111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US007960424B2
`
`c12) United States Patent
`Calderari et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,960,424 B2
`*.Jun. 14, 2011
`
`(54) LIQUID PHARMACEUTICAL
`FORMULATIONS O F PALONOSETRON
`
`(75)
`
`Inventors: G iorgio Calderari, Rancate (CB);
`Daniele Bonadeo, Varese OT); Roberta
`C annella, Varese (IT); Enrico Braglia,
`Pazzallo (CH); Ricca rdo Braglia,
`Pazzallo (CH); A11drew M iksztal, Palo
`Alto, CA (US); Thomas Malefyt,
`Carmel Valley, CA (US); K athleen M.
`Lee, Palo Alto, CA (US)
`
`(73)
`
`Assignees: Oclsinn Oealthcarc S.A., Lugano (C[ !);
`Roche Palo Alto LLC, Palo Alto, CA
`(US)
`
`( *)
`
`Notice:
`
`Subject to any disclaimer, the term oftb.is
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`Th.is patent is subject to a terminal dis-
`claimer.
`
`(21)
`
`Appl. No.: 11/388,270
`
`(22)
`
`Filed:
`
`Mar. 24, 2006
`
`(65)
`
`Prio·r Publication Data
`US 2006/0167073 AI
`Jul. 27, 2006
`
`Related U.S. Applica tion Data
`Continuation of application No. 11/ 186,311, filed on
`Jul. 21, 2005, now Pat. No. 7,947,724, wh.icb is a
`continuation of application No. PCTIEP2004/000888,
`filed on Jan. 30, 2004.
`Provisional application No. 60/444,351, filed on Jan.
`30,2003.
`
`Int. CI.
`(2006.01)
`AOJN 43152
`U.S. Cl. .. ..................................................... 514/397
`Field of Classification Search ................... 514/397
`See application file for complete search history.
`
`Refe rences Cited
`
`(63)
`
`(60)
`
`(51)
`
`(52)
`(58)
`
`(56)
`
`U.S. PATENT DOCUMENTS
`911987 Coates et a.I. .... ............ 514/397
`4,695,578 A
`4,753,789 A
`6/1988 Tyers et al. ..................... 424/10
`4,886,808 A
`1211989 King ........ ....... ............. 514/299
`4,906,755 A
`3/1990 Gittos ............................ 546/94
`511990 Tyers et al. . .... . .. .. .. ...... . 5 14/397
`4,929,632 A
`6/1990 King ........ .................... 514/299
`4,937,247 A
`4/1991 Gittosetal. .................. 514/294
`5,011,846 A
`711991 King ................ ............. 514/299
`5,034,398 A
`4/1993 Berger et al. .... ............. 514/296
`5,202,333 A
`5,240,954 A
`811993 Tyers et al. ................... 514/395
`1211993 Blase et a!.
`5,272,137 A
`5,344,658 A
`911994 Collin .......................... 424/489
`5,578,628 A
`1111996 Tyerset al. ................... 514/397
`1111996 Tyers et al. ................... 514/397
`5,578,632 A
`411997 Collin .......................... 424/489
`5,622,720 A
`1211998 Gambhir
`5,854,270 A
`7/1999 Tyers eta!. ...... ............. 514/397
`5,922,749 A
`5,955,488 A
`91! 999 Winterborn ................... 514/399
`5/2000 Winterborn .... . .. .... .. .... .. 5 I 4/397
`6,063,802 A
`
`91200 I Castillo et al. .
`6,284,749 Bl •
`9/200 I Dickinson
`6,287,592 Bl
`9/200 1 James ........... .
`6,294,548 Bl
`9/200 1 James .......... ..
`2001/0020029 AI
`5/2003 Dugger, III ... .
`2003/0095926 AI
`FOREIGN PATENT DOCUMENTS
`WO 03/100091 A
`12/2003
`W0-2004045615 AI *
`6/2004
`8/2004
`W02004067005
`W0-2004073714 AI *
`9/2004
`
`wo
`wo
`WO wo
`
`514/159
`
`514/299
`514/299
`. .. 424/43
`
`OTHER PUBLICATIONS
`Matsumoto et al., "Yakuzaigakll Manual", I st edition, Nanzando Co.,
`Ltd. (1989) 2 pages.*
`Baiton (Citrate Bu!Ier Calculation, 2000, 2pgs."'
`Eglen, R. M. et al., Pharmacological Characterization ofRS 25259·
`197, a Novel and Selective 5·HT3 Receptor Antagonist, in vivo,
`extracted from British Journal of Pharmacology, 1995, vol. 114, No.
`4, pp. 860·866.
`Chelly, Jacques et al., Oral RS·25259 Prevents Postoperative Nausea
`and Vomi ling Following Laparoscopic Surgery, extracted from Anes-
`thesiology, 1996, vol. 85, No. 3A, p. A2.1.
`Sorbe, Bengt, 5-HT3 Receptor Antagonists as Antiemetic Agents in
`Cancer Chemotherapy, extract.ed fTom E:;.pert Opinion on lnvestiga-
`lional Drugs, 1996, vol. 5, No. 4, pp. 389-407.
`Gaster, Laramie M. and King, Frank D., Serotonin 5-HT3 and 5-t!T4
`Receptor Antagonists, extracted from Medicinal Research Reviews,
`1997, vol. 17, No. 2, pp. 163·214.
`Tang, Jun et al., Efficacy ofRS-25259, aNovel5-HT3 Antagonist, in
`the Prevention of Postoperative Nausea and Vomiting After Major
`Gynecologic Smgery, abstract extracted from Anesthesiology, 1997,
`vol. 85, No.3, suppl. p. A329.
`Tang, Jun et al., The Efficacy ofRS·25259, a Long-Acting Selective
`5-HT3 Receptor Antagonist, for Preventing Postoperactive au sea and
`Vomiting After Hysterectomy Procedures, extracted from Anesthesia
`and Analgesia, 1998, vol. 87, pp. 462-467.
`Adis R&D Profile, Palonosetron RS 25259, RS 25259 197, e.xtracted
`from Drugs in R&D, Oct. 1999, vol. 2, No. 4, pp. 251-252.
`Piraccini, Gaia et al., An IJJteresting 5·HT3 Receptor Antagonist
`Antiemetic for Patients Unde•going Chemotherapy-Based Condi-
`tioning Regimens?, extracted from Blood, Nov. 16,200 I, vol. 98, No.
`11, prut 2, p. 350b, abstract No. 5169.
`Stacher, Georg, Palonosetron Helsinn, extracted from Currelll Opin-
`ion in Investigational Drugs, Oct. 2002, vol. 3, No. 10, pp. 1502·
`J 507.
`
`(Continued)
`
`Primary Examiner- Michael G Hartley
`Assistant Examiner - Sh.irley V Gembeh
`(74) Attorney, Agent, or Firm - Arnall Golden Gregory
`LLP; Clark G. Sullivan
`
`(57)
`
`AUSTRAC T
`
`The present invention relates to shelf-stable liquid formula-
`tions of palonosetron for reducing chemotherapy and radio-
`therapy induced emesis with palonosetron. The formulations
`are particular!
`Dr Reddy's Laboratories Ltd et a l
`oral liquid mec
`·
`'
`.,
`·
`v.
`Helsinn Healthcare SA, et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1004
`
`

`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US007960424B2
`
`(12) United States Patent
`Calderari et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,960,424 B2
`*Jun. 14,2011
`
`(54) LIQUID PBARl.'IACEUTICAL
`FORMULATIONS OF PALONOSETRON
`
`(75)
`
`Inventors: Giorgio Caldcrari, Rancatc (CH);
`Daniele Bonadeo, Yarest: (In; Roberta
`Cannella, Varese (JT); Enrico Braglia,
`Pazzallo (CII); lliccardo Draglia,
`Pazzallo (CH); Andrew :\'liksztal, Palo
`Alto, CA (US); Thomas Malefyt,
`Carmel Valley, CA (US); Kathleen M.
`Lee, Palo Alto, CA (US)
`
`(73) Assignees: Oelsinn Oealtbcare S.A., Lugano (CII);
`Roche Palo Alto LLC, Palo Alto, CA
`(US)
`
`(") Noti~:e:
`
`Subject to any di~claimer, the term ofthi~
`patent is extended or ad!justed under 35
`U .S.C. 154(b) by 0 days.
`·n1is patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 11/388,270
`Mar. 24, 2006
`
`(22) Filed:
`
`(65)
`
`Prior Publication Data
`Jul. 27, 2006
`US 2006/0167073 AJ
`
`(63)
`
`(60)
`
`Related l!J.S. Application Data
`Continuation of application No. 1J/n86,3J J, filed on
`Jul. 21 , 2005, now Pat. No. 7,947,724, wl1ich is a
`continuation of application No. PCl'/EP2004/000888,
`filed on Jan. 30, 2004.
`Provisional application No. 60/444,351 , filed on Jan.
`30, 2003.
`
`(5 1)
`
`Int.CI.
`AOJN 43152
`(2006.01)
`....................................................... 514/397
`(52) U.S. C t .
`(58) Field of Classific ation Search ................... 514/397
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`Coates et al. ................. 514/397
`4,695.578 A
`9/ 1987
`4,753.789 A
`6/ t988
`Tyers et al.
`............... 424/ t 0
`4,886.808 A
`1211989
`King .... .. .. ............. .. ...... 514/299
`4,906.755 A
`3/ 1990
`Gittos .... .. ... .......... .. ........ 546194
`4,929.632 A
`Tyers et al.
`............. 5 14/397
`51t990
`4,937.247 A
`6/ t990
`King ............................. 5 14/299
`5,011.846 A
`Gilles eta!. .................. 5141294
`4/ 1991
`5,034.398 A
`King .....
`. .. ...... 514/299
`7/ 1991
`Berger et al. ......... .. ...... 514/296
`5,202.333 A
`4/ t993
`Tyers et al. ................... 514/395
`5,240.954 A
`8/ 1993
`13Jase et al.
`5,272.137 A
`12/1993
`5,344,658 A
`9/ t994
`Collin ... ....................... 424/489
`Tyers et al.
`.......... 514/397
`5,578.628 A
`11/ 1996
`1111996
`5,578.632 A
`Tycrs ct al.
`.......... 514/397
`5,622.720 A
`4/ t997
`Collin ...
`. ......... 424/489
`5,854.270 A
`12/1998
`Gambbir
`7/ 1999
`.......... 514/397
`Tyers et al.
`5,922.749 A
`5,955.488 A
`9/ 1999
`Winterborn .................. 514/399
`6,063.802 A
`5/2000
`Winterborn . ....... . . .. ...... 514/397
`
`912001 Castillo et al. .......... ..... 514/159
`6,284,749 8 1 •
`912001 Dickinson
`6,287,592 131
`912001 James .... ................. ..... 5141299
`6,294,548 1:31
`912001 James ........................... 514/299
`200 J/0020029 AI
`512003 Dugger, III .............. ....... 424/43
`2003/0095926 A1
`FOREIGN PATENT DOCUMENTS
`12/2003
`WO 03/100091 A
`W0-2004045615 A I •
`6/2004
`W02004067005
`8/2004
`W0-2004073714 A I •
`9/2004
`
`wo
`wo
`wo wo
`
`OTHER PUBLICATIONS
`Matsumoto et al., "Yakt1zaigala• Manual" , I st edition, Nanzando Co.,
`Ltd. ( 1989) 2 pages."'
`1:3arton (Citrate Butter Calculation, 2000, 2pgs.•
`Egleo, R. M. el a!., Pbannacological Characterization ofRS 25259-
`t97, a Novel anct Seleclive 5-HT3 Receptor Anlagonist, in vivo,
`extracted from BritisltJoumal ofPhannacology, 1995, vol. 114, No.
`4, pp. 860-866.
`Chelly, Jacques et al., Om! RS-25259 Prevents Postoperative Nause.1
`and Vomiting Following Laparoscopic Surgery, extracted from Anes-
`thesiology, 1996, vol. 85, No. 3A, p. A21.
`Sorbe, Bengt, 5-HT3 Receptor Antagonists as Antiemetic Agems in
`Cancer Chemotherapy, extracted from /:.xpert Opinion on investiga-
`tional Drugs, 1996, vol. 5, No. 4 , pp. 389-407.
`Gaster, l.aramie M. and King, Frank D., Serotonin 5-HT3 anct 5-HT4
`Receptor Antagonists, extracted from Medicinal Research Reviews,
`1997. vol. 17, No.2. pp. 163-214.
`Tang, .Jun et: al., F.fficacy ofRS-25259, a Novel5-HT3 Anragonisr, in
`the Prevention of Postoperative Nausea and Vomiting After Major
`Gynecolo<..;ic Surgery, abstract extracted from Anesthes;o/ogy, 1997,
`vol. 85, No . 3, suppl. p. A329.
`Tang, Jun et at., The Efficacy of RS-25259, a Long-Acting Selective
`5-HT 3 Receptor Antagonist, for Preventing Postoperative Nausea and
`Vomiting Aller Hysterectomy Procedures, extracted from Auestliesia
`and Analgesia, 1998, vol. 87, pp. 462-467.
`Adis R&D Profile, Palonosetron RS 25259, RS 25259 197, extracted
`from Drugs in R&D, Oct. 1999, vol. 2. ~o. 4, pp. 25 1-252.
`Piraccini, Ua.ia et al., An Interesting 5-HT3 RecepiOT .A.ntagonist
`Antiemetic for Patients Undergo ing Chemotherapy-Ba sed Condi-
`tioningRegimens?, extracted from/Jiood, Nov. 16,2001 , vol. 98, No.
`II, prut 2, p. 350b, abstJact ·o. 5 169.
`Stacher, Ge01g, Palonosetron Helsinn, extracted from Currem Opiu-
`iou in Investigational Dmgs, ()ct. 2002, vol. 3, No. 10, pp. 1502-
`1507.
`
`(Continued)
`
`Primary Examiner - Michael G Hartley
`Assistant /:!~~a miner - Shirley V Gembeh
`(74) Allomey, Agem, or Firm- Arnall Golden Gregory
`LLP; Clark G. Sullivan
`
`(57)
`
`ABSTRACT
`
`The present invention relates to shelf-stable liquid formula-
`tions of palonosctron for reducing chemotherapy and radio-
`therapy induced emesis with palonosetron. The formulations
`are particularly useful in the preparation of intravenous and
`oral liquid medicaments.
`
`6 t:laims, No Drawings
`
`Exh. 1004
`
`

`
`US 7,960,424 B2
`Page2
`
`OTHER PUBLICATIONS
`N:tvari, Rudolph M., Pathogenesis-Rased Treatment of Chemo-
`lherapy-lndttced ~ausea and Vomiting- Two 1ew Agents, extracted
`from Journal 0{Supportive OncoloJzy, 2003, vol. I (2). pp. 89-103.
`Michael J. Pika!, "Freeze Drying'', Encyclopedia of Ph:u-maceutical
`Technology. Third Edition, Jan. 2007, pp. 1824-1825, vol. 3, lnfonna
`PhRrmaceulicals & l lealthcare.
`Oppostion Brio.:f filo.:d by Dr. Reddy's laboratorio.:s (UK) Limilw,
`opposition to European Patent No. 160 1359 Bl, Jul. 7, 2009.
`Photolytic and oxidative degradation of an antiemetic agent, RG
`129 15 (Won C. ~ . Et al, International Journal ofPhannaceulics 121
`(1995) 95-105 (1995).
`Palonosetron: a phase II dose ranging study to assess over a 7 day
`period the singl~ dose pharmacokinctic profile of palonosctron in
`patients receiving highly emelogenic chemotherapy. Piraccini Get
`al., Proc. Am. Soc. Clin Onco12002 2 1 Abs 449 (2002).
`Formulation and administration techniques to minimize injection
`pain a.nd tissue damage associated with parenteral products. Larry A .
`Gatlin; Carol A Brister Gatlin, [from Injectable Drug Development:
`Techniques to Reduce Pain and Irritation [Edited by Pramod K.
`Gupta, Gayle A. Brazeau; Published by lnfonna Health Care (origi-
`nal copyright of 1999 by lnterpha.nna Press), 1999; ISBN
`1574910957, 978 15749 10957)], p. 401-421.
`Parenteral Dosage Forms. Joanne Broadhead. [from Part 11- Eatly
`drug development, Phannaceutica1 prefonnulatio11 and formulation:
`a practice guide from candidate drug selection to commercial dosage
`form [Edited by ~ark Gibson; Published by lnterpharma Press,
`200 I ; ISB'-1 I 5749 J .120 I, 9781574911206)], p. 33 1-353.
`Opposition Brief filed by Tccnimcde Socicdadc Tccnico-Mcdicinal
`S.A., opPQsirion to European Patent No. 160.1359 B l, Jul. 8, 2009.
`Response brief filed by Helsinn Heallhcare S.A. dated Jul. 13, 2007,
`in response to the communicMion pursuant to Art. 96(2) F.PC of .Tan.
`3, 2007 regarding Serial No. 04 706 657.6-2123
`european Patent Office official conununication dated Jul. 19, 2006
`regarding Serial No. 04 706 657 .6.
`Response of Hclsinn Hcalthcare S.A. dated Nov. 29, 2006 regarding
`c PO official communication dated Jul. 19, 2006.
`La~hman d al.. Th<: Th<XJIY and Pr-a~tice of Industrial Phrumacy,
`1986. third edition, pp. 652-784.
`Smn mary of Product Characteristics for Aloxi 250.
`Declamtion of Valentino J. Stella, Ph.D.
`Opposition Brief filed by Martin Paul While, opposition to Emopean
`Patent No. 1601359 81, Jul. 8, 2009.
`
`Wong eta.!. ( 1995), in 13ritish Jou rnal ofPhannacology, vol. .1.14, pp.
`851-859 and Eglen el al. (.1995), .in British Journal of Pharmacology,
`vol. 114, pp. 860-866.
`Cover page and pp. 642-644 and 783-784 of The Theory and Practice
`oflndustrial Pha.nnacy, Third Edition, Lea and l'ebiger (1986).
`Cover page and pp. 514-515 of Modern Pharmaceutics. Second Edi-
`tion, Marcel Dekker (1990).
`Cover page and pp. 142-143 o f Pharmaceutical Dosage Forms:
`Parenteral Medications vol. I. Second 13ditioo, Marcel Dekker
`(1992).
`Scientific Discussion from lhe E uropean Public Assessment Report
`for AJoxi (Palonosetron Hydrochloride).
`Kranke et at. 2007. "Recent advances, trends and economic consid-
`erations in ... "Expert Opinion Phannacotber., 8 (.18): 3217 -3235).
`Morrow e t al. 1995, Progress in reducing nausea and emesis. Com-
`parisons of ondansetron, granisel..ron, and tropisetron. Cancer, vol. 76
`No. 3 pp. 343-357.
`Daniele Bonadeo, "Supplemental Declaration of Daniele Bonadeo
`37 C.FR. 1.132", U.S. Appl. No. 11/3!!!!,270, Jun. M, 2009.
`Chaitow, J 990, 3 pages.
`USPTO Office Action, U.S. Appl. 1o. 111388,268, filing Date Mru·.
`24, 2006, Mail Dare Mar. 29, 2010.
`USPTOOfficeAction, U.S . Appl. 1o. 111129,839. MaiiDateJan. 15,
`2010.
`lsraili, ZllfM 11., Clinical Pharmacology of Serotonin Receptor
`Type-3 (5-HT3) Antagonists, Curr. Med. Chem.-Central No:rvous
`SystemAgenrs,2001. I , 171 -199.
`USPTO Office Action, U.S . Appl. No. 11/201,035, Mail Date Aug.
`19,2009.
`Response of Helsinn HealthcMe to opposition of EP Serial ;..,to. 04
`706 657.6 dated Feb. I I, 20.10.
`Annex I (Statement of Waldo Mossi, Ph.D.) to Response of llelsinn
`Healthcare to opposition ofEP Serial No. 04 706 657.6 dated feb. 11,
`2010.
`Annex 2 to Response of 1-lelsinn Healthcarc to opposition of EP
`Serial No. 04 706 657.6 dated Feb. 11,2010.
`Annex 3 to Response of l-lelsinn Healthcare to opposition of liP
`Serial No. 04 706 657.6 dated Feb. I I, 2010.
`6"' Edition, Handbook ofPhannaccutical Excipients (2009), pp. 247-
`250n (RPS Publishing).
`* cited by examiner
`
`Exh. 1004
`
`

`
`1
`LTQUTD PHARMACEUTICAL
`FORMULAl'IO~S OF PALONOSETRO~
`
`US 7,960,424 B2
`
`2
`-continued
`
`Ingredient
`
`S odiwn Hydroxide
`WI'J
`
`0.18 mg.
`To 1.0 ml.
`
`ll1e present invention claims priority to PCT/EP04/
`000888, filt:d Jan. 30, 2004, which claims priority to U.S. 5
`Provisional Patent Application No. 60/444,351, tiled Jan. 30,
`2003. Tit<:: prt:S<:::ut applil:atiou is alsv a wutiuuativu of l:ur-
`rently pending U.S. patent application Ser. No. 11/186,311,
`filed Jul. 21.2005. The content of these applications is incor-
`porated herein by reference.
`
`10
`
`RACK GROUND OF THR lNVRNTlON
`
`l l1t: pn:st:nt inv.:ntion rdi:ttes to shelf-life stab It: liquid for-
`mulations of palonosetron that are especially usefi.ll in the
`preparation of injectable and oral medicaments.
`Emesis is a devastating consequence or cytotoxic therapy,
`radiotht:ntpy, and post-opt:rcttivt: t:nvironrnt:nls that drasti-
`cally affects the quality of life of people 1llndergoing such
`t.rt:alments. ]n rt."Cent years a class of drugs referred to as
`5-HT3 (5-hydroxytryptamine) receptor antagonists has been
`developed that treat such emesis by antagonizing cerebral
`fw1ctions associated wit h the 5-HT3 receptor. See Drugs Act-
`ing on 5-Hydruxylryptumine Receptors: Tbe Lancet Sep. 23, 25
`1989 and references cited therein. Drugs within this class
`include ondansetron, granisetron, alosetron, tropisetron, and
`dolasetron. These 5-HT3 antagonists are often administered
`intravenously shortly before chemotherapy or radiotherapy is
`initiated, and can be administered more than once during a 30
`cycle of chcmot:hcrnpy or radiotherapy. In addition, they arc
`often supplied as tablets or oral elixirs to eitbersupplerneotan
`intrnvennus administration, nr to ease hmne usage nfthe drug
`if the patient is self-administering the chemotherapeutic regi-
`men.
`Because some chemotherapeutic agents can induce emesis
`over extended periods of severn] days even when tbey are
`administered ottly once, it would be desirable to administer an
`emesis-inhibiting drug such as a 5-HT 3 antagonist every day
`umil tht: risk of t:mt:sis has subswntially subsided. Tilt: 40
`present class of5-HT3 antagonists bas not proven especially
`hclpfi.tl mccting this need, however, because the 5-HT3 recep-
`tor antagonists currently marketed have proven to be less
`effective in controlling delayed nausea and vomiting than
`they are at controlling acme emesis. Sabra, K, Choice of a 45
`5HT 3 Receptor Antagonist/or the Hospital Formulary. EHP,
`October 1996; 2 (suppl l ):SJ9-24.
`Recently, clinical investigations have bee11 made concern-
`ing palonosetron, a new 5-HT3 receptor antagonist reported in
`U.S. Pat. No. 5,202,333. These investigations have shown so
`that the drug is an order of magninrde more potent than most
`existing 5-HT 3 receptor antagonists, has a surprising half-life
`of about 40 hours, and is effective to reduce delayed-onset
`nausea induced by che111otberapeutic agents. However, for-
`mulating palonosetron in liquid Jormulations has not proven 55
`an easy task, t>•pically due to shelf-stability issues. U.S. Pat.
`No. 5,202,333 discloses an intravenous fonnu1ation of pal-
`onosetron in example 13 that contains the following ingredi-
`ents:
`
`'!be fonnulationhasa pH of3.7 and a shelf stability ofless
`than the 1-2 year time period required by health authorities in
`various countries.
`Ondansetron, its uses, and medicaments made with
`ondansetron are disclosed in U.S. Pat. Nos. 4,695,578, 4,753,
`789, 4,929,632, 5,240,954, 5,344,658, 5,578,628, 5,578,632,
`5,922,749, 5,622,720, 5,955,488, and 6,063,802. Conuner-
`15 cially it is distributed by Glax:oSmithKiint: as Zofmn® and is
`indicated for prevention of postoperative nausea and vomit-
`ing (PO NV), cancer chemotherapy-induced nausea and vom-
`iting (C1NV), and radiotherapy-induced nausea amd vomiting
`(RJNV) and it is available as an injection, tablets and solution,
`20 and as Zofran ODT® (ondansetron) Orally Dis integrating
`Tablets.
`Granisetron, its uses, and medicaments made with granis-
`etron are disclosed in U.S. Pat. Nos. 4,886,808, 4,937,247,
`5,034,398 and 6,294,548. Com.lllercially it is distributed by
`Roche Laboratories Inc. as Kytril®, indicated for the preven-
`tion of nausea and vomiting associated with chemotherapy or
`radiation therapy, and is offered in tablet f01m , oral solution,
`and as an injection.
`Alosetron, its uses, and medicaments made with alosetron
`are disclosed in U.S. Pat. Nos. 5,360,800 and 6,284,770.
`Commercially it is distributed by GlaxoSmithK!ine as
`Lotronext&:.
`Tropisetron is conunercially available as Navoban® (No-
`35 vanis) CAS-89565-68-4 (tropisetron); CAS-105826-92-4
`(tropisetron hydrochloride) and it is indicated for t!reatment of
`PONV and ONV.
`Dolasetron, its uses, and medicaments made with
`ondansetron are disclosed in U.S. Pat. Nos. 5,011,846, and
`4,906,755. Commercially it is distributed by Avcntis Phamla-
`ceuticals Inc. as Anzemet®, indicated for prevention of both
`PONV andCJNV, and it is offered in the form of a tablet or an
`intravenous solution.
`Therefore, there exists a need for a palonosetron fonnula-
`tion with increased stability and thereby increased shelf life.
`TI1ere also exists a need for a n appropriate range of concen-
`trations for both the 5-HT 3 receptor antagonist and its phar-
`maceutically acceptable carri crs that would facilitate making
`a formulation with this increased stability.
`1 t is an object of the present invention to provide a fornlll-
`lation of Palonosetron hydrochloride with increased pharma-
`ceutical stability for preventing and/or reducing emesis.
`It is an.otherobject of the invention to provide an acceptable
`range of concentrations which will stabilize a formulation
`conmining Palonosetron hydrochloride.
`It is a further object of the invention to provide a fonnula-
`tioo of Palonosetron which would allow for prolonged stor-
`age.
`It is also an object of the invention to provide a formulation
`60 ofPalonosetron which would allow tem1inal sterili?ation.
`
`Palonosetron HCI
`Dextrose Monohydrate
`Citric Acid Monohydrate
`
`Mg
`
`10- 100 mg.
`q. s. to make lsotOJtic
`1.05 mg.
`
`SUMMARY OF THE INVENTION
`
`The inventors have made a series of discoveries that sup-
`65 port a surprisingly effective and versatile formulation for the
`treatment and prevention of emesis using pa lonoset:ron.
`'L11ese fonnulations are shelf stable tor periods eater than 24
`
`Exh. 1004
`
`

`
`US 7,960,424 B2
`
`4
`
`•HCI
`
`3
`months at room temperature and thus can be stored without
`refrigeration, and n1atmfacn1red using non-aseptic, terminal
`slerili.~:ation processes.
`In one aspect, the inventors have discovered that formula-
`tions which include the active ingredient palonosctron require 5
`in some instances only 1/w'" the amotmt of other previously
`known comp01mds for treating emesis, which surprisingly
`allows the use of concentrations of palonosetron far below
`those that would ordinarily be expected. Thus, inoneembodi- 10
`ment the invention provides a pharmaceutically stable soltl-
`tion for preventing or reducing emesis comprising a) from
`about 0.01 mglmL to about 5 mglmL palonosetron or a phar-
`maceutically acceptable salt thereof and b) a pharmaceuti-
`cally acceptable carrier.
`'Jl1e inventors have further discovered that by adjusting the
`formulation's piJ at](i/or excipient concentrations it is pos-
`sible to iJJcrease the stability of palonosetron formulations.
`Therefore, in another embodiment, the invention provides a
`pharmaceutically stable solution for preventing or reducing 20
`emesis comprising a) palonosetron or a phamtaceutically
`acceptable salt thereof; and b) a pham1aceutkally acceptable
`carrier, at a pH from about 4.0 to about 6.0. In another
`embodiment the invention provides a pharm<'tceutically stable 25
`solution for preventing ·Or reducing emesis comprising from
`about 0.01 to about 5.0 mg/1 palonosetron or a phanuaceuti-
`cally acceptable salt thereof; from about 10 to about 100
`millimoles citrate buffer, and from about 0.005 to about I 0
`mglml EDTA.
`TI1e inventors have further discovered that the addition of
`mannitol at1d a chelating agent can increase the stability of
`palonosetron fonnulations. 111erefore,
`in still another
`emb odiment the inventio n provides a pharmaceutically stable
`solution for preventing or reducing emesis comprising a)
`palonosetron or a pbanuaceutically acceptable salt thereof
`and b) a phamtaceutically acceptable carrier, wherein the
`pharmaceutically acceptable carrier comprises a chelating
`agent and mamtitol.
`
`Concentrations- When concentrJtions of palonosetron
`are given herein, the concentration is measured in tem1s of the
`15 weight of the free base. Concentrations of all other ingredi-
`ents are g iven based on the weight of ingredient added to the
`solution.
`"Pharmaceutically acceptable" means that which is useful
`in preparing a pharmaceutical composition that is generally
`safe, non-toxic and neither biologically nor otherwise unde-
`sirdble;: and include;:~ that which i~ acceptable for vete;:rin<:~ry
`use as well as human pharmaceutical use.
`"Pillirmace;:utic.;<:~lly acceptable;: ~alts" means ~<tit~ wltic.;h are;:
`phannaceutically acceptable, as defined above, and which
`possess the desired pharmacological activity. Such salts
`include acid addition salts fonued with inorganic acids such
`as hydrochloric acid, hydrobromic acid, sulfilric acid, nitric
`acid, phosphoric acid, and the lie; or with organic acids such
`30 as acetic acid, propionic acid, hexanoic acid, hepttru1oic acid,
`cyclopentanepropionic acid, glycolic acid, pymvic acid, lac-
`tic acid, malonic acid, succinic acid, malic acid, maleic acid,
`fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-
`hydroxybenzoyl)benzoic acid, einnamic acid, mandelic acid,
`35 methanesulfonic acid, ethanesulfonic acid, 1,2,-ethanedisul-
`fonic acid, 2-hydroxyethaoesulfonic acid, benzenesulfonjc
`acid p-cWorobenzenesulfonic acid, 2-naphthalenesulfotlic
`acid, p-to luenesulfonic acid, camphorsulfottic acid, 4-meth-
`ylbicyclo(2 .2.2]oct-2-ene-l-carboxylie acid, glucoheptotlic
`40 acid, 4,4'-mcthylcncbis(3-hyclroxy-2-cnc-1-carbo·xylic acid),
`3-pheoylpropionic acid, trimethylacetic acid, tertiary buty-
`lacetic acid, Iaury! sulfilric ac:id, gluconic acid, glutamic acid,
`hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
`acid, and the like.
`In addition, pharmaceutically acceptable salts may be
`formed when an acidic proton present is capable of reacting
`with inorganic or organic bases. Acceptable inorganic bases
`include sodium hydroxide, sodium carbonate, potassium
`hydroxide, aluminum hydroxide and calcium hydroxide.
`so Acceptable organic bases include ethanolamine, dietbanola-
`mioe, triethanolamine, tromethamine, N-methylglucamine
`and the like.
`
`45
`
`Discussion
`
`55
`
`The fact that palonosetron can be fommlated in some
`instances at concentrations of only about Y•o'1
`' the amount of
`other previously known compounds for treating emesis, sur-
`prisingly allows the use of concentrations of palonosetron far
`60 below those that would ordinarily be expected. Thus, in one
`embodiment the invention provides a pharmaceutically stable
`solution for preventing or reducing emesis comprising a)
`from about 0.01 mglmL to <tboul 5 mglmL palono sdron or a
`phannaceutically acceptable salt thereof; and b) a phamla-
`65 ceutically acceptable carrier. Sin1ilarly, in another embodi-
`ment the invention provides a method offonnularing a phar-
`maceutically stable solution of palonosetron comprising
`
`Exh. 1004
`
`DETAILED DESCRIPTION or TilE INVENTJON
`
`Definitions
`
`'~1ial" means a small glass container sealed with the most
`suitable stopper and seal, other suitable primary containers
`may be used, for instance but not limited to, p-filled syringes.
`Vial also means a sealed container of medication that is used
`one tin1e only, and includes breakable at1d non-breakable
`vials, breakable plastic vials, miniature screw-top jars, and
`any other type of container of a size capable of holding only
`one unit dose of palonosetron (typically about 5 lllls.).
`ll1roughout thi~ specification the word "compri~e," or
`variations such as "comprises" or "comprising," will be
`understood to imply the inclusion of a stated element, integer
`or step, or group of elements, integers or steps, but not the
`exclusion of any other element, integer or step, or group of
`elements, integers or steps
`"Palonosetron" means (3aS-2,3,3a,4,5,6-Hexahydro-2-
`r(S)-l-Azabicyclorz.2.2]oct-3-yl]2,3,3a,4,5,6-hcxahydro-1-
`oxo-1 Hbenz( de]isoquinoline, and is preferably present as the
`monohydrochloride. Palonosetron monohydrochloride can
`be represented by the following chemical smure:
`
`

`
`US 7,960,424 B2
`
`5
`admixing from about 0.01 mg/mL to about 5 mg!mL pal-
`onosetron or a pharu1aceutically acceptable salt thereof with
`a phamtaceutically acceptable carrier. In alternative embodi-
`ments, the formulation iocludes palooosetron or a pbanna-
`ceutically acceptable salt thereof in a concentration ii:om 5
`about 0.02 mg/mL to about 1.0 mglmL, from about 0.03
`mg/mL to about 0.2 m/nlL, and most optimally about 0.05
`mglml.
`A particular advantage associated with the lower dosages
`of intraveoous palonosetron is the ability to administer the 10
`dntg in a single intravenous bolus over a short, discrete time
`period. This time period generally extends from about 10 to
`about 60 seconds, or about 10 to about 40 seconds, and most
`preferably is about 10 to 30 seconds. In one particular
`embodimeot the palooosetron is supplied in vials that com- 15
`prise 5 mi. of solution, which equates to about 0.25 mg of
`palonosetron at a concentration of about 0.05 mglml.
`TI1e inventors have further discovered tbatt by adjusting the
`formulation's pH and/or excipient conccntratioos it is pos-
`sible to increase the stability of palonosetron fommlations. 20
`Therefore, in another embodiment, the invention provides a
`pharmaceutically stable solution for preventing or reducing
`emesis comprising a) palonosetron or a pbam1aceutically
`acceptable salt thereof; and b) a phanuaceu6cally acceptable
`carrier, at a pH from a bout 4.0 to about 6.0. Similarly, io 25
`another embodiment the invention provides a method of for-
`mulating a pharmaceutically stable solution of palooosetron
`comprising admixing a) palonosetron or a pharmaceutically
`acceptable salt thereof; and b) a pham1aceutjcally acceptable
`carrier, at a pi! from about 4.0 to about 6.0. In altemative 30
`embodinlents, the pH is from about 4.5 to about 5.5, and most
`optimally about 5 .0. Tltere are many examples to those of skill
`in the art of suitable solutions to adjust the pH of a fonnula-
`tion. Two exemplary solutions are sodium hydroxide and
`hydrochloric acid solution, either ofwluch could be used to 35
`adjust the pH of the fonnulation.
`In another embodiment the invention provides a phamla-
`ccutically stable solution for preventing or reducing emesis
`comprising from about O.Oito about 5.0 mglml palonoserron
`or a phannaceutically acceptable salt thereof and (i) from 40
`about 10 to about 100 millimoles citrate buffer, and/or (ii)
`from about 0.005 to about 1.0 mg/ml EDTA. Similarly, in
`another embodiment the invention provides a method of for-
`mulating a phannaceutically stable solution of palonosetron
`comprising admixing from about 0.01 to about 5.0 mglml 45
`palonosetron or a pbarruaceutically acceptable salt thereof
`and (I) from about 10 to about 100 millimoles citrate buffer,
`and/or (ii) from about 0.005 to about 1 .0 mg/ml ELHA. Tbe
`citrate buffer can be in the fom1 of citric acid and/or a salt of
`citric acid such as trisodium citrate. In various embodiments, so
`the ranges of one or more of the foregoing ingredients can be
`modified as follows:
`'Jl1e formulation may comprise palonoset.ron or a phamla-
`ccutically acceptable salt thereof in acouccntratioo from
`abour0.02mglmJ, ro about 1.0 rnglmJ ,, from about 0.03
`mglmL to about 0.2 mglmL palonosetron hydrochlo-
`ride: and most optimally about 0.05 mg/mL
`TI1e formulation may comprise citrate buffer in a concen-
`trationoffrom about 10 to about 40 millimoles, or I 5-30
`millimoles.
`TI1e formulation may comprise EDTA in a concenrration of
`from about 0.005mglml to about J .0 mg/ml, or about 0.3
`to about 0.7 mg/ml, and most optimally <:tbout 0.5
`mglml.
`'ll1e inventors have further discovered that the addition of 65
`mannitol and a chelating agent can increase the stability o f
`palonosetron
`tonnulations. ·nJeretore,
`in still another
`
`6
`embodiment the invention provides a pharm<:tceutically stable
`solution for preventing or reducing emesis comprising a)
`palonosetron or a pharmaceutically acceptable salt thereof
`and b) a pbanuaceutically acceptable carrier, wherein the
`pharmaceutically acceptable carrier comprises a chelating
`agent and mannitol. Similarly, in another embodiment the
`invention provides a method offonuulating a phar