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US010292977B2 (12 ) United States Patent (10 ) Patent No. : US 10 , 292 , 977 B2 Azhir (45 ) Date of Patent: *May 21, 2019 ( 54 ) COMPOSITIONS AND METHODS FOR 7 ,718 ,677 B2 5 /2010 Quik et al . TREATMENT RELATED TO FALL AND 8 , 192 ,756 B2 6 / 2012 Berner et al. FALL FREQUENCY IN 2005 /0021092 A1 1 / 2005 Yun et al . 2006 / 0053046 A1 3 / 2006 Bonnstetter et al. NEURODEGENERATIVE DISEASES 2008 /0260825 A1 10 / 2008 Quik et al . 2011/ 0268809 AL 11/ 2011 Brinkley et al . (71 ) Applicant: Neurocea, LLC , Los Altos, CA (US ) 2013/ 0017259 A1* 1 / 2013 Azhir .. .. A61K 31 /465 424 /461 (72 ) Inventor : Arasteh Ari Azhir , Los Altos , CA (US ) 2016 /0220553 AL 8 /2016 Azhir ( 73 ) Assignee : NEUROCEA , LLC , Los Altos , CA 2016 /0235732 AL 8 /2016 Quik (US ) 2018 /0125837 AL 5 /2018 Azhir FOREIGN PATENT DOCUMENTS ( * ) Notice : Subject to any disclaimer, the term of this patent is extended or adjusted under 35 WO WO -9712605 A1 4 /1997 U . S . C . 154 ( b ) by 0 days . WO WO - 9855107 Al 12 / 1998 WO WO - 03039518 A15 / 2003 This patent is subject to a terminal dis WO WO -03061656 A1 7 / 2003 claimer . WO W O - 2009003147 Al 12 / 2008 (21 ) Appl. No. : 15 / 853 , 151 OTHER PUBLICATIONS ( 22 ) Filed : Dec . 22, 2017 Wikipedia page for Parkinsonian gait; retrieved Aug. 23, 2018 ( Year: 2018 ) . * (65 ) Prior Publication Data Abood , et al. Structure -activity studies of carbamate and other esters : agonists and antagonists to nicotine . Pharmacol Biochem US 2018 /0177775 A1 Jun . 28, 2018 Behav . Jun . 1988 ;30 ( 2 ) :403 - 8 . Meshul, Charles K . et al . Nicotine Affects Striatal Glutamatergic Related U . S . Application Data Function in 6 -OHDA Lesioned Rats . Advances in Behavioral Biol (63 ) Continuation - in -part of application No . 15 /484 , 960 , ogy , 54 (Basal Ganglia VI) , 589 -598 , 2003 . filed on Apr. 11 , 2017 , now Pat. No . 10 , 143 ,687 . Chung , K . A . et al. Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease . Neurology . Oct . 5 , (60 ) Provisional application No . 62/ 320 , 871, filed on Apr. 2010 ;75 ( 14 ) : 1263 - 9 . Epub Sep . 1 , 2010 . 11 , 2016 . Damaj, et al. Antinociceptive responses to nicotinic acetylcholine receptor ligands after systemic and intrathecal administration in (51 ) Int. Ci. mice . J Pharmacol Exp Ther. Mar . 1998 ; 284 ( 3 ) : 1058 -65 . A61K 31465 ( 2006 . 01 ) International Application No. PCT/ US17 /68271 International Search A61P 25 / 26 ( 2006 . 01 ) Report and Written Opinion dated May 1 , 2018 . A61K 45 /06 ( 2006 .01 ) ( 52 ) U . S . CI. (Continued ) CPC .. .. .. .. A61K 31/ 465 ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; A61P 25 / 26 ( 2018 .01 ) Primary Examiner — Sarah Pihonak (58 ) Field of Classification Search CPC . .. .. .. .. .. .. .. .. .. .. A61K 31/ 465 ; A61P 25 / 26 Assistant Examiner — Jason Deck See application file for complete search history . (74 ) Attorney , Agent, or Firm — Wilson Sonsini Goodrich & Rosati ( 56 ) References Cited U . S . PATENT DOCUMENTS (57 ) ABSTRACT 4 , 321 , 387 A 3 / 1982 Chavdarian et al . The present disclosure provides methods and compositions 4 , 327, 725 A 5 / 1982 Cortese et al . 4 , 332 ,945 A 6 / 1982 Edwards, III for treating fall - related symptoms in patients with neurode 4 , 442 , 292 A 4 / 1984 Edwards, III generative diseases such as Parkinson ' s disease or Parkin 4 ,452 ,984 A 6 / 1984 Edwards , III son -related diseases. In some embodiments , the disclosure 4 ,590 ,278 A 5 / 1986 Edwards, III 5 , 232 , 704 A 8 / 1993 Franz et al. utilizes nicotine or a salt thereof in combination of dop 5 , 965 , 571 A 10 / 1999 Hutchinson aminergic agent treatments for reducing fall - related symp 5 ,972 , 389 A 10 / 1999 Shell et al . toms such as reducing frequency of fall, reducing injuries 6 ,024 , 981 A 2 / 2000 Khankari et al. related to fall , reducing severity of injuries related to fall , 6 , 120 , 803 A 9 /2000 Wong et al. 6 , 221, 392 B1 4 / 2001 Khankari et al. freezing of gait, improving posture stability , improving 6 , 238 ,689 B1 5 / 2001 Rhodes et al. locomotion ability , improving balance and gait. In some 6 , 365, 182 B1 4 / 2002 Khankari et al . embodiments , the methods predict fall frequency and ten 6 , 368 ,625 B1 4 / 2002 Siebert et al . dency of recurrent falls in patients with Parkinson ' s disease , 6 ,723 , 340 B2 4 / 2004 Gusler et al. 6 , 911 , 475 B16 / 2005 Cesaro et al. in particular, patients with typical Parkinson ' s disease . 7 , 229 ,641 B2 6 / 2007 Cherukuri 7 , 282 ,217 B1 10 / 2007 Grimshaw et al . 7 , 384 ,653 B2 6 / 2008 Wright et al . 18 Claims, 12 Drawing Sheets US 10 , 292 , 977 B2 Page 2 ( 56 ) References Cited Lieberman , A . et al. Comparison of Parkinson Disease Patients Who Fell with Patients Who Fell More than Once (Recurrent Fallers ) . Journal of Alzheimer ' s Disease & Parkinsonism 4 ( 2 ) : 1 - 4 (Mar . 15 , OTHER PUBLICATIONS 2014 ) . Ishikawa, A . et al. Effects of smoking in patients with early - onset U . S . Appl. No. 15 /484 , 960 Non - Final Office Action dated Jul. 11 , Parkinson 's disease . Journal of Neurological Sciences , 117 ( 1 - 2 ) : 2018 . 28 -32 ( Jul. 1 , 1993 ) . Co -pending U . S . Appl . No . 16 / 109 ,458 , filed Aug . 22 , 2018 . Lieberman . Pharmaceutical Dosage Forms. vol . 1 , 2nd ed .. New Co -pending U . S . Appl. No . 16 / 109 , 463 , filed Aug. 22 , 2018 . York Marcel Dekker, Inc . 1989 ; 195 - 246 . Co -pending U . S . Appl . No . 16 / 151, 203 , filed Oct . 3 , 2018 . Lieberman . Pharmaceutical Dosage Forms. vol. 1 , 2nd ed .. New Fasano , Alfonso et al . Falls in Parkinson ' s Disease : A Complex and York Marcel Dekker, Inc . 1989 ; 266 - 271 . Quik , et al . Nicotine and Parkinson ' s disease : implications for Evolving Picture , Movement Disorders , vol. 32 , No . 11 , ( 2017 ) . therapy . Mov Disord . 2008 ; 23 ( 12 ) : 1641 - 52 . U . S . Appl . No. 15 / 484 , 960 Notice of Allowance dated Sep . 25 , Quik et al. Nicotine and Nicotinic Receptor . Neuro Toxicology 23 ; 2018 . 581 - 594 ( 2002 ) . U . S . Appl . No . 16 / 109 ,458 Non - Final Office Action dated Nov. 23 , Quik , Maryka Smoking , nicotine and Parkinson ' s disease , Trends in 2018 . Neurosciences 27 ( 9 ) ; 561 -568 (Sep . 2004 ) . U . S . Appl. No. 16 / 109 ,463 Non - Final Office Action dated Nov . 15 , Villafame, Gabriel et al. Long - Term Nicotine Administration Can 2018 . Improve Parkinson ' s Disease Report on a Case After Three Years of Treatment. Revista Neurologica Argentina , 27 ( 2 ) ; 95 -97 (2002 ) . * cited by examiner U . S . Patent May 21, 2019 Sheet 1 of 12 US 10 ,292 , 977 B2 FIG.1 U . S . Patent May 21 , 2019 Sheet 2 of 12 US 10 ,292 , 977 B2 **** FIG.2 WY WWW atent May 21 , 2019 Sheet 3 of 12 US 10 ,292 , 977 B2 1111111111111111111111111111111111111111111111111111111111111111111111111111111111111 3mg te 4 mg PlasmaNicotine(ngmi) . wwwwwwww wwwwwwwwww 200 300 400 FIG . 3 Dyskinesiaratings/timepoint FIG . 4 U . S . Patent May 21 , 2019 Sheet 4 of 12 US 10 ,292 , 977 B2 ATA * V . t FIG . 5 1932 . MM Fakty Screening v? Dose Escalation and Treatment ( 10 wie1 FIG . 6A U . S . Patent May 21 , 2019 Sheet 5 of 12 US 10 ,292 , 977 B2 SafetyAntyos 2wks NicotineWithdrawal Dose jade 12 HYY Visit3,6mg 491383 DoseEscalationand Treatment(10wks) FIG.6B Visit2,4 buu ygitana SAMZK Visit1,2 every6h 2 SYMZkona? ALATAN 49Alasa SXML Screening U . S . Patent May 21, 2019 Sheet 6 of 12 US 10 ,292 , 977 B2 FIG . 7 PercentDissolved(%) pomimmediate Release so thingsMultiparticulate Release at 6 hours tempo 2 Pulse Combination 8 10 12 14 16 Time (hours ) FIG . 8 atent May 21 , 2019 Sheet 7 of 12 US 10, 29 , 977 B2 3 % % % % % % %% %% ?? ?? ???? ?* FIG . 9 , " : )Dissolved(%Percent ? * ? se immediate Release men in Delayed Release $ 246 3333 34 36 - -- -- - - -- - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - -- - - - Time (hours ) FG. 1 U . S . Patent May 21, 2019 Sheet 8 of 12 US 10, 292 , 977 B2 PlasmaNicotino(ng/ml) DO FIG . 11A * wwinguin FIG . 11B U . S . Patent May 21 , 2019 Sheet 9 of 12 US 10 ,292 , 977 B2 . *. FIG . 12 * * * * * * * 1111 111111111 ???????? ???????????? ??????? ?????????????? ???????????? ??? ? WY FIG . 13 U . S . Patent May 21, 2019 Sheet 10 of 12 US 10 ,292 , 977 B2 * * * *** FIG . 14 + FIG . 15 Very Vigorous METS . Moderate Wed Thurs Fri Sat Sun Mos 10 Jan 11 Jan 12 Jan 13 Jan 19 180 15 last 16 jan 17 lans FIG . 16 atent May 21 , 2019 Sheet 11 of 12 US 10 ,292 , 977 B2 FIG . 17 rrrrrrr ONPOO2 Placebo Week 10 FIG . 18 U . S . Patent May 21, 2019 Sheet 12 of 12 US 10 ,292 , 977 B2 Decrease in FOG Assessed by Hart ll of the UPDRS , ' , , , V , V , V , V , V , V , V , V , V , . ONP002 Placebo Week 10 FIG . 19 NP002 kogenuriBuowaroxis Placebo Week 10 FIG . 20 US 10 , 292 , 977 B2 COMPOSITIONS AND METHODS FOR form . The administration of the nicotine or salt thereof may TREATMENT RELATED TO FALL AND result in a peak plasma nicotine levels above 7 . 5 ng/ mL FALL FREQUENCY IN about 25 minutes to about 50 minutes followed by a plasma NEURODEGENERATIVE DISEASES nicotine level of below about 5 ng /mL about 180 minutes after administration of the dosage form . The administration CROSS -REFERENCE of the nicotine or salt thereof may result in a peak plasma nicotine level above 5 ng /mL about 25 minutes to about 50 This application is a continuation -in -part of U . S . patent minutes after administration of the dosage form . The admin application Ser. No . 15 /484 , 960 , filed Apr. 11, 2017 , which istration of the nicotine or salt thereof may result in a peak claims the benefit of U .
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  • Efforts Towards the Synthesis of Epibatidine By: Marianne Hanna

    Efforts Towards the Synthesis of Epibatidine By: Marianne Hanna

    Efforts Towards the Synthesis of Epibatidine By: Marianne Hanna (Junior-Biochemistry major) Faculty Advisor: Dr. Thomas Montgomery Duquesne University- Bayer School of Natural Sciences 1 Abstract: Epibatidine is a naturally toxic chemical found in the secretion of poison dart frogs. Given its structural similarities to the compound nicotine epibatidine binds strongly to nicotine receptors in the central nervous system (CTS). Epibatidine’s bioactivity arises from its unique geometry which allows it to bind to the α4β2 subunit in the nicotinic receptor. This triggers an analgesic effect without a release of dopamine, differentiating its activity from opioids. Prior efforts towards synthesizing epibatidine and its analogs have involved many steps making them untenable for pharmaceutical use. By using computational and experimental methods to study the mechanism for an interrupted Polonovski [3+2] cycloaddition which will give direct access to the epibatidine core motif. By synthesizing strategic derivatives of epibatidine through this route we will investigate opioid alternatives which lack many of their addictive qualities. Background: Epibatidine is a toxic alkaloid that is isolated from the skin of poison dart tree frog Epipedobates tricolor, secretions from the frog are used by indigenous tribes in darts for hunting.1 The chemical structure was established in 1992 using NMR spectroscopy (proton NMR).2 Epibatidine possesses significant medicinal properties, it functions as an analgesic agent by binding to the nicotinic acetylcholine receptors (nAChRs) instead of the opioid receptors.3 Moreover it displays an affinity for said receptors that is 100- to 200-fold higher than nicotine. The alkaloid interacts with Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels and are expressed central and peripherally.