAME A61K 31/ 465 ( 2006 .01 ) A61K 31 /27 ( 2006 . 01) (71 ) Applicant: NeuroDerm , Ltd ., Rehovot ( IL ) A61K 31/ 167 (2006 . 01) A61K 31/ 4439 ( 2006 .01 ) ( 72 ) Inventor: Eliahu Heldman , Rehovot ( IL ) A61K 31/ 136 ( 2006 .01 ) A61K 9 / 00 ( 2006 .01 ) (21 ) Appl. No. : 15 /827 , 293 A61K 31/ 4406 ( 2006 . 01 ) A61K 31/ 55 (2006 . 01) (52 ) U . S . CI. ( 22 ) Filed : Nov . 30, 2017 CPC ...... A61K 31/ 465 (2013 . 01 ) ; A61K 31/ 27 ( 2013 . 01 ) ; A61K 31/ 167 ( 2013 . 01 ) ; A61K Related U . S . Application Data 31/ 4439 ( 2013 .01 ); A61K 2300 / 00 ( 2013 .01 ); (63 ) Continuation of application No . 15 / 259, 752 , filed on A61K 9 /0014 (2013 .01 ) ; A61K 31/ 4406 Sep . 8 , 2016 , now abandoned , which is a continuation (2013 .01 ) ; A61K 9 / 0053 ( 2013 .01 ) ; A61K of application No . 14 /554 ,660 , filed on Nov. 26 , 2014 , 31/ 55 (2013 . 01 ) ; A61K 31/ 136 ( 2013 .01 ) now abandoned , which is a continuation of applica ( 57 ) ABSTRACT tion No . 13 / 593 ,911 , filed on Aug . 24 , 2012 , now Pat. The disclosure is directed at least in part to compositions and No. 8 , 921 ,356 , which is a continuation of application methods comprising nicotinic agonists for treating e. g . , No. 12 /323 ,779 , filed on Nov . 26 , 2008 , now Pat. No . nervous system disorders , in particular, to combination 8 ,273 , 731 . therapies that include a nicotinic ( for example , (60 ) Provisional application No . 60 / 990 , 161, filed on Nov . ) and a nicotinic receptor desensitiza 26 , 2007 . tion inhibitor (for example , opipramol) . Patent Application Publication Oct. 25 , 2018 Sheet 1 of 11 US 2018 /0303818 A1

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COMPOSITIONS COMPRISING NICOTINIC to which they preferentially bind . For example , the agonists AGONISTS AND METHODS OF USING ACh and ( - ) - nicotine stabilize first the active state and then SAME the desensitized state . [0006 ] The nACHR is involved in the regulation of a RELATED APPLICATIONS variety of brain functions such as thermoregulation , cogni tion , attention etc. Thus, potentially , treatment with nicotine [0001 ] This application is a continuation of U . S . Ser . No. or drugs that directly or indirectly activate the nACHR may 15 /259 , 752 , filed Sep . 8 , 2016 , which is a continuation of provide beneficial effects in alleviating cognitive dysfunc U . S . Ser. No. 14 /554 ,660 , filed Nov . 26 , 2014 , which is a tions such as dementia of Alzheimer' s type, cognitive continuation of U . S . Ser. No. 13 / 593 , 911 , filed Aug . 24 , impairment associated with schizophrenia, attention deficit, 2012 , which is a continuation of U . S . Ser. No . 12 /323 ,779 , e . g . , in attention deficit hyperactivity disorder ( ADHD ) . filed Nov . 26 , 2008 , which claims priority to provisional Nicotine has also been shown to be neuroprotective and a application U . S . Ser. No . 60 / 990 , 161, filed Nov . 26 , 2007 , negative correlation between smoking and the development the entire disclosure of each of which is incorporated by of neurodegenerative disorders such as Parkinson ' s disease reference herein . and Alzheimer ' s disease has also been reported . In addition , nicotine is also used in cessation of smoking . FIELD [0007 ] Over the past several years , a variety of research [0002 ] The present invention relates generally to compo groups have focused on the development of selective nico sitions and methods of treating and / or controlling a disease , tinic agonists . Nicotinic agonists may be useful in the disorder or addiction responsive to the administration of a treatment of a variety of neurological disorders including . At least in part, the invention relates , to Alzheimer' s disease , Parkinson ' s disease , and chronic pain . compositions that include a nicotinic agonist and a nicotinic For example , nicotinic agonists such as , epiboxi acetylcholine receptors (nAChRs ) desensitization inhibitor. dine , ABT -418 , ABT- 594 , and SIB - 1508 ( ) have been shown to exhibit analgesic properties suggesting that BACKGROUND NACHR may be used as targets for novel analgesics . [0003 ] Nicotinic ACh receptors (nAChRs ) comprise a [ 0008 ] The rapid desensitization of the nACHR may make class of pentameric (containing five subunits ) ligand - gated nicotine, and other agents that activate directly or indirectly ion channels present in the central (CNS ) and the peripheral the nicotinic receptors, ineffective as therapeutic drugs . In (PNS ) nervous systems as well as in the striated muscle . The addition , nicotinic agonists may be ineffective due to a NACHR of the nervous system and those found in peripheral process of uncompetitive blockade (open -channel block ). neurons differ in structural ( subunits composition ) and func Furthermore , prolonged activation appears to induce a long tional aspects from nACHR found in striated muscles . lasting receptor inactivation . It would be desirable to find Whereas the striated muscle receptors contain 2 a subunits drugs that would retard desensitization of the receptor, thus ( al ) and one ß (B1 ) , one y and one d (or one ? ) subunits , the prolonging the positive effect of nicotinic agonists or mak neuronal nACAR is composed of only a (at least two ing them more effective during repeated administration . subunits among the a2 to al0 subtypes) and ß ( generally three subunits among the ß2 to 34 subtypes ). The amino acid SUMMARY sequence for the a subunits of the neuronal nACAR ( a2 to [ 0009 ] The present invention relates , in one aspect , to a a10 ) consists of a glycolipid region ( which contains the ACh pharmaceutical composition comprising a nicotinic agonist binding site and four hydrophobic regions that span the and a nACHR desensitization inhibitor , and a pharmaceuti membrane . The neuronal B subunits ( B2 to B4 ) do not have cally acceptable carrier . an adjacent pair of cystines , which are present in the a [0010 ] Any nicotinic agonist can be used in the composi subunit ligand -binding region . tions of the invention , such as, but not limited to , nicotine , [0004 ] In general terms, two molecules of ACh binds to nicotine metabolites , bromide , epibatidine , each of the a - subunits of the receptor and induce a confor , , , epiquinamide; ABT 418 , mational change in all the receptor subunits , resulting in an i. e ., ( S ) - 3 -methyl - 5 - ( 1 -methyl - 2 -pyrrolidinyl ) isoxazole , an opening of Na + / K + channel, causing a local depolarization . isoxazole analog of ( - ) - nicotine that is an a4B2 nACAR The local depolarization may develop to an action potential, agonist; ABT- 594 , an azetidine derivative of epibatidine ; leading to physiological response such as muscle contraction ABT- 894 ; DMXB - A , i . e . , 3 - ( 2 , 4 -dimethoxybenzylidene ) when summed with the action of several receptors in the anabaseine (also known as GTS - 21 ) , an a7 -NACHR selec neuromuscular junction . Nicotinic receptors possess a rela tive agonist; SIB - 1508 (altinicline ); and RJR 2403 (metani tively low affinity for ACh at rest. The affinity for acetyl cotine ), and pharmaceutically acceptable salts and isomers is increased after the binding of the first ACH thereof . Examples of active nicotine metabolites contem molecule ( through an allosteric mechanism , which increases plated by the invention include , nornicotine, nor the likelihood of another molecule of ACh binding to the cotinine, nicotine N -oxide , cotinine N - oxide, 3 -hydroxy other a subunit ) . After prolonged exposure to ACh and at cotinine , 5 -hydroxy - cotinine and pharmaceutically e .g ., high concentrations of this neurotransmitter, the recep acceptable salts thereof. Examples of nicotine salts include tor channel may be closed in spite of an e . g . , increase affinity nicotine citrate and nicotine maleate . In a preferred embodi of ACh to the receptor and the receptor subsequently can ment , the nicotinic agonist is nicotine or a pharmaceutically become desensitized . acceptable salt or N - oxide thereof. [0005 ] An allosteric transition state model of the nACAR [0011 ] Exemplary nACHR desensitization inhibitors that involves at least a resting state , an activated state and a can be used in the compositions of the invention include , but “ desensitized ” closed channel state . Different nACHR are not limited to , ion channel inhibitors , sodium channel ligands can differentially stabilize the conformational state inhibitors , potassium channel inhibitors , calcium channel US 2018 /0303818 A1 Oct. 25 , 2018 inhibitors , beta blockers , sigma receptor antagonists , nor opipramol and a pharmaceutically acceptable carrier which epinephrine (NE ) reuptake inhibitors , selective serotonin is capable of delivering the composition in a pre -determined reuptake inhibitors , muscarinic agonists , adenosine antago delivery rate to a patient, for example wherein the pre nists , kappa - opioid agonists , and / or serotonin determined delivery rate is substantially continuously over receptor antagonists , neurosteroids , sigma 1 receptor ago at least 12 hours, or over at least 1 day , or over at least 3 nists , and acetylcholine esterase inhibitors . days , or over at least 7 days ( one week ) . [0012 ] Examples of ion channel inhibitors include lido [0019 ] The pharmaceutical composition of the invention is caine and mepivacaine ; of sodium channel inhibitors include useful for prevention or reduction of the transition of the phenytoin , carbamazepine, lamotrigine, quinidine, procaina NACHR to a “ desensitized ” closed channel state normally mide , disopyramide , mexiletine , tocainide , flecainide , occurring after prolonged exposure to e . g ., a nicotinic ago propafenone ; of potassium channel inhibitors include nist . The compositions are useful for treatment of nervous nibetan , sotalol, amiodaraone , bretylium ; of calcium channel system disorder, disease or condition such as CNS and PNS inhibitors include verapamil , diltiazem ;, of beta blockers disorder, disease or condition . On one embodiment, the include propranolol , timolol , atenolol, metoprolol; of sigma compositions are useful for treatment of cognitive dysfunc receptor antagonists include opipramol, rimcazole ; of NE tion or cognitive disorders . In some other embodiments, the reuptake inhibitors include dosulepin , lofepramine, nortrip compositions are useful for treatment of CNS disorders tyline , protriptyline ; of selective serotonin reuptake inhibi including , but not limited to , anxiety , depression , Alzheim tors include clomipramine; of muscarinic agonists include er ' s disease , Parkinson ' s disease , schizophrenia , attention McN - A -343 , , cevimeline ( AF - 102B ), AF - 150 , and deficit hyperactivity disorder (ADHD ) , attention deficit dis AF - 267B ; of adenosine antagonists include ; of order ( ADD ) , vascular dementia , Lewy body disease, post kappa - opioid agonists include codeine or pentazocine ; of traumatic dementia , Pick ' s disease, multiple sclerosis , dopamine and / or serotonin receptor antagonists include clo - Jakob - Creutzfeldt disease , drug addition such as nicotine zapine , DHA , or quetipine; of neurosteroids include alphax addiction , addiction , cannabis addiction and olone , minaxolone ; of sigma 1 receptor agonists include addiction , obsessive disorders , compulsive disorders , pentazocine ) . In preferred embodiments , the nACAR desen impulse -control disorders , neurological conditions associ sitization inhibitor may be selected from opipramol, MeN ated with acquired immune deficiency syndrome (AIDS ) , A - 343 , , lidocaine and clomipramine, or a phar analegesia , and Huntington ' s disease . In someother embodi maceutically acceptable salts , ester or prodrug thereof. Other ments , the compositions are useful for treatment of PNS NACHR desensitization inhibitors may include trazodone, disorders including, but not limited to , neuropathies includ norfluoxetine, fluoxetine, or zimelidine . ing mononeuropathies and polyneuropathies such as carpal [ 0013 ]. In some embodiments , the pharmaceutical compo tunnel syndrome, Guillain - Barre syndrome, facial palsy (or sition may include a nicotinic agonist and a nACHR desen Bell ' s palsy ) , neuropathies caused by infectious agents , or sitization inhibitor in a weight ratio of nicotinic agonist: diabetic , amyloid , and / or brachial plexus neuropathies , NACHR desensitization inhibitor of about 1 : 2 to about 1 : 100 , [0020 ] In one preferred embodiment , the composition of or about 1: 5 to about 1 :20 , e .g . about 1 :14 . the invention is useful for treating or suppressing or [ 00141 Contemplated compositions of the invention may nicotine dependence or usage, thus inducing smoking ces further comprise a pharmaceutically acceptable carrier. In an sation . embodiment, the pharmaceutically acceptable carrier is suit (0021 ] Administration of a composition of the invention able for transdermal or topical administration . may provide for an effect of a subsequent administration of [0015 ] In preferred embodiments , the nicotinic agonist is the nicotinic agonist to a patient that is substantially more nicotine, an isomer , pharmaceutically acceptable salt or therapeutically effective as compared to a subsequent N -oxide thereof, and the nACHR desensitization inhibitor is administration of a nicotinic agonist using a method for opipramol, McN - A - 343 , lidocaine, galantamine or clomip treatment consisting of administering a nicotinic agonist ramine , or a pharmaceutically acceptable salt or prodrug alone . Additionally or separately , the disclosed compositions thereof. In a more preferred embodiment, a pharmaceutical may provide for an effect of the nicotinic agonist that is composition is provided that comprises: a ) nicotine or a substantially prolonged following said co - administration of pharmaceutically acceptable salt or N - oxide thereof, and b ) the nACHR desensitization inhibitor as compared to admin opipramol or a pharmaceutically acceptable salt , ester, or istering to a patient a nicotinic agonist alone . For example , prodrug thereof. the effect of nicotinic agonist after co - administration of [0016 ] Contemplated compositions of the invention may NACHR desensitization inhibitor may be about twice as be suitable for any one of: oral, parenteral, transcutaneous, effective as compared to administering to the patient the mucosal , transdermal or inhalation administration , and may nicotinic agonist alone . In some embodiments , the nACAR be in the form of a chewing gum , sachet, thin film , trans desensitization inhibitor may reduce the desensitization of dermal patch , capsule , tablet , or nasal spray. said nicotinic agonist for at least about 3 hours , at least about [0017 ] For example , provided herein is a transdermal 12 hours , or at least about 1 day , at least about 3 days or patch comprising the composition comprising nicotine , more . opipramol and a pharmaceutically acceptable carrier suit 0022 ] The nicotinic agonist and the nACHR desensitiza able for transdermal or topical administration , wherein said tion inhibitor may be administered together in the same carrier may comprise a skin penetration enhancer . Such a dosage form , or in separate dosage forms, e . g . different transdermal patch may be formulated to provide substan dosage forms. In some embodiments , the nicotinic agonist tially continuous delivery of the nicotine and the opipramol and the nACAR desensitization inhibitor may be adminis to a patient. tered sequentially or may be administered successively [0018 ] Also provided herein is a controlled release com separated by about 10 minutes to about 4 hours, or about 10 position for delivery of a composition comprising nicotine, minutes to about 12 hours , or 10 minutes to about 24 hours US 2018 /0303818 A1 Oct. 25 , 2018 or more . Contemplated herein are embodiments wherein the a patient in need thereof a therapeutically effective amount nicotinic agonist and the nACER desensitization inhibitor of a nicotinic agonist and a nACHR desensitization inhibitor. are each administered via a formulation chosen from : oral, parenteral , mucosal, inhalation and transdermal formula BRIEF DESCRIPTION OF THE DRAWINGS tions , or a combination thereof, for example , the nicotinic agonist and the nACER desensitization inhibitor may be [0030 ] FIG . 1 depicts the effect of opipramol on nicotine co - administered in the form of chewing gum , sachets, thin induced calcium uptake in human neuroblastoma cells film , transdermal patches , capsules , tablets , lozenges, or treated with : 1 . growth medium alone (DMEM ) containing nasal sprays. For example , the nicotinic agonist may be 45 Ca2+ (without any addition ) ; 2 . as 1 with 50 uM nicotine ; administered transdermally , and the nACER desensitization 3 . as 1 with 50 uM nicotine + 10 uM opipramol; 4 . as (2 ) but inhibitor may be administered orally or may be administered after incubating the cells for 15 min and treated with 50 uM transdermally . nicotine + 10 uM opipramol; and 5 . as ( 2 ) but after preincu [ 0023 ] In some embodiments , the contemplated composi bating the cells for 15 min and treated with 50 uM nicotine + tions include the nicotinic agonist and the nACER desensi 10 uM opipramol. Radioactivity of intracellular 45 Ca2 + was tization inhibitor each administered in a substantially con measured after washing the cells with DMEM and expressed tinuous manner over at least 12 hours , or over at least 1 day , as disintegrations per minute (DPM ) . or over at least three days , or over at least one week . For [0031 ] FIG . 2 depicts the effect of opipramol on nicotine example , in one embodiment, the nicotinic agonist and the induced smooth muscle contraction using a Guinea pig nACHR desensitization inhibitor may be administered in one ileum preparation experiment , where muscle contraction is transdermal patch . In another embodiment, the nicotinic shown as percent of contraction resulting from the addition agonist is delivered in a first transdermal patch and the of ( 1 ) 25 uM nicotine , (2 ) 25 uM nicotine in the presence of NACHR desensitization inhibitor is administered in a second 10 um opipramol, ( 3 ) as ( 1 ) but after the muscle was transdermal patch . stimulated once with 25 uM nicotine ; and ( 4 ) as ( 1 ) but after [0024 In accordance with the invention , the administra the muscle was stimulated once with 25 uM nicotine in the tion of the nicotinic agonist and the nACHR desensitization presence of 10 uM opipramol. Opi = opipramol, inhibitor may be repeated several times , e . g . within about 1 day , or about 2 days, of the previous administration of a Nic = nicotine . contemplated co - therapy . [ 0032 ] FIGS. 3A - 3B depict the effect of 20 mg/ kg opip 10025 ]. In some embodiments , the daily dosage may ramol on nicotine ( 2 mg /kg ) induced hypothermia in rats . include about 5 mg/ day to about 21 mg/ day of nicotine FIG . 3A : Each point is the Mean + S . E . M . of the change in and / or about 50 mg/ day to about 150 mg/ day, or about 50 mg body temperature compared to the temperature measured at to about 200 mg of opipramol. In this way, the nicotinic time 0 (before the first injection ) for at least five rats . FIG . agonist may be effective for at least about 1 day , or at least 3B shows a bar histogram representing mean + S . E . M . of the about 3 days or more . maximum change in body temperature compared to the [0026 ] The invention further comprises a kit comprising : temperature measured just before the injection . D = day. a ) a pharmaceutical composition comprising a nicotinc Injection (Inj ) of nicotine ( filled circles) , opipramol ( tri agonist , preferably nicotine , an isomer, pharmaceutically angles ) , and nicotine + opipramol ( filled squares ). acceptable salt or N - oxide thereof, b ) a pharmaceutical [0033 ] FIGS . 4A - 4B depict the effect of opipramol (Opi ) composition comprising a nACHR desensitization inhibitor, ( 20 mg/ kg ) or galantamine (Gal ) ( 5 mg/ kg ) on nicotine (Nic ) preferably opipramol, a pharmaceutically acceptable salt, ( 2 mg/ kg ) induced hypothermia . FIG . 4A : Each point is the ester or prodrug thereof, and c ) a leaflet with instructions for Mean : S . E . M . of change in body temperature compared to administration of said compositions for treatment of a CNS the temperature measured at time 0 (before the first injec or PNS disease , disorder or condition and for induction of tion ) for at least five rats . 4B Bar histogram representing smoking cessation . In a preferred embodiment, the kit mean _ S . E . M . of the maximum change in body temperature contains said compositions in the form of transdermal compared to the temperature measured just before the injec patches . For this purpose, also provided by the invention is tion . a transdermal patch comprising opipramol. [0034 ] FIGS . 5A - C depict the effect of opipramol ( 10 [ 0027 ] In another aspect, the present invention provides a mg/ kg ) or galantamine ( 5 mg/ kg ) with nicotine ( 0 . 5 mg/ kg combination of a nicotinic agonist and a nACER desensiti or 2 mg/ kg ) on anxiety in rats as assessed by their perfor zation inhibitor for treatment of a CNS or PNS disease , mance in an elevated plus maze . Bar histograms represent disorder or condition or for induction of smoking cessation . mean of time spent in open arms _ S . E . M . 5A : Results of low [0028 ] In a further aspect, the invention relates to the use dose of nicotine (0 . 5 mg/ kg ) ; 5B : Results of high dose of of a combination of a nicotinic agonist and a nACAR nicotine ( 2 mg/ kg ) ; 5C : Comparison between galantamine desensitization inhibitor for the preparation of a pharmaceu and opipramol with the low and high doses of nicotine . tical composition for treatment of a CNS or PNS disease , [0035 ] FIG . 6 depicts the effect of opipramol ( 10 mg/ kg ) disorder or condition or for induction of smoking cessation . and nicotine ( 0 . 5 mg/ kg ) on the expression of brain derived [ 0029 ] In still another aspect , the invention relates to a neurotrophic factor (BDNF ) mRNA expression in rat cere method of prevention or reduction of the transition of the bral cortex . nACHR to a “ desensitized ” closed channel state normally occurring after prolonged exposure to e . g ., a nicotinic ago [0036 ] FIG . 7 depicts the effect of clomipramine (30 nist. In this aspect , the invention is directed to methods for mg/ kg ) on nicotine - induced (2 mg/ kg ) hypothermia in rats . treatment of nervous system disorder , such as a central 100371 FIGS. 8A - B depicts the effect of lidocaine ( 15 nervous system disorder or a peripheral nervous system mg /kg ) on nicotine ( 2 mg/ kg ) induced hypothermia in rats . disorder as defined above , that includes co -administering to The drugs were injected during two days ( day 1 and day 2 ) . US 2018 /0303818 A1 Oct. 25 , 2018

DETAILED DESCRIPTION [0042 ] The components of the combination may be admin istered to a patient simultaneously or sequentially . It will be Definitions appreciated that the components may be present in the same [0038 ] For convenience, certain terms used in the speci pharmaceutically acceptable carrier and , therefore , are fication , examples, and appended claims are collected in this administered simultaneously . Alternatively , the active ingre section . dients may be present in separate pharmaceutical carriers , [0039 ] The term “ carrier ” refers to a diluent, adjuvant, such as, conventional oral dosage forms, that can be admin excipient, or vehicle with which a contemplated agent or istered either simultaneously or sequentially. therapeutic is administered . The carriers in the pharmaceu [0043 ]. The term " continuously ” as used herein refers to a tical composition may comprise a binder, such as microc drug delivered substantially slowly and substantially unin rystalline cellulose , polyvinylpyrrolidone (polyvidone or terrupted for e . g . 2 , 3 , 8 , 12 , or more hours or even 1 , 2 , 3 , povidone ) , gum tragacanth , gelatin , starch , lactose or lactose 5 , 7 or 10 or more days . In some embodiments , the term monohydrate ; a disintegrating agent, such as alginic acid , continuously refers to delivery of a drug or agent that is maize starch and the like ; a lubricant or surfactant, such as substantially longer as compared to bolus single or multiple magnesium stearate , or sodium lauryl sulphate ; a glidant, doses . For this purpose, the transdermal patches according to such as colloidal silicon dioxide; a sweetening agent, such as the invention are suitable . sucrose or saccharin ; and / or a flavoring agent, such as [0044 ] The terms, “ individual, " " patient, ” or “ subject” are peppermint, methyl salicylate , or orange flavoring . used interchangeably herein and include any mammal, 10040 ] The phrase " combination therapy , ” as used herein , including animals , for example , primates, for example , refers to co -administering a nicotinic agonist , for example , humans, and other animals, for example, dogs , cats , swine, nicotine, and a nicotinic desensitiza cattle, sheep , and horses . The compounds of the invention tion inhibitor, e . g . , opipramol, as part of a specific treatment can be administered to a mammal , such as a human , but can regimen intended to provide the beneficial effect from the also be other mammals , for example , an animal in need of co -action of these therapeutic agents . The beneficial effect of veterinary treatment, for example , domestic animals ( for the combination includes, but is not limited to , pharmacoki example , dogs , cats , and the like ), farm animals ( for netic or pharmacodynamic co - action resulting from the example , cows, sheep , pigs, horses , and the like ) and labo combination of therapeutic agents . Administration of these ratory animals ( for example, rats , mice , guinea pigs , and the therapeutic agents in combination typically is carried out like ) . over a defined time period ( usually weeks, months or years [0045 ] The term “ nicotinic agonist ” refers to agents that at depending upon the combination selected ) . Combination least partially bind and / or activate a nicotinic therapy is intended to embrace administration of multiple receptor, including postganglionic nicotinic receptors , neu therapeutic agents in a sequential manner, that is , wherein roeffector junctions in the peripheral nervous system , and / or each therapeutic agent is administered at a different time, as at nicotinic receptors in the central nervous system . The term well as administration of these therapeutic agents , or at least “ nicotinic agonist " is meant to encompass nicotine and other two of the therapeutic agents , in a substantially simultaneous compounds that substantially or at least partially bind a manner Substantially simultaneous administration can be nicotine receptor and provide a pharmacological effect . The accomplished , for example , by administering to the subject term encompasses the compounds described hereinabove . In a single tablet or capsule having a fixed ratio of each addition , it also encompasses naturally occurring com therapeutic agent or in multiple , single capsules or tablets for pounds ( including , but not limited to , small molecules , each of the therapeutic agents. Sequential or substantially polypeptides, peptides , etc . , particularly naturally -occurring simultaneous administration of each therapeutic agent can plant alkaloids, and the like ), endogenous ligands ( e. g ., be effected by any appropriate route including , but not purified from a natural source , recombinantly produced , or limited to , oral routes , intravenous routes, intramuscular synthetic , and further including derivatives and variants of routes , and direct absorption through mucous membrane such endogenous ligands ) , and synthetically produced com tissues . The therapeutic agents , e . g . nicotinic agonists and pounds ( e . g . , small molecules , peptides, etc . ) . nACER desensitization inhibitor , can be administered by the [0046 ] The term “ indirect nicotinic agonist ” refers to same route or by different routes. For example , a first agents capable of increasing the level of Ach and thus therapeutic agent of the combination selected may be admin activating the nACHR indirectly . Indirect nicotinic agonists istered transdermally while the other therapeutic agents of may include reversible choline esterase inhibitors such as the combination may be administered orally . Alternatively , physostigmine, donepezil , tacrine , rivastigmine, pyridostig for example , both therapeutic agents may be administered mine , neostigmine, and the like , and may include non orally or both may be administered transdermally . reversible choline esterase inhibitors such as echothiphate . [0041 ] Combination therapy can also embrace the admin [ 0047 ] The term “ nicotine” is intended to mean the natu istration of the therapeutic agents as described above in rally occurring alkaloid known as nicotine , having the further combination with other biologically active ingredi chemical name S - 3 - ( 1 -methyl - 2 - pyrrolidinyl )pyridine , ents and non - drug therapies. Where the combination therapy which may be isolated and purified from nature or syntheti further comprises a non - drug treatment, the non - drug treat cally produced in any manner This term is also intended to ment may be conducted at any suitable time as long as a encompass nicotine metabolites and derivatives and like beneficial effect from the co - action of the combination of the compounds, for example cotinine , norcotinine , nornicotine , therapeutic agents and non - drug treatment is achieved . For nicotine N -oxide , cotinine N -oxide , 3 -hydroxycotinine and example , in appropriate cases , the beneficial effect is still 5 -hydroxycotinine as well as pharmaceutically acceptable achieved when the non - drug treatment is temporally salts thereof e . g . commonly occurring salts containing phar removed from the administration of the therapeutic agents , macologically acceptable anions , such as hydrochloride , perhaps by days or even weeks . hydrobromide, hydroiodide, nitrate , sulfate or bisulfate , US 2018 /0303818 A1 Oct. 25 , 2018 phosphate or acid phosphate , acetate , lactate , citrate or acid alleviate or reduce the cognitive disorder symptoms in citrate , tartrate or bitartrate , succinate , maleate , fumarate , dementia associated with the diseases , disorders and condi gluconate , saccharate , benzoate , methanesulfonate , ethane tions as mentioned above . sulfonate , benzenesulfonate , p -toluene sulfonate , camphor [0053 ] The terms“ pharmaceutically acceptable ” or “ phar ate and pamoate salts , as well as N -oxides , esters or prodrugs macologically acceptable ” refer to molecular entities and thereof. . compositions that do not produce an adverse , allergic or 10048 ] The term “ nicotinic acetylcholine receptor desen other untoward reaction when administered to an animal, or sitization inhibitor” or “ nACHR desensitization inhibitor” to a human , as appropriate . The term , " pharmaceutically refers to an agent that at least partially reduces, inhibits, or acceptable carrier " includes any and all solvents , dispersion retards nicotinic acetylcholine receptor desensitization , for media , coatings, antibacterial and antifungal agents , isotonic example at least partially reduces the desensitization caused and absorption delaying agents and the like. The use of such by repeated ( e . g . two or more doses ) administration of media and agents for pharmaceutical active substances is nicotine to a patient. Such nACAR desensitization inhibitors well known in the art. Except insofar as any conventional may attenuate nACHR desensitization from a slight decrease media or agent is incompatible with the active ingredient, its to full inhibition ( i . e . no apparent reduction in nicotinic use in the therapeutic compositions is contemplated . Supple action between the first application of a nicotinic agonist and mentary active ingredients can also be incorporated into the consequent repeated applications of said agonist ) . compositions. [ 0049 ] The term “ therapeutically effective ” refers to the [ 0054 ] Pharmaceutically acceptable salts of the disclosed ability of an active ingredient, alone or in combination with compounds can be synthesized , for example, from the parent another active agent , to elicit the biological or medical compound , which contains a basic or acidic moiety , by response that is being sought by a researcher , veterinarian , conventional chemicalmethods . Generally , such salts can be medical doctor or other clinician . prepared by reacting the free acid or base forms of these [0050 ] The term “ therapeutically effective amount” compounds with a stoichiometric amount of the appropriate includes the amount of an active ingredient, or combination base or acid in water or in an organic solvent, or in a mixture of active ingredients , that will elicit the biological or medical of the two ; generally, non - aqueous media like ether, ethyl response that is being sought by the researcher, veterinarian , acetate , ethanol, isopropanol, or acetonitrile . Lists of suit medical doctor or other clinician . The compounds of the able salts are found in Remington ' s Pharmaceutical Sci invention are administered in amounts effective for treating ences , 20th ed ., Lippincott Williams & Wilkins, Baltimore, a CNS or PNS disorder. Alternatively , a therapeutically Md. , 2000 , p . 704 . effective amount of an active ingredient is the quantity of the [0055 ] The term “ prodrug ” refers to compounds that are compound required to achieve a desired therapeutic and / or transformed in vivo to yield a disclosed compound or a prophylactic effect, such as the amount of the active ingre pharmaceutically acceptable salt , hydrate or solvate of the compound . The transformation may occur by various dient that results in the prevention of or a decrease in the mechanisms, such as through hydrolysis in blood . For symptoms associated with the condition ( for example , to example , if a nACHR desensitization inhibitor, or a phar meet an end -point ) . maceutically acceptable salt , hydrate or solvate of this [0051 ] The terms " cognitive disorder ” or “ cognitive dys compound contains a carboxylic acid functional group , a function ” refer to mental conditions that cause patients to prodrug can comprise an ester formed by the replacement of have difficulty in thinking with symptoms generally marked the hydrogen atom of the acid group with a group such as by impaired attention , perception , reasoning, memory and (C - C , Jalkyl, ( C2- C , Jalkanoyloxymethyl, 1 - ( alkanoyloxy ) judgment. One type of cognitive disorder is dementia , which ethyl having from 4 to 9 carbon atoms, 1 -methyl - 1 - ( al is characterized by gradual impairment ofmultiple cognitive kanoyloxy ) -ethyl having from 5 to 10 carbon atoms, alkoxy abilities including memory , language and judgement. carbonyloxymethyl having from 3 to 6 carbon atoms, Memory deficit and dementia states can be caused by, or 1 - ( alkoxycarbonyl- oxy ) ethyl having from 4 to 7 carbon associated with , neurodegenerative or neurological diseases, atoms, 1 -methyl - 1 - ( alkoxycarbonyloxy ) ethyl having from 5 disorders or conditions such as Alzheimer' s disease , Parkin to 8 carbon atoms, N - ( alkoxycarbonyl ) aminomethyl having son ' s disease , Huntington 's disease , Lewy body disease , from 3 to 9 carbon atoms, 1 - ( N - ( alkoxycarbonyl )amino ) Pick ' s disease , Jakob - Creutzfeld disease , multiple sclerosis , ethyl having from 4 to 10 carbon atoms, 3 -phthalidyl , anxiety , depression , schizophrenia , limbic encephalitis, nor 4 - crotonolactonyl, gamma- butyrolacton - 4 - yl, di- N , N - (C1 mal pressure hydrocephalus, age -related memory impair C ) alkylamino ( C2 - C Jalkyl (such as B -dimethylamino ment; brain damage caused by stroke , brain injuries and ethyl) , carbamoyl- (C , -C2 ) alkyl, N , N -di ( C , -C2 ) alkylcar vascular dementia ; infectious diseases such as neurosyphilis , bamoyl- ( C1 - C2 ) alkyl and piperidino - , pyrrolidino - or acquired immune deficiency syndrome (AIDS ) , fungal morpholino (C2 -C3 ) alkyl . infections , tuberculosis ; drug intoxication such as alcohol, [0056 ] Similarly , if a nicotinic agonist or nACHR desen nicotine , cannabis , and cocaine addiction or heavy metal sitization inhibitor contains an alcohol functional group , a exposure . Attention deficit disorder ( ADD ) and attention prodrug can be formed by the replacement of the hydrogen deficit hyperactivity disorder ( ADHD ) are types of cognitive atom of the alcohol group with a group such as (C1 -C .) dysfunction found both in children and adults . alkanoyl - oxymethyl, 1 - ( C , - C ) alkanoyloxy ) ethyl, [0052 ] . The term “ treating ” is used herein to denote treat 1 -methyl - 1 -( C , -C .) alkanoyloxy ) ethyl (C ,- C .) alkoxycarbo ing the disease , disorder or condition , or ameliorating , nyloxymethyl, N - (C ,- C )alkoxycarbonylaminomethyl , alleviating , reducing, or suppressing symptoms of the dis succinoyl, (C1 - C )alkanoyl , a -amino (C1 - C4) alkanoyl, ary ease , or slowing or stopping the progress of the disease . lacyl and c - aminoacyl, or a -amino -acyl - a - aminoacyl, Thus, in some embodiments , administration of the compo where each a - aminoacyl group is independently selected sition or combination of the invention may ameliorate , from the naturally occurring L - amino acids, P ( O ) (OH ) 2 , US 2018 /0303818 A1 Oct. 25 , 2018

— P ( O ) ( O ( CZ -C6 )alkyl ) 2 or glycosyl ( the radical resulting istering the nicotinic inhibitor, ( iv ) successively , separated from the removal of a hydroxyl group of the hemiacetal form by for example about 10 minutes to about 4 hours , about 1 - 4 of a carbohydrate ) . hours , about 1 - 8 hours , about 1 hour to about 12 or 24 or [0057 ] If a nACAR desensitization inhibitor or nicotinic more hours, or more or ( v ) individually followed by the agonist incorporates an amino functional group , a prodrug combination . The methods disclosed herein may occur can be formed by the replacement of a hydrogen atom in the before, during , or after other dosing regimens that may amino group with a group such as R - carbonyl, RO - carbonyl, include , for example nicotinic agonists , a nACAR desensi NRR '- carbonyl where R and R ' are each independently tization inhibitor, and other agents e . g . , for treating CNS or ( C , -C10 )alkyl , (C3 - C ,) cycloalkyl, benzyl , or R - carbonyl is a PNS diseases, disorders or conditions. In an embodiment, a natural a -aminoacyl or natural a -aminoacyl - natural disclosed methods may comprise a combination therapy , a - aminoacyl, - C (OH ) C ( O )OY , wherein Y , is H , ( C . - C . ) which can be achieved by co -administering to a patient an alkyl or benzyl, - C (OY ) Y wherein Y , is ( C1- C4 ) alkyl indirect nicotinic agonist and a nACER desensitization and Yz is ( C - C . )alkyl , carboxy ( C , - C . )alkyl , amino ( CZ -C4 ) inhibitor . alkyl or mono - N - or di- N , N - ( C , -C . )alkylaminoalkyl , [0063 ] For example, a nACER desensitization inhibitor, in - C (Y4 ) Y , wherein Y4 is H or methyl and Y , is mono -N - or some embodiments , may be administered prior to , concomi di- N , N - ( C . - C . ) alkylamino , morpholino , piperidin - 1 - yl or tantly with , or shortly after , administration of the nicotinic pyrrolidin - 1 - yl. agonist. In an embodiment, a nACHR desensitization inhibi [ 0058 ] The term “ transdermal delivery ” refers to drug tor may be administered concomitantly with the nicotinic delivery across the skin , usually accomplished without agonist , for example in the same composition . For example , breaking the skin . in an embodiment, the naChR desensitization inhibitor may be administered orally , and the nicotinic agonist is admin Methods istered transdermally . For example , administration of nico [0059 ] Provided herein are methods of treating CNS and tine may be less suitable for oral delivery because it may, for PNS diseases, disorders or conditions using disclosed com example , cause unacceptable adverse events , and / or may be positions or formulations . In some embodiments , a disclosed absorbed from the gut into the portal blood and degrade method provides for an effect of a subsequent administration promptly by the liver. In certain embodiments , however, the of a nicotinic agonist , after, e . g . a first administration of NACER desensitization inhibitor can be administered with nicotinic agonist and nACHR desensitization inhibitor, to nicotinic agonist in dosage forms that deliver nicotinic said patient is substantially more therapeutically effective as agonist to the systemic circulation via absorption through compared to , e . g . a subsequent administration of a nicotinic mucosal membranes or the skin , including dosage forms agonist, or a nicotinic agonist and a nACAR desensitization such as chewing gum , thin films ( e . g . orally dissolving thin inhibitor using a method for treatment consisting of first films) , sachets , transdermal patches, capsules, tablets , loz administrating to said patient a nicotinic agonist alone . For enges, nasal sprays and oral inhalation devices. example , in some embodiments , the nACHR desensitization [ 0064 ] Alternatively , the nicotinic agonist and the nACHR inhibitor of the disclosed combination may reduce desensi desensitization inhibitor may be administered topically or tization of an administered nicotinic agonist for at least transdermally ( e . g . via a transdermal patch ) to a patient. For about 3 hours , at least about 6 hours, at least about 12 hours, example , the nACHR desensitization inhibitor and / or the or at least about one , two, three days , or about 1 week or nicotinic agonist may be administered to a patient substan more . tially continuously, e . g . by transdermal patch and / or by a [ 0060 ] Also provided herein are methods of treating CNS sustained release composition . For example , the nicotinic and PNS diseases such as those above , that may provide for agonist and the nACHR desensitization inhibitor may be an effect of a subsequent administration of an indirect administered via one transdermal patch (e . g. , substantially nicotinic agonist , after e . g . a first administration of indirect continuously ) , or the nicotinic agonist may be administered nicotinic agonist and nACHR desensitization inhibitor. in a first transdermal patch and the nACHR desensitization [ 0061] In another embodiment, a method provides for inhibitor may be administered in a second transdermal substantially prolonged nicotinic agonist effect following patch , which is different than the first ( e . g . , both may be said co - administering in said patient , for example , as com administered substantially continuously via two patches, or pared to the nicotinic effect obtained by administering to a the first patch may have a different delivery rate than the patient a nicotinic agonist alone . For example , the disclosed second patch , and / or the first patch may have a different methods may provide a nicotinic agonist effect, after co surface area as compared to the second patch ) . In an administration , that is about, e. g . 1 . 5 times , twice or even embodiment, a first patch may be placed at one location on three times as effective or 1 . 5 times , twice , or even three a patient and the second patch may be placed at another times prolonged as compared to administering the nicotinic location which may be substantially near the first patch or agonist alone . may be at a substantially different location . [0062 ] Disclosed methods comprise , for example , a com [ 0065 ] In another embodiment , the nicotinic agonist and bination therapy , which can be achieved by co -administering NACHR desensitization inhibitor may be administered to a to a patient a nicotinic agonist and a nACER desensitization patient in a substantially continuous manner , e . g . , provide inhibitor. The nicotinic agonist and a nACAR desensitization substantially steady amounts over 1 day , 3 days, 1 week , 10 inhibitor can be administered as a ( i ) single dosage form or days , or more . In another embodiment, disclosed methods composition , ( ii ) simultaneously as separate dosage forms or may further comprise re -administering to the patient a pharmaceutical compositions, ( iii ) sequentially , as separate therapeutically effective amount of a nicotinic agonist and dosage forms starting with the nicotinic agonist and then an ACHR desensitization inhibitor, for example, within administering nACHR desensitization inhibitor, or starting about 12 hours, 1 day, 2 days or more , of the previous with the nACHR desensitization inhibitor and then admin administration . US 2018 /0303818 A1 Oct. 25 , 2018

[0066 ] In some embodiments , the nicotinic agonist is neuroprotective agent , wherein the neuroprotective effect administered in escalating doses . Such escalating doses may may be enhanced by e . g . co - administration of a nACAR comprise a first dose level and a second dose level . In other desensitization inhibitor . embodiments , escalating doses may comprise at least a first [0072 ] In a particular embodiment, methods are disclosed dosage level , a second dosage level, and a third dosage level, that provide treating or suppressing tobacco or nicotine and optionally a fourth , fifth , or sixth dosage level. The dependence or usage , said method comprising administering nicotinic acetylcholine receptor desensitization inhibitor to a human a disclosed composition or dosage form or may be provided in one dosage level when in administered combination therapy . Also provided are methods of treating in combination with a nicotinic agonist , or may be admin drug addiction , dependence or tolerance to such istered in escalating doses. as nicotine , cannabis or cocaine , comprising administering to a patient a composition or dosage form or combination [0067 ] A first, second, third or more dosage levels can be therapy . administered to a patient for about 2 days to about 6 months [0073 ] Also provided herein are methods for increasing or more in duration . For example , first , second and /or third blood flow to ischemic tissue in patient, comprising admin dose levels are each administered to a subject for about 1 istering a disclosed composition or dosage form or combi week to about 26 weeks, or about 1 week to about 12 weeks , nation therapy effective to stimulate angiogenesis and or about 1 week to about four weeks. Alternatively , the first, increase blood flow to the ischemic tissue . Contemplated second and / or third dosage levels are administered to a herein , in an embodiment, are methods for providing neu subject for about 2 days to about 40 days or to about 6 ronal protection , e . g . from oxidative stress , or such methods months. may provide for e . g . delayed death of e . g . hippocampal [0068 ] The nicotinic agonist may be administered in a neurons that may be e . g . ischemia induced . For example , in therapeutically effective amount. In some embodiments the an embodiment, a method for treating and /or ameliorating contemplated therapeutically effective dosages of a nicotinic stroke in a patient who is at risk of, or who has had a stroke agonist , while not effective when used in monotherapy, may or other vascular disease , is provided herein . Also provided be effective when used in the combinations disclosed herein . herein are methods for treating and/ or ameliorating diseases related to neuronal death ( for example motor neuron death ) , [ 0069 ] Exemplary methods contemplated herein and com e .g . amyotrophic lateral sclerosis . prising administering to a patient a disclosed composition or [0074 ] Also provided herein are methods for treating dosage form or combination therapy include methods of peripheral nervous disorders such as carpal tunnel syn treating Alzheimer ' s disease , Parkinson ' s disease , schizo drome, Guillain -Barre syndrome, or diabetic , amyloid , and / phrenia , attention deficit hyperactivity disorder (ADHD ) , or brachial plexus neuropathies, comprising administering attention deficit disorder ( ADD ) , vascular dementia , Lewy disclosed compounds , co - therapies, and / or dosage forms. body disease, post- traumatic dementia , Pick 's disease , mul [0075 ] For example , a method for increasing the efficacy tiple sclerosis , Jakob -Creutzfeldt disease , nicotine addiction , of a nicotinic agonist by inhibiting or reducing the desen alcohol addiction , cannabis addiction , cocaine addiction , sitization of nAChRs in an individual being treated with said obsessive disorders , compulsive disorders , impulse - control nicotinic agonist is provided , which comprises co - adminis disorders, neurological conditions associated with acquired tering to the individual a therapeutically effective amount of immune deficiency syndrome (AIDS ) , aging and / or Hun a compound capable of reducing the nACER desensitization , tington ' s disease . In another embodiment, a method for managing and / or treating pain in a patient is provided . In thus increasing the efficacy of the nicotinic agonist . some embodiments , a method of treating a cognitive disor [0076 ] Disclosed methods of e. g ., treating a CNS or PNS der or dysfunction is contemplated , comprising administer disease , disorder or condition may , in some embodiments , ing to a patient a disclosed composition or dosage form , for further include administering a desensitization inhibitor of a example , a method of treating dementia , Alzheimer 's dis receptor other than nACHR . In some embodiments , for ease , Parkinson ' s disease , schizophrenia , or nicotine or other example, such an inhibitor may be the same or different than addiction . In an embodiment, a method is also provided for the nACHR desensitization inhibitor contemplated herein . treating and/ or ameliorating mild cognitive impairment e . g . [0077 ] In an exemplary embodiment, the nACHR desen sitization inhibitor is a tricyclic antidepressant such as a patient in early stages of Alzheimer ' s disease . opipramol or imipramine, or a tetracyclic antidepressant [0070 ] The present invention , in some embodiments , pro such as galantamine (a tetracyclic alkaloid ) , an inhibitor of vides a method for smoking cessation , comprising admin acetylcholine esterase , mirtazapine, or maprotiline . In istering to a smoking individual a disclosed composition , another embodiment , the nACER desensitization inhibitor is e . g . a composition comprising nicotine and a compound McN - A - 343 , a drug that may selectively activate certain capable of reducing the nACER desensitization caused by subclasses of muscarinic receptors . the nicotine . In other embodiments , provided herein are methods for treating anxiety , depression , restless legs syn Compositions and Formulations drome, Tourette' s syndrome, chronic tic disorder, or essen [0078 ] Compositions provided herein may include at least tial tremor, comprising administering to a patient a disclosed one nicotinic agonist, at least one nACHR desensitization composition or dosage form or combination therapy . A inhibitor, and a pharmaceutically acceptable carrier. In an method is also provided for treating behavioral e . g . com exemplary embodiment, a pharmaceutical composition pulsive disorders , such as obsessive- compulsive disorder comprises nicotine and opipramol , or its pharmaceutically and / or generalized anxiety disorders . acceptable salts , esters and / or prodrugs thereof. In other [0071 ] Also disclosed is a method for slowing or amelio embodiments , the pharmaceutical composition may com rating the progression of Parkinson ' s disease , for example , prise nicotine and galantamine , clomipramine, lidocaine or upon administration , the nicotinic agonist may act as a MeN - A - 343 . US 2018 /0303818 A1 Oct. 25 , 2018

[0079 ] In some embodiments , the disclosed compositions cellulose , dextran and the like, supramolecular biovectors , may include a nicotinic agonist ( e . g . nicotine ) and a nACAR which comprise a non - liquid hydrophilic core (e . g. , a cross desensitization inhibitor ( e . g . opipramol) in a weight ratio of linked polysaccharide or oligosaccharide ) and , optionally, nicotinic agonist: nACHR desensitization inhibitor of about an external layer comprising an amphiphilic compound , 1 : 100 to about 100 : 1 , e . g . , about 1 : 1 to about 1 : 50 , about 1 : 1 such as a phospholipid ( see e . g . , U . S . Pat. No . 5 , 151, 254 , to about 1 : 5 , 1 : 5 to about 1 :50 , about 1 : 5 to about 1 : 20 , or WO 94 /20078 , WO / 94 /23701 and WO 96 /06638 ), biode about 1 : 10 to about 1 : 15 , e . g . about 1 : 14 , or about 1 : 13 . gradable microspheres (e .g ., polylactate polyglycolate ) (see [ 0080 ] The pharmaceutical compositions may be in any e . g . U . S . Pat. Nos . 4 ,897 , 268; 5 , 075 , 109 ; 5 , 928 ,647 ; 5 , 811 , suitable form including forms for oral , parenteral , transcu 128 ; 5 ,820 ,883 ; 5 ,853 , 763 ; 5 ,814 , 344, 5 , 407, 609 and 5 , 942 , taneous, mucosal, or inhalation administration . In some 252 . ) and calcium phosphate core particles . embodiments , the compositions may be administered in the [0085 ] Contemplated dosages of a nicotinic agonist for use form of chewing gum , sachets, transdermal patches , cap in the disclosed methods and compositions should be large sules , tablets , lozenges, or nasal sprays . enough to produce the desired effect, whereby , for example , [0081 ] For topical administration , the disclosed composi desensitization of the nACHR is substantially prevented and tions may be administered in the form of a gel, a cream , a the action of the nicotinic agonist is prolonged , and further , paste , a lotion , a spray, a suspension , a powder, a dispersion , where the symptoms of the disease , disorder or condition are a salve and an ointment. substantially reduced or ameliorated . The doses should not [0082 ] In some embodiments , the composition for trans be so large as to cause adverse side effects . In some dermal delivery is a transdermal ointment, cream , gel, lotion embodiments , a therapeutically effective amount of nicotinic or other transdermal solution or suspension . Preferably , for agonist may range from 1 to 100 mg per patient. For transdermal delivery, a transdermal patch can be used that example , nicotine may be administered at about 5 mg/ day to may be a single layer drug in adhesive patch , a multi - layer about 21 mg/ day, or about 10 mg/ day to about 21 mg /day , or drug in adhesive patch , a reservoir patch , a matrix patch , a about 15 mg/ day , 20 mg/ day, or about 7 mg/ day. In other microneedle patch or an iontophoretic patch , which typically embodiments , a nictonic agonist , e . g ., nicotine is adminis requires applying a direct current. For example , a transder tered from about 0 . 05 mg/ kg / day to about 5 mg/ kg / day . In mal delivery system (patch ) may be used , such as a trans situations where a nicotinic agonist is administered continu dermal nicotine delivery device described in U . S . Pat. No . ously , the dosage may, in some embodiments , be kept in the 4 , 839 , 174 . The compositions for transdermal delivery lower ranges to avoid undesired side -effects . including the patches may include a skin penetration [0086 ] Opipramol may be, for example , administerrd at enhancer as known in the art . In still further embodiments, dosage of about 50 mg or about 100 mg/ day , e . g . about 10 the transdermal patch is adapted for sustained release . mg/ day to about 300 mg/ day , about 50 mg/ day to about 200 [0083 ] In certain embodiments , the disclosed composi mg /day , about 50 mg/ day to about 150 mg/ day or about 50 tions may be administered orally . For oral administration , mg/ day to about 250 mg/ day . For example , 200 mg /day , or the active ingredients may take the form of solid dose forms, 125 mg/ day , 150 mg/ day or 250 mg/ day of opipramol may for example , tablets (both swallowable and chewable be administered . In another embodiment, opipramol may be forms ) , capsules or gel caps , prepared by conventional administered from about 0 . 2 mg/ kg / day to about 20 mg/ kg means with pharmaceutically acceptable excipients and car day . riers such as binding agents ( e . g . pregelatinised maize [008 ] In some embodiments, lidocaine may be adminis starch , polyvinylpyrrolidone, hydroxypropylmethylcellu tered from about 0 . 1 mg/ kg /day to about 10 mg/ kg /day . For lose and the like ), fillers ( e . g . lactose , microcrystalline example , a total dose for percutaneous administration may cellulose , calcium phosphate and the like ) , lubricants ( e . g . be about 5 to about 300 mg. magnesium stearate , talc , silica and the like ) , disintegrating [0088 ] The present invention also relates to the use of a agents ( e . g . potato starch , sodium starch glycollate and the compound capable of reducing nACER desensitization like ) , wetting agents ( e . g . sodium laurylsulphate ) and the caused by a nicotinic agonist , for the preparation of a like . Such tablets may also be coated by methods well medicament comprising also a nicotinic agonist or for known in the art . Alternativley , a pharmaceutical preparation administration with a medicament comprising a nicotinic may be in liquid form , for example , solutions, syrups or agonist , for treatment of a disease , disorder or condition suspensions, or may be presented as a drug product for responsive to the administration of a nicotinic agonist. reconstitution with water or other suitable vehicle before [0089 ] The present invention also provides for a package use . Such liquid preparations may be prepared by conven - or kit for treatment of a disease , disorder or condition tional means with pharmaceutically acceptable additives responsive to the administration of a nicotinic agonist, e . g ., such as suspending agents (e .g . , sorbitol syrup , cellulose a CNS or PNS disease, disorder or condition , said kit derivatives or hydrogenated edible fats ); emulsifying agents comprising a pharmaceutical composition comprising a ( e . g ., or acacia ) ; non -aqueous vehicles ( e . g . , almond nicotinic agonist, a pharmaceutical composition comprising oil, oily esters, or fractionated vegetable oils ); and preser a nACHR desensitization inhibitor, and a leaflet with instruc vatives ( e . g . , methyl or propyl p -hydroxybenzoates or sorbic tions for administration of said compositions for treatment acid ) . of a disease , disorder or condition responsive to the admin [0084 ] The disclosed compositions may be administered istration of a nicotinic agonist. as single or multiple doses in any suitable form as described [0090 ] The pharmaceutical compositions of the kit may be above or they may be administered substantially continu comprised each in one container and the kit will comprise ously through a drug delivery device or a sustained release two containers , a first container containing a nicotinic ago composition . For example , a sustained release composition nist and a pharmaceutically acceptable carrier and the sec may include such excipients as poly ( lactide - co - glycolide ) ond container containing a nACER desensitization inhibitor e . g. , microparticles of PLGA ; polyacrylate , latex , starch , and a pharmaceutically acceptable carrier, and the leaflet . US 2018 /0303818 A1 Oct. 25 , 2018

The two pharmaceutical compositions may be in similar a silent environment under dim light. The animals were formulation form , for example , each is in the form of a carried to the laboratory and left there undisturbed for 1 h transdermal patch , or in different formulation forms, for before the experiment. Each rat was individually placed on example , one is presented as a transdermal patch and the the central platform 5x5 facing toward an open -arm and was other is presented as oral form . For example , nicotine may observed for 5 min by two observers sitting in the same be comprised within a transdermal patch and opipramol as room , recording the time that the animals spent in the open tablets . In another embodiment, the kit includes a first arm . dosage form , e . g . a transdermal patch , that includes a [0098 ] ( vi) Statistical analysis — The results are expressed nicotinic agonist ( e . g ., nicotine ) , and a second dosage form , as means : S . E . M of the data obtained from all the animals in e . g . a transdermal patch that includes a nACHR desensiti each treatment group . The results were analyzed using zation inhibitor ( e . g . , opipramol) , and instructions for use ANOVA ( a = 0 . 05 ) or Student t -test when appropriate . [0091 ] Also provided is controlled release medical device for delivery of a composition comprising a ) nicotine, b ) Example 1 opipramol or pharmaceutically acceptable salts , esters , and prodrugs thereof; which is capable of delivering the com Effect of Opipramol and MCN - A - 343 on position in a pre - determined delivery rate to a patient. In one Nicotine- Induced Calcium Influx in Cultured Cells embodiment, the pre - determined delivery rate is substan [ 0099 ] SK - N -SH human neuroblastoma cells , known to tially continuously over at least 1 day . express nACHR , were grown in Dulbecco /Vogt Modified [ 0092 ] The examples that follow are intended in no way to Eagle ' s Minimal Essential Medium (DMEM ) to confluency limit the scope of this invention but are provided to illustrate in a 24 -well plate . DMEM containing 45Ca2 + without any the methods of the present invention . Many other embodi other addition ( 1 ) or with 50 uM nicotine ( 2 ) or with 50 uM ments of this invention will be apparent to one skilled in the nicotine + 10 UM opipramol (3 ) was added to cells grown in art . 24 - well plates and preincubated with medium alone for 15 minutes, then washed rapidly . Intra cellular radioactivity EXAMPLES was determined for each condition . The same medium with nicotine was added also to cells that were preincubated for Materials and Methods 15 minutes with either 50 uM nicotine alone ( 4 ) or with 50 [0093 ] (i ) Cells — SK -N - SH human neuroblastoma cell uM nicotine + 10 um opipramol ( 5 ) . 45Ca2 + uptake was line was obtained from the American Type Culture Collec determined after 10 min . Activation of the nicotinic recep tion (ATTC ) . tors causes calcium influx so it is a measure of the nicotinic [ 0094 ] ( ii ) Animals — Young adult ( 240 g -290 g ) male receptor activity . Sprague - Dawley rats ( Charles River, USA or Harlan , Israel) 0100 The results with opipramol are shown in FIG . 1 . were used in the experiments . The first exposure to nicotine caused an increase in calcium [ 0095 ] ( iii) Drugs — Nicotine (Sigma ) ; opipramol (Rafa influx ( 2 ) compared to basal uptake in the absence of Laboratories Ltd . Jerusalem , Israel) , McN - A - 343 ( 4 - ( N - [ 3 nicotine ( 1 ) . Simulation of the cells for the first time with chlorophenyl] - carbamoyloxy } - 2 -butynyl - trimethylammo nicotine in the presence of opipramol, also caused a signifi nium chloride — from R . B . I, USA ), galantamine (Sigma , cant rise in calcium uptake ( 3 ) which was only slightly Israel) , lidocaine (Sigma ) and clomipramine (Sigma ) were smaller compared to that obtained with first stimulation with dissolved in 0 . 9 % saline solution before use. nicotine alone . However, when the cells were exposed to [0096 ] ( iv ) Determination of nicotine- induced hypother nicotine for the second time ( 4 ) , calcium influx was con mia — Rats were placed individually in experimental cages siderably reduced due to nACHR receptor desensitization . kept at 25° C . and were allowed to rest for 1 h before drug By comparison , when the cells were stimulated with nico injection . During this period , body temperature was mea tine and opipramol during the first stimulation only a slight sured at 15 - or 30 -min intervals in order to exclude the effect decrease in 45Ca2 + uptake was observed and in the second of handling on animal temperature . Body temperature was stimulation nACAR desensitization was remarkedly reduced measured with a rectal thermistor probe ( M . R . C , Israel, ( 5 ), indicating that opipramol reduces receptor desensitiza sensitivity 0 . 1° C . ) . The probe was lubricated with petro tion . DPM , disintegrations per minute . Similar results were leum before being inserted into the rectum to a depth of 2 obtained when 10 uM Mc- N - A -343 was used instead of cm . The data are presented as changes in rectal temperature opipramol ( not shown ). from the basal values . Basal values are those taken imme diately before the drug injection (time 0 ) . Example 2 100971. ( v ) Elevated Platform Maze ( EPM ) - The purpose of the EPM is to determine the anxiolytic effects of tested Effect of Opipramol on Nicotine - Induced Smooth drugs . The time that the experimental animals spend in the Muscle Contraction and on Nicotine Induced open arm of the maze is an indication for the anxiolytic Desensitization in the Guinea Pig Ileum Preparation effect , the longer the time the higher the anxiolytic effect. 10101 ] The free end of a smooth muscle of a guinea pig The EPM is a wooden , cross - shaped device , consisting of ileum was attached to a force displacement transducer . four arms arranged in the shape of a plus sign . Two of the Isometric tension of the smooth muscle was continuously arms have no side or end walls ( open - arms; 30x5x0 . 25 cm ) . monitored by outputting the preamplified transducer signal The other two arms have side walls and end walls , but are to a computer. Addition of 25 uM nicotine caused muscle open on top ( closed arms; 30x5x15 cm ). The maze is contraction . The peak obtained with this concentration of elevated to a height of 50 cm . The animals are kept in a nicotine was quantified by the displacement transducer and relatively dark box before exposure to the maze in order to was normalized and defined as 100 % contraction as shown increase their exploratory behavior . The tests were done in US 2018 /0303818 A1 Oct. 25 , 2018

[0102 ] Opipramol reduced the effect of nicotine to about injected with and without nicotine. Body temperature was 50 % of that induced by nicotine alone ( 1st stimulation ; bar recorded at 30 min intervals . FIG . 4 depicts the results . FIG . 2 ) . The ileum preparation was washed by physiological 4A : Each point is the Mean _ S . E . M . of change in body solution 10 min after the addition of nicotine and then temperature compared to the temperature measured at time nicotine at a final concentration of 25 uM was added again 0 (before the first injection ) for at least five rats . 4B Bar to the muscle preparation for additional 10 min (2nd stimu histogram representing mean : S . E . M . of the maximum lation ; bar 3 ) . As can be seen , nicotine did not induce muscle change in body temperature compared to the temperature contraction during the second stimulation (2nd stimulation ; measured just before the injection . bar 4 ) due to receptor desensitization . However, if the first stimulation was done in the presence of opipramol (as Example 5 described by bar 2 in the 1st stimulation ) , nicotine induced almost full response during the second stimulation (bar 4 ) , Effect of Repeated Nicotine Administration on indicating that opipramol prevented or reduced the nACAR Anxiety in Rats desensitization . [0106 ] This test is used to assess anxiety . Rats were [0103 ] When nicotine was administered together with randomly assigned into five groups each containing 5 ani opipramol the effect of nicotine was maintained steady for mals and then tested in an Elevated Plus Maze ( EPM ) . In the one hour until the removal of the drugs by washing ( data not first ( control) group , rats were injected with saline once a shown ) indicating that opipramol effectively prevents day ; in the second group rats were injected with nicotine ( 0 . 5 NACHR desensitization . mg /kg or 2 mg /kg ) three times a day and were tested in the Example 3 maze after the third injection ; in the third group rats were injected with opipramol ( 10 mg/ kg ) three times a day and Effect of Opipramol on Nicotine- Induced then were tested in the maze ; in the fourth group , rats were Hypothermia in Rats injected with opipramol ( 10 mg/ kg ) or galantamine (5 [0104 ] Rats were divided into three treatment groups, each mg/ kg ) , and nicotine ( 2 mg/kg or 0 . 5 mg/ kg ) three times a of 5 rats , as follows: 1 . treatment with nicotine ( 2 mg/ kg ) ; 2 . day and were tested in the maze after the last injection . The treatment with opipramol (20 mg/ kg ) ; 3 . treatment with behavioral response to nicotine in the EPM was assessed 30 opipramol ( 20 mg/ kg ) together with nicotine ( 2 mg/ kg ) . Rats min after the first injection , and then again 30 minutes after were injected with nicotine twice on the first day ( FIG . 3A , the third injection . As can be seen from FIG . 5 , one injection D - 1 , left panel) and three times on days 2 (FIG . 3A , D - 2 , of nicotine significantly increased the time that the rats spent middle panel) and 3 ( FIG . 3A , D - 3 , right panel) . The in the open arm , indicating the anxiolytic effect of nicotine . intervals between the injections were 3 hours according to However , nicotine at both doses 0 . 5 mg/ kg and 2 mg/ kg did the time needed for returning to normal body temperature . not induce an anxiolytic effect during the second injection Nicotine was injected with and without opipramol , and body due to receptor desensitization . When nicotine was injected temperature was measured at 30 min intervals. The results together with either galantamine or opipramol, the anxi are shown in FIG . 3 . ( FIG . 3A : Filled circles — Rats injected olytic effect was seen in the second injection ( at 0 . 5 mg/ kg with nicotine ( 2 mg/ kg ) three times a day in intervals of 3 nicotine ), indicating that both galantamine and opipramol hours for three consecutive days ( N = 5 ) ; Inversed triangles inhibited nACHR desensitization . Opipramol appears more Rats injected with opipramol (20 mg/ kg ) three times a day effective in this test as it also inhibited desensitization when in intervals of 3 hours for three consecutive days ( N = 5 ) ; the dose of nicotine was raised to 2 mg/ kg . Galantamine was Filled squares — Rats injected with nicotine ( 2 mg/ kg ) and not effective in inhibiting nACER desensitization at this opipramol ( 20 mg/ kg ) three times a day in intervals of 3 nicotine dose . Bar histograms represents mean of timespent hours for three consecutive days ( N = 5 ) . D , day ; Inj. , Injec in open arms S . E . M . FIG . 5A depicts the results of low dose tion ; Opi, opipramol; Nic , nicotine. ) When nicotine ( 2 of nicotine (0 . 5 mg/kg ) , FIG . 5B depicts high dose of mg /kg ) was repeatedly injected for three consecutive days , nicotine ( 2 mg/ kg ) , FIG . 5C shows a comparison between the magnitude of the decrease in body temperature induced galantamine and opipramol with different doses of nicotine . by a constant dose of nicotine became progressively smaller ( P < 0 .05 ) , indicating desensitization of the nACER . When Example 6 opipramol was injected together with nicotine in the second and the third day, the magnitude of the reduction in body Effect of Nicotine and Opipramol on BDNF mRNA temperature was significantly larger than that induced by Expression in Rat Cortex nicotine alone ( P < 0 .001 ) after the second and the third [0107 ] Nicotine alone (0 .5 mg/ kg ) or opipramol ( 10 injections . Opipramol alone caused only a slight decrease in mg/ kg ) or nicotine ( 0 . 5 mg/ kg ) + opipramol ( 10 mg/kg ) were body temperature . FIG . 3A : Each point is the Mean + S . E . M . injected intraperitoneally ( ip ) to rats ( 5 per group ) at inter of change in body temperature compared to the temperature vals of 2 hours during a single day . The drugs were dissolved measured at time 0 ( before the first injection ) for at least five in saline and used in the same day . Each injection had a rats . FIG . 3B depicts a bar histogram representing mean : S . volume of 1 ml/kg body weight. . Animals were sacrificed 90 E . M . of the maximum change in body temperature com min after each injection and brain derived neurotrophic pared to the temperature measured just before the injection . factor (BDNF ) and ß -actin mRNA were determined in Example 4 homogenates of the cerebral cortex of each animal. [0108 ] Homogenates of the cerebral cortex were prepared Effect of Opipramol or Galantamine on as follows: Rat brain tissues were sonicated for 15 sec and Nicotine- Induced Hypothermia in Rats total RNA was obtained using the Trizol Reagent (Molecular [0105 ] Following a similar protocol to that of Example 3 , Research Center, Cincinnati , Ohio , USA ), according to the opipramol (20 mg/ kg ) or galantamine (5 mg/ kg ) were manufacturer' s instructions. RNA concentrations were US 2018 /0303818 A1 Oct. 25 , 2018

quantified by measuring the absorbances at 260 and 280 nm . 1 - 4 . (canceled ) RNA was reverse transcribed into cDNA during 45 min at 5 . A method of treating or suppressing tobacco or nicotine 42° C . The cDNA products were diluted 1 :40 for BDNF and dependence or usage , comprising co -administering to a 1 : 1000 for ß - actin ( a housekeeping gene for internal stan - patient in need thereof a therapeutically effective amount of dard ). In order to amplify gene specific sequences , PCR a nicotinic agonist and a nicotinic acetylcholine receptor techniques were applied using ReadyMix PCR Master Mix (NACHR ) desensitization inhibitor. (AB - genes , Surrey , UK ) and specific primer sequences for 6 - 32 . ( canceled ) BDNF and beta actin . The products were separated by 33 . The method of claim 5 , wherein the nACAR desen electrophoresis on agarose and quantification of the bands s itization inhibitor is selected from the group consisting of: was done by an image analyzer. opipramol, galantamine , clomipramine ,mirtazapine , mapro [0109 ] FIG . 6 depicts results (mean + SEM of the ratio of tiline, lidocaine, and pharmaceutically acceptable salts , BDNF mRNA levels / ß actin ) of injections of a control esters , and prodrugs thereof. ( saline ), nicotine alone ( first and third injections) , opipramol 34 . The method of claim 5 , wherein the nicotinic agonist alone (third injection ) and opipramol/ nicotine injection is nicotine and the nACHR densitization inhibitor is opip ( third injection ) . As can be seen , BDNF mRNA is increased ramol or a pharmaceutically acceptable salt or ester thereof. as a result of treatment of the animals with nicotine . A 35 . The method of claim 4 , wherein about 5 mg /day to repeated injection of nicotine was accompanied with a much about 21 mg/ day of the nicotine is administered . smaller rise in BDNF mRNA as a result of nACER desen 36 . The method of claim 34 , wherein about 50 mg/ day to sitization . However , when nicotine was injected together about 250 mg/ day of opipramol is administered . with opipramol, the desensitization of the nACAR was 37 . Themethod of claim 5 , wherein the nicotinic agonist inhibited and BDNF mRNA level was rising even above that is effective for at least about 1 day . which was observed with nicotine alone , indicating that 38 . The method of claim 5 , wherein the nicotinic agonist opipramol can enhance the effect of nicotine and inhibit is effective for at least about 3 days . NACHR desensitization . Opipramol alone had no effect on 39 - 56 . ( canceled ) the level of BDNF mRNA . 57 . A transdermal patch for administration of a co - therapy to a patient, wherein said patch comprises : Example 7 a ) nicotine , b ) opipramol or pharmaceutically acceptable salts , esters, Effect of Clomipramine on Nicotine - Induced and prodrugs thereof, and Hypothermia in Rats c ) a pharmaceutically acceptable carrier suitable for trans [0110 ] Following a similar protocol to that of Example 3 , dermal or topical administration to a patient . nicotine ( 2 mg/ kg ) alone or in combination with clomip 58 . The transdermal patch of claim 57 , wherein the patch ramine ( 30 mg/ kg ) was injected to rats 3 times , 2 h apart. is formulated to provide substantially continuous delivery of The body temperature ( 0 C . ) was measured 30 min post the nicotine and the opipramol to a patient. injection . FIG . 7 depicts the maximum decrease in body 59 -61 . ( canceled ) temperature after each injection . As can be seen , when 62. A controlled release medical device for delivery of a nicotine was injected alone, a gradual decrease in the composition comprising : hypothermic effect was seen , indicating nACAR desensiti a ) nicotine , and zation . Clomipramine inhibited to some extent the effect of b ) opipramol or a pharmaceutically acceptable salt , ester, nicotine in the first injection , but no further reduction in the or a prodrug thereof; wherein the device is capable of hypothermic effect of nicotine was noted in consecutive delivering the composition in a pre - determined deliv injections, suggesting that clomipramine inhibits nACAR ery rate to a patient. 63. The controlled release medical device of claim 62 , desensitization . wherein the pre - determined delivery rate is substantially Example 8 continuously over at least 1 day. 64 . The controlled release medical device of claim 63 , Effect of Lidocaine on Nicotine - Induced wherein the pre -determined delivery rate is substantially Hypothermia in Rats continuously over at least 1 day. [0111 ] The experimental design was similar to that 65 . A kit comprising : described in Example 3 . Nicotine ( 2 mg/ kg ), lidocaine ( 15 a first pharmaceutical composition comprising a nicotinic mg/ kg ), and nicotine + lidocaine ( 2 mg /kg + 15 mg /kg ) were agonist, administered to rats 2x day for two days, following the a second pharmaceutical composition comprising a above protocol. FIGS. 8A -8B depicts the results on day 1 NACHR desensitization inhibitor, and and day 2 , respectively , indicating that lidocaine maintained instructions for administration of the first and second the hypothermic effect of nicotine compared to the loss of compositions. the hypothermic effect of nicotine when it was given alone . 66 . The kit of claim 65 , wherein the first and second These results show that lidocaine inhibits nACHR desensi compositions form a transdermal patch . tization . * * *