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 AGONISTS 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 agonist ( for example , (60 ) Provisional application No . 60 / 990 , 161, filed on Nov . nicotine ) and a nicotinic acetylcholine receptor desensitiza 26 , 2007 . tion inhibitor (for example , opipramol) . Patent Application Publication Oct. 25 , 2018 Sheet 1 of 11 US 2018 /0303818 A1 Fig . 1 $ca*uptake(DPM)well XXN 2442 Miha IN 1 2 3 4 5 Fig . 2 Nicotine alone " Nic + 10uM api Degreeofmusclecontraction (%ofcontractionby1stnic) 1234 Patent Application Publication Oct. 25 , 2018 Sheet 2 of 11 US 2018 /0303818 A1 Opi-Nic Nic Opi 1860 someone 1740 InjIII Sayu 1320|1440156016801800T 1620 InjII 1500 www . 1380 vidiwww D3-InjI der 1260 3 1200 1170 1050 InjIII Fig.3A 930 Shes 810 InjII Time(min)afterinjection 690 D2-InjI wwwwwwwwwwwww5T120240T360T480510T630T750870990|1110 570 420 InjII www 300 180 D1-InjI 60 -5.0h ) °C( temperature body in Change Patent Application Publication Oct. 25 , 2018 Sheet 3 of 11 US 2018 /0303818 A1 mannase TEB! T VV -EVE WWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWW ) c ( temperature body in Diference Patent Application Publication Oct. 25 , 2018 Sheet 4 of 11 US 2018 /0303818 A1 Day3-InIII 008900904#SUIS08Ott046098CQ0€0LLOFYOU Fig.4A Day3-InjII Lewidywanikumbukumbumumkanhakiknekoliko Time(min)afterinjection 081OSTOUT08 kol 09 . i ko 08 ????????????????????????????????????????????????????????????????????????????????????????????????????????? ?? ????????????????????? ????????????????????? ?????????????????????? ????????????????????? 1 ) C ( ature temper body in - Change Patent Application Publication Oct. 25 , 2018 Sheet 5 of 11 US 2018 /0303818 A1 iiiiiiiiiiiiiiiiii Day3InjIII P<0.04 Fig.4B : : Day3-InjII +4 W Patent Application Publication Oct. 25 , 2018 Sheet 6 of 11 US 2018 /0303818 A1 IIIInj-NicOpi-W Nic-InjINic-InIII Gal-InjIII Opi-InjIII Con Gal anatoarea S FIG.5A P<0.01 P<0.00 P<0.00 P<0.01"00 Mean?S.EM W Timein open arms (sec) Patent Application Publication Oct. 25 , 2018 Sheet 7 of 11 US 2018 /0303818 A1 Gal-NicInjIII Opi-NicInjIII Nic-InjI Nic-InjIII Opi-InjIII Con zGal-InjIII P<0.001 FIG.5B P<0.00 V2 * P<0.00 P<0.02 .4 4.3 P<0.0201 MeanES.EM 01 )sec ( arms open in Time Patent Application Publication Oct. 25 , 2018 Sheet 8 of 11 US 2018 /0303818 A1 wGal-NicInjIII TODD.Opi-NicInjIII TL <0.00 Nic(2.0mg) P * * FIG.5C Nic(0.5mg) 300 ) sec( arms open in Time Patent Application Publication Oct. 25 , 2018 Sheet 9 of 11 US 2018 /0303818 A1 Opi-NicInjIII InjINic- Nic-InjIIIZmOpi-InjIII Con 04.0<P FIG.6 02.P0 MeanÍS.EM 25 FCBDNF iRNALevels B-actin Patent Application Publication Oct. 25 , 2018 Sheet 10 of 11 US 2018 /0303818 A1 Fig . 7 Nicotine 2mg/ kg + Nicotine 2mg / kg Clomipramine 30 mg /kg - 1 . 2 - 14 .. ** * * injection14 - 1 . 6 Slnjection ! 774 Injection !! ! . Patent Application Publication Oct. 25 , 2018 Sheet 11 of 11 US 2018 /0303818 A1 Fig . 8A 38 .5 38 . 1 37. 9 37 . 7 BodyTemperature(°C) 37 . 5 37 . 1 36 . 9 36 . 7 36 . 5 36 . 3 36 . 1 35 . 9 35 . 7 240300 Time Post Nicotine injection (min ) * Nicotine 7 mg/ kg Nicotine 2 mg /kg * 15 mg /kg lidocaine Lidocaine 15 mg/ kg Fig . 8B 38 . 3 38 . 1 37 .9 °C)Temperature(Body 36omto . 9 36 ,7 36 . 5 36 . 3 36 . 1 35 . 9 35 . 7 50 150 Time Post Nicotine Injection (min ) wa PY 1 Us1 1 7 C US 2018 /0303818 A1 Oct. 25 , 2018 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 nicotinic agonist. 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 epibatidine , epiboxi acetylcholine receptors (nAChRs ) desensitization inhibitor . dine , ABT -418 , ABT -594 , and SIB - 1508 (altinicline ) 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 , decamethonium bromide , epibatidine , each of the a - subunits of the receptor and induce a confor lobeline, varenicline , epiboxidine , 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 .