111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US00794 7725B2
`
`(12) United States Patent
`Calderari et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,947,725 B2
`*May 24, 2011
`
`(54) LIQUID PHARMACEUTICAL
`FORMULATIONS O F PALONOSETRON
`
`(75)
`
`)JWentors: G iorg io C alde ra ri, Rancate (CH);
`D aniele Bonadeo, Varese OD; R oberta
`Cannella, Varese (IT); Enrico Braglia,
`Pazzallo (CH); R iccardo Braglia ,
`Pazzallo (CH); An d rew M iksztal, Palo
`A lto, CA (US); T hom as Malefyt,
`Carmel Valley, CA (US); Kathleen M.
`L ee, Palo A lto, CA (US)
`
`(73) Assignees: Helsinn Healthcare S.A., Lugano (CH);
`Roche Pa lo Alto LLC , Palo Alto, CA
`(US)
`
`( *) N otice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adju sted under 35
`U .S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer .
`
`(21) Appl. No.: 11/388,268
`
`(22) Filed:
`
`M ar. 24, 2006
`
`(65)
`
`US 2006/0 167071 AI
`
`P rior Publication Da ta
`Jul. 27, 2006
`
`Related U.S. A pplication Data
`(63) Continuatio n of application No. 11/186,3 11, filed on
`Jul. 21 , 2005.
`
`(60) Provisional application No. 60/444,351, filed on Jan.
`30, 2003.
`
`(5 1)
`
`Int.CJ.
`A01N 43152
`(2006.0 1)
`(52) U.S. C I • ............... ........................................ 514/397
`(58) F ield of C lassification Sea rch . . .. . .. ... ... .. ... . 5 I 4/397
`See applicatio n file for com plete search history.
`
`(56)
`
`R efe rences C ited
`
`U.S. PATENT DOC UMENTS
`Coates et a!. ................ 514/397
`4,695,578 A
`911987
`Tyerset al.
`... 424/10
`4,753,789 A
`611988
`4,886,808 A
`1211989
`King ........
`. ...... 514/299
`4,906,755 A
`Gittos ...... ....... ............... 546/94
`311990
`Tyers et a!. ...... ............. 514/397
`4,929,632 A
`511990
`4,937,247 A
`611990
`King ........ ....... ............. 514/299
`Gittos et al. ..... ............. 514/294
`5,0 11,846 A
`4/1991
`King ................ ............. 514/299
`5,034,398 A
`711991
`5,202,333 A
`411993
`. ....... 514/296
`Berger et a!. ..
`Tyers et al. ...... ............. 514/395
`5,240,954 A
`811993
`5,272,137 A
`1211993
`Blase et al.
`5,344,658 A
`911994
`Collin ...... .................... 424/489
`........ 514/397
`Tyers et al.
`I 111996
`5,578,628 A
`I 111996
`Tyers et al. ...... ............. 514/397
`5,578,632 A
`411997
`Collin ...... ....... ............. 424/489
`5,622,720 A
`1211998
`Gambhir
`5,854,270 A
`................... 514/397
`7/J999
`Tyers et al.
`5,922,749 A
`Winterborn ................... 514/399
`5,955,488 A
`911999
`6,063,802 A
`5/2000
`Winterborn .... .............. 514/397
`6,284,749 Bl •
`912001
`Castillo et al. ................ 514/159
`6,287,592 Bl
`912001
`Dickinson
`
`514/299
`9/200 1 James ........... .
`6,294,548 Bl
`5 141299
`9/200 I James .......... ..
`200110020029 AI
`.. ....... 424/43
`5/2003 Dugger, III .. ..
`2003/0095926 AI
`FOREIGN PATENT DOCUivlENTS
`W003/100091 A
`12/2003
`6/2004
`W0-2004073714 A
`g/2004
`W02004067005
`9/2004
`W0-2004045615 AI "'
`
`"'
`
`WO wo
`wo
`wo
`
`OTHER PUBLICATIONS
`
`Mitsuo Matsumoto, et al., "Yakuzaigaku Manu:tl", 1st edition,
`Nanzando Co., Ltd. (1989) 2 pages."'
`Barton (C itrate Buffer Calculation), 2000, 2pgs."'
`Eglen, R. M. eta!., Pharmacological Characrerizalion ofRS 25259-
`197, a Novel and Selective 5-HT3 Receptor Alllagonisl, in vivo,
`extracted fromBritishJoumal of Pharmacology, 1995, vol. ll4, No.
`4, pp. 860-866.
`Chelly, Jacques eta!., Oral RS-25259 Prevents Postoperative Nausea
`and VomiJinR FollowinR Laparoscopic Sw'f?eJy, extracted from Anes-
`rhesiology, 1996, vol. 85, No. 3A, p. A21.
`Sorbe, Bengt, 5-HT3 Recepror Antagonists as Allliemetic Agents in
`Cancer Chemotherapy, extracted from E:.yJert Opinion on Investiga-
`tional Drugs, 1996, vol. 5, No. 4, pp. 389-407.
`Gaster, Lanunie M. and King, Frank D., Serotonin 5-HT3 and 5-HT4
`Receptor Antagonisrs, extracted from Medicinal Re$·earch Reviews,
`1997, vol. 17, No. 2, pp. 163·214.
`Tang, Jun eta!., Efficacy ofRS-25259, a Novei5-HT3 Antagonist, in
`the Prevention oj'Postoperarive Nausea and Vomir;ng After Major
`Gpzecologic Surge1y, abstract extracted from Anesthesiology, 1997,
`vol. 85, No. 3, suppl. p. A329.
`Tang, .Jun et al., 111e Fjfir.ary r>f RS-25 259, a l.nng-Ar.ting Seler.rive
`5-HT3 Recepror Antagonist. for Prevem ing Posroperarive Nausea
`and Vomiting After Hysterecromy Procedures, extracted from Anes-
`lhesia and Analgesia, 1998, vol. 87, pp. 462-467.
`Adis R&D Profile, Palonoserron RS 25259, RS 25259197, extracted
`from Drugs in R&D, Oct. 1999, vol. 2, No.4, pp. 251-252.
`Piraccini, Gaia et a!., An lnteresring 5-HT3 Recepror Antagonist
`Allliemetic for Palients Undergoing Chemotherapy-Based Condi-
`tioning Regimens?, extracted from Blood, Nov. 16, 2001, vol. 98, No.
`J I, part 2, p. 350b, abstract No. 5169.
`Stacber, Georg, Palonosetron Helsim1, extracted from Current Opin-
`ion inlnvesligational Drugs, Oct. 2002, vol. 3, No . 10, pp. 1502-
`1507.
`Navari, Rudolph M., Pathogenesis-Based Ti·eatment of Chemo-
`therapy-Induced Nausea and Vomiting- 1ivo New Agents, extracted
`from Joum al of Supportive Oncology, 2003, vol. 1(2), pp. 89- 103.
`Michael J. l'ikal, "f reeze Drying", Encyclopedia of Pharmaceutical
`Technology, Third Edition, Jan .. 2007, pp. I 824-1825, vol. 3, Jnfonna
`Pharmaceuticals & Hea1thcare.
`Daniele Bonadeo, "Supplemental Declaration of Daniele Bonadeo
`37 C.F.R. 1.132", U .S. Appl. No. I J/388,270, Jun. 8, 2009.
`
`(Continued)
`
`Primary Examiner - B rando n J Fetterolf
`Ass is tan/ Examiner - S hirley V Gembeh
`(74) Allorney, Agent, or Firm - Arnall Golden Gregory
`LLP; Clark G. Sullivan
`
`ABSTR AC T
`(57)
`The present invention relates to shelf-stable liq uid fonnula-
`tions of palonosetron for reduc ing chem otherapy and radio-
`therapy induce ! emesis w ith
`T he"-
`· 1s
`are particularly
`Dr. Reddy's La boratories, Ltd., et al.
`v.
`oral liquid med
`Helsinn Healthc a re S.A., et al.
`U.S. Pate nt No. 8,729,094
`Reddy Exhibit 1003
`
`

`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US00794 77258 2
`
`oz) United States Patent
`Calderari et al.
`
`(lO) Patent No.:
`(45) Date of Patent:
`
`US 7,947,725 B2
`*May 24, 2011
`
`(54) LIQUID PH ARMACEUTICAL
`FOR\\1ULATIONS OF PALONOSE TRON
`
`(75)
`
`Inventors: G iorg io Caldera rl, Rancate (CH);
`Daniele Bonadeo, Varese (IT); Roberta
`C annella, Varese (IT); Enrico Braglia,
`Pazzallo (CH); Riccardo Braglia,
`Pazzallo (CH); Andrew Miksztal, Palo
`Alto, CA (US); Thomas Malefyt,
`Cannel Valley, CA (US); Kathleen M.
`Lee, Palo Alto, CA (US)
`
`(73) Assignees: Relsinn Oealtbcare S.A., Lugano (CH);
`Roelle Palo Alto LLC, Palo Alto, CA
`(US)
`
`( ~ ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U .S.C. J54(b) by 0 days.
`This patent is subject to a tenninal dis·
`claimer.
`
`(2 1) Appl. No.: 11/388,268
`
`(22) Filed:
`
`Mar. 24, 2006
`
`(65)
`
`Prior Publication Data
`US 2006/0167071 AI
`Jul. 27, 2006
`
`Related U.S. A pplication Da ta
`(63) Continuation of application No. ll/J 86,3J J, filed oo
`Jul. 21. 2005.
`(60) Provisional appli:cation No. 60/444,351, filed on Jan.
`30,2003.
`
`(51)
`
`lot. Cl.
`AOIN 43151
`(2006.01)
`(52) U.S. Cl .
`..................................................... 514/397
`(5R) Field ofCiasslficadon Search ........ .......... 514/397
`See application file tor complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`9/ 1987
`..... 5141397
`4,695,578 A
`Coates et al.
`Tyers et al. ..................... 4241 I 0
`4,753,789 A
`6/ 1988
`4,886,808 A
`12/1989
`King ........
`.......... ...... 5 141299
`4,906,755 A
`3/ 1990
`G ittos .... ........................ 546194
`Tyers et al.
`................. 514/397
`4,929,632 A
`5/ 1990
`4,937,247 A
`King ......
`.. ............... 5141299
`6/ 1990
`5,0JI,846 A
`4/ 199 1
`G ittos et al. .................. 5141294
`7/ 1991
`5,034,398 A
`King ............................ 514/299
`13erger eta! .................. 5141296
`4/ 1993
`5,202,333 A
`................. 514/395
`Tycrs ct al.
`5,240,954 A
`811993
`5,272,137 A
`1211993
`13lase et al.
`5,344,658 A
`9/ 1994
`Collin ......
`Tycrs ct a!.
`5,578,628 A
`11/ 1996
`5,578,632 A
`11/ 1996
`Tyers et al.
`Collin ....
`5,622,720 A
`4/ 1997
`5,854,270 A
`12/1998
`Gambhir
`5,922,749 A
`7/ 1999
`Tyers et al. .... ............... 5141397
`Wintcrbom .................. 514/399
`5,955,488 A
`9/ 1999
`Wintcrbom ................... 5141397
`6,063,802 A
`5/ 2000
`6,284,749 B l •
`Castillo ct a!. ............... 5141159
`9/ 2001
`6,287,592 B l
`Dickinson
`912001
`
`.. .............. 4241489
`. ............... 5141397
`................. 5141397
`................. 4241489
`
`WO
`WO
`WO
`WO
`
`5141299
`514/299
`424/43
`
`91200 I James ............... ..
`6,294,548 BJ
`91200 I James ............... .
`200 1/0020029 A J
`2003/0095926 AI
`512003 Dugger, III .... .
`FOREIGN PATENT DOCUMENTS
`WO 03/100091 A
`1212003
`W0-2004073714 A
`• 612004
`W02004067005
`812004
`W0-200404561 5 A I • 912004
`OTHER PtJBLlCATIONS
`Mitsuo Matsumoto, ct al., "Yalmz,'ligaku Manual", 1st edition,
`Nanzando Co .. Ltd. (1989) 2 pages.•
`Barton (Citrate Buffer Calculation), 2000. 2pgs-*
`Eglen, R. M. et al., Pharmacological Characreriza1ion ofRS 25259-
`197, a Novel and Selerrive 5-HT3 Rereprnr Amago,isr, in vivo,
`extracted from /JritishJoumal of Pharmacology, 1995, vol. 1.14, No.
`4, pp. 86(}·866.
`Chelly, Jacque~ et al., Oral RS-25259 Prevems Posroperarive Nausea
`and Vomiting Following Laparoscopic Surgery, extracted from Anes-
`lhesiology, 1996, vol. 85. No. 3A, p. A21.
`Sorbe, Bengt. 5-HT3 Receptor Antagonists as Amiemetic Agel/Is li1
`Cancer Chemotherapy, extracted from Experr Opinion onlnve.wiga-
`Jional Drugs, 1996, vol. 5, No. 4, pp. 389-407.
`Gaster, Laramie M. and King, Fr.ank D., Serotonin 5-HT3 and 5-HT4
`Receptor Antagonists, extracted from Medicinal Reseanh Reviews,
`1997, vol. 17, :-lo. 2, pp. 163-214.
`Tang, Jun et.al.,E.ficacyofRS-25259, a Nove/5-HT3 Amagonist, in
`rile Prevenrion of Postopemtive Nausea and Vomiti11g After Major
`Gp1ecologic Surgety, abstract exiiacted from Anesthesiology, 1997,
`vol. 85, 1\"o. 3, suppl. p . .1\329.
`Tang, Jun ct al., The Efficacy of RS-25259, a Long-Acting Selective
`5-HT3 Receptor Antagonist. for Preventing Postoperarive Nausea
`and Vomiting After Hysterectomy Procedures, extracted from Anes-
`thesia and Analgesia, 1998, vol. 87, pp. 462-467.
`Adis R&D Profile, Palonoset1·on RS 25259, RS 25259!97, extracted
`from Drugs in R&D, Oct. 1999, vol. 2, No.4, pp. 251-252.
`Piraccini, Gaia et al., An lmercsting 5-l!T3 Receptor Antagonist
`Antiemetic for Paliems Undergoing Chemotllerapy-/Jased Condi-
`rioning Regimens?, extmcteo from /J/ood. 'ov. 16, 200 1, vol. 9R, o.
`II, part 2, p. 350b, abstract 'o. 5169.
`Stacher, Georg, Palonosctron Hclsinn, extracted from O wrenr Opin-
`ion inltwestigational Drugs, Oct. 2002, vol. 3, No. 10, pp. 1502·
`1507.
`Navari. Rudolph M., Pathogenesis-Based 1i·earmem of Cliemo-
`theropy-inducf'd Nousf'a and Vomiting- Two New Agf'ms, extracted
`from Jouma/ of Supportive Oncology, 2003, vol. 1(2), pp. 89-103.
`Michael J. Pikal, "Freeze Drying", Encyclopedia of Pharmaceutical
`Technology, Third Edition. Jan. 2007, pp. J 824·1825, vol. 3, Infonna
`Pharmaceuticals & Healthcare.
`Daniele Bonadeo, "Supplemental Declaration of Daniele Bonadeo
`37 C.F.R. 1.132". U.S. Appl. No. 11/J88,270, Jun. 8, 2009.
`(Continued)
`
`Primary Examiner - Brandon J Fetterolf
`Assistant Examiner - Shirley V Gembeh
`(74) Allorney, Agent. or Firm - Arnall Golden Gregory
`LLP; Clark G. Sullivan
`
`ABSTRACT
`(57)
`Tl1e present invention relates to shelf-stable liquid fonnu la-
`tioos of palooosetron for reducing chemotherapy and radio-
`therapy induced emesis with palonosetron. The formulations
`arc particularly useful in the preparation of imravenous and
`oral liquid medicaments.
`
`2 Claims, No Drawings
`
`Exh. 1003
`
`

`
`US 7,947,725 B2
`Page2
`
`OTHER PUBLICATIONS
`Kranlce ct al. 2007, .. Kccenl advances. trends and economic consid-
`erations in ... ~ E.xpcn Opinion PhannacOlbcr .. 8(18):3217-3235) .
`Morrow el al. 1995. Progress in reducing nausea an emesis. Com-
`p."lrisons of ondansctron, graoiselron. and rropisetton. Cancer, vol. 76
`o. 3 pp. 343-357.
`Chai1ow, 1990,3 pages.
`USPTO No1ice of Allowance and Fee Due, U.S. Appl. No.
`11/388.270. filed Mar. 24. 2006. Date Mailed Jan. 26, 2010.
`USPTO Office Aclion, U.S. Appl. No. l l/129,839, Dale Mailed J:m.
`15, 2010.
`lsmili, Zafar H., Clinical Pharmacology of Serotonin Receptor
`Typ<:-3 (5·11T3) Anlagoni sts, Curr. Med.Chcm.-Central Nervous
`Sy:;tcm Agents. 2001. I . 17 1-199.
`tJSL'TO OITiccAction.IJ.S. Appl. No. 11/201,035, Date Mailed Aug.
`19, 2009.
`Response of Helsinn He:ollhcare to opposition of EP Serial No. 04
`706 657.6dntcd reb. 11. 2010.
`AI111CX 1 (Statement of Waldo Mossi, Ph.D.) to Response of Helsinn
`llcalthcarc to oppositionofEP Serial No. 04 706657.6 dated Feb. 11.
`20 10 .
`AnnclC 2 10 Response of llelsinn Hcaltbcarc to opposition of bP
`Serial No. 04 706 657.6 daled Feb. I I, 20 10.
`Annex 3 to Response of llelsinn llealthcare to opposition of EP
`Serial No. 04 706 657.6 dated Feb. II, 20 10.
`Opposition Brief filed by Dr. Reddy's Laboratories (UK) Limited.
`opposition to European Patent "o. 1601359 Bt. Jul. 7. 2009.
`'lang J. ct at: ... , he ellicacy of RS-25259. a long-acting selective
`5-HT3 receptor anlagonist, for preventing postoperative nausea and
`vomiting allcr hysterectomy procedures." Anestll Analg 1998; 87:
`462-7 (1998).
`Phololylic and oxidruive degradalion of an anliemetic agem. RG
`129 15(Won C. M. Et at, International Journal of Pharmaceutics 12 1
`( 1995) 95-105 (1995).
`Palonosctron: a phase II dose ranging study to assess over a 7 day
`period the single dose pharmacokinetic profile of palonosetron in
`palients receiving highly emetogenic chemotherapy. Piraccini Get
`at., Proc. Am. oc. Clio. Oncol 2002 21 Abs 449 (2002).
`
`Formulalion and administration techniques lo minimize injection
`pain and tissue damage associate<! wilh parenleral products. Larry A.
`Gatlin: Carol A Brister Gatlin. [from Injectable Drug Development:
`Techniques 10 Reduce Pain and lrrilation (Edited by Pramod K.
`Gupta. Ca ylcA. Brazeau; Published by lnfonna Health Care (origi-
`nal copyrighl of 1999 by lnterpharma Press). 1999; ISB~
`15749 10957, 9781574910957)), p. 401-421.
`Parenteml Dos.1gc Forms. Joanne Broadhead. [from Pan H-Earty
`drug development, Phnnnaccutical prcformulation and fonnulation:
`a practice guide from candidatcdn1g selection to commercial dosage
`form (edited by Mru<k Gibson; Pub! ished by lnterphanna Press,
`2001; ISBN 1574911 201. 978 1574911206)]. p. 331-353.
`Palonoset ron llclsinn. Gco1g Slacher. Cuncnl Opinion in lnvestiga-
`lional Drugs 2002 3(10).
`Oppostion Brief filed by Tccnimede Sociedade Tecnico-Mcdicinal
`S.A., opposilion to Emo pcan Patent l\"o. 1601359 Bl. .Jiul. 8, 2009.
`R~spons<: brief fitoo by 1lelsinn Hcaltllc;u·e S .A. dated .Jul. 13, 2007,
`in response to 1hc communication pursuant to An. 96(2) EPC of Jan.
`3. 2007 regarding 'erial :-lo. 04 706 657 6-2.123.
`European P3tcnl Ollicc oflicinl co1rununication dated Jul. 19, 2006
`rcg.."lfding Serial No. 04 706 657.6
`Response of llclsinn l lcahhcarc S.A. dated Nov. 29, 2006 reg."lfding
`EPO ullicial commun ication <llllcd Jul. 19. 2006.
`Lachman el at.. The Theory and Practice of Industrial Phannacy,
`19l!6. third edition, pp. 652-7l!4.
`Opposition Brief filed by Martin Paul White. opposition 10 European
`Palc.nt o. 1601359 Bl. Jul. 8, 2009.
`Wong et al. ( 1995). in British Jou rnal of Pharmacology. vol. 114. pp.
`851·859 and Eglen cl at (1995). in Bri1ish Journal of Pharmacology.
`vol. 114, pp 860-866.
`Cover page and pp. 642-644 and 783-784 of !he Theory and Practice
`oflndustrinJ Phannacy, Third Edition, Lea and Fcbiger ( 1986).
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`tion. Marcel D<:kker ( 1990).
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`Parcntcml Medications vol. I, Second Edition, Marcel Dekker
`(1992).
`• cited by examiner
`
`Exh. 1003
`
`

`
`US 7,947,725 B2
`
`1
`LIQUlD PHARMACEUTICAL
`FORM:ULATIONS OF PALONOSETRON
`
`The present invention claims priority to PCfiEP04/
`000888, filed Jan_ 30, 2004, which claims priority to U.S
`Provisional Patent Application No. 60/444,351, filed Jan. 30,
`2003. The present application is also a continuation of cur-
`rently pending U.S. patent application Ser. No. J J/186,311 ,
`filed Jul. 2 1, 2005. The content ofthese applications is incor-
`porated herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`1l1e present invention relates to shelf-life stable liquid for-
`mulations of palonosetron that are especially usefi.1l in the 15
`preparation of injectable and oral medicaments.
`Rmesis is a devastating consequence of cytotoxic therapy,
`radiotherapy, and post-operative environments that drasti-
`cally affects the quality of life of people undergoing sucb
`treatments. In recent years a class of drugs referred to as 20
`5-UT3 (5-hydroxytryptamioe) receptor antagonists has been
`developed that treat such emesis by antagonizing cerebral
`functions associated with the 5-HT3 receptor. Sec Drugs Act-
`ing on 5-Hydro.>.JIIryptamine Receptors: The Lancet Sep. 23,
`1989 and references cited therein. Drugs within this class 25
`include ondansetron, granisetron, alosetron, tropisetron, and
`dolasetron. TI1ese 5-HT 3 antagonists are often administered
`intravenously shortly before chemotherapy or radiotherapy is
`initiated, and can be administered more than once during a
`cycle of chemotherapy or radiotherapy. In addition, they are 30
`often supplied as tablets or oral elixirs to either supplement an
`intravenous administration, or to ease home usage of the drug
`if the patient is self-administering the chemotherapeutic regi-
`men.
`Because some chemotherapeutic agents can induce emesis
`over extended periods of several days even when they are
`administered only once, it would be desirable to administer ao
`emesis-inhibiting drug such as a 5-HT 3 antagonist every day
`until the risk of emesis has substantially subsided. The
`present class of5-IIT, antagonists has not proven especially
`helpful meeting 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 :a~.:ute eme~i~. Sabra, K, Choice of a
`5HT3 Receptor Antagonist for the Hospital Formulary. EHP,
`October 1996;2 (suppl l ):S 19-24.
`Recently, clinical investigations have bee-n made concern-
`ing palonosetron, a new 5-HT 3 receptor antagonist reported in
`U.S. Pat. No. 5,202,333. These investigations have shown
`that the drug is an order of magnitude more potent than most
`existing 5-HT3 receptor antagonists, has a surprising half-life
`of about 40 hours, and is effective to reduce delayed-onset
`oausea induced by chemotherapeutic agents. However, for-
`mulating palonosetron in liquid forl!lulations has not proven
`an easy task, typically due to shelf-stability issues. U.S. Pat.
`No. 5,202,333 discloses an intravenous fomltllation of pal- 55
`onosetron in example 13 that contains the following ingredi-
`ents:
`
`2
`The Jormulation bas a 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 medican1ents made with
`5 ondansetron are disclosed in lL~ . Pat. Nos_ 4,695,578, 4,751,
`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. Commer-
`cially it is distribtued by Glax:oSmithKiine as Zofran® and is
`indicated for prevention of postoperative nausea and vomit-
`10 ing (PONY), cancer chemotherapy-induced nausea and vom-
`iting (CINV), and radiotherapy-induced nausea and vomiting
`(RJNV) and it is available as an iqjection, tablets and solution,
`and as Zofran ODT® (ondansetron) Orally Disintegrating
`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. Conuuercially it is distributed by
`Roche Laboratories Inc. as Kytril®, indicated for 1he preven-
`tion of nausea and vomiting associated with chemotherapy or
`radiarion therapy, and is oJTered in tablet fom1, oral solution,
`and as an injection.
`Aloselron, 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 GlaxoSmith.Kline as
`Lotronex®.
`Tropisctron is conuuercially available as Navo·ban® (No-
`vartis) CAS-89565-684 (tropisetron); CAS- I 05826-92-4
`(tropisetron hydrochloride) and it is indicated for treatment of
`PONV and CINV.
`Dolasetron, irs uses, and medican1ents made with
`ondansetron are disclosed in U.S. Pal. Nos. 5,01 1,846, and
`4,906,75 5. Commercially it is distributed by Aventis Phan11a-
`ccuticals Inc. as Anzcmct®, indicated for prevention of both
`PO NV and CINV, and it is offered in the form of a tablet or an
`35 intravenous solution.
`Therefore, there exists a need for a palonosetron formula-
`tion with increased stability and thereby increased shelf life.
`Tbere also exists a need for an appropriate range of concen-
`trations for both the 5-l-IT3 receptor antagonist alild its phar-
`40 maceutically acceptable carriers that would faci litate making
`a formulation with this increased stability.
`It is an object of the preset invention to provide a formula-
`tion of Palonosetron hydrochloride with increased pharma-
`ceutical stability for preventing and/or reducing
`It is another object oftbc invention to providcatlacccptablc
`range of concentrations which will swbilize a formulation
`containing Palonosetron hydrochloride.
`It is a further object oftbe invention to provide a formula-
`tion of Palonosetron which would allow for prolonged stor-
`50 age.
`It is also an object of the invention to provide a fommlation
`ofPalonosetron which would allow terminal sterilization.
`
`45
`
`SUMMARY OF THE INVENTION
`
`The inventor.> have made a series of discoveries that sup-
`port a surprisingly effective and versatile formulation for the
`treatmeu t aud prevention of emesis using pa]onosetron.
`Tbese formulations are shelf stable for periods greaterrhan 24
`60 months at room temperature, and thus can be stored without
`refrigeration, and manufacn1red using non-aseptlic, terminal
`sterilization processes.
`ln one:: aspect, the inventor:s have dis~.:overed th:at formula-
`tions which include the active ingredient palonosetron require
`65 in some instances only 1/Jo'" the amount of other previously
`known compounds for treating emesis, which surprisingly
`allows the usc of concentrations of pa]onosctron far below
`
`Ingredient
`
`:'vlg
`
`Palonosctron H Ci
`De11.trose Monohydrnte
`Citric Acid Monohydrate
`Sod;w, Hydroxide
`W FJ
`
`10-100 mg.
`q.s. to make J soton_ic
`1.05 mg.
`0. t8 mg.
`To 1.0 ml.
`
`Exh. 1003
`
`

`
`US 7,947,725 B2
`
`3
`those that would ordinarily be expected. Thus, in one embodi-
`ment the invention provides a pharmaceutically stable solu-
`tion for preventing or reducing emesis comprising a) from
`about 0.01 mglmL to about 5 mglmL palonosetron or a phar-
`maceurically acceptable salt thereof; and b) a pharmaceuti-
`cally acccptab lc carrier.
`l l1e inventors have fi~rther discovered that by adjusting the
`formulation's p H and/or excipient concentrations it is pos-
`sible to increase the stability of palonosetron formulations.
`Therefore, in another embodiment, the invention provides a
`pharmaceutically stable solution for preventing or reducing
`emesis comprising a) palonosetron or a pharmaceutically
`acceptable salt thereof; and b) a phannaceutically acceptable
`carrier, at a pH from about 4.0 to about 6.0. In another
`embodiment the invention provides a pharmaceutically stable
`solution for preventing or reducing emesis comprising from
`about 0.01 to about 5.0 mg palonosetron or a pharmaceuti-
`cally acceptable salt thereof; from about 10 to about 100
`millimoles citrate buffer and from about 0.005 to about 1.0
`mglml ED'JA.
`l be inventors have further discovered that the addition of
`mamtitol and a chelating agent can increase the stability of
`palonosctron fonnulations. TI1crcforc,
`in still another
`embodiment the inventio n provides a pharmaceutically stable
`solution for preventing or reducing emesis comprising a)
`palonosetron or a pharmaceutically acceptable salt thereof
`and b) a pharmaceutically acceptable carrier, wherein the
`pharmaceutically acceptable carrier comprises a chelating
`agent and mannitol.
`
`DE1AILED DESCRlPTlON OF TilE INVENTION
`
`4
`Concentrations-When concentrations of palonosetron
`are given herein, the concentration is measured in tenns of the
`weight of the free base. Concentrations of all other ingredi-
`ents are g iven based on the weight of ingredient added to the
`5 solution.
`"Pharmaceutically acceptable" means that which is uscfc1l
`in preparing a pharmaceutical cot.nposition that is generally
`safe, non-toxic and neither bnologically nor otherwise unde-
`sirable and includes that which is acceptable for veterinary
`to use as well as htUJ1an pharmaceutical use.
`"Pbarmaceutically acceptable salts" means salt·s which are
`pham1aceutically acceptable, as defined above, and whlch
`possess the desired phannacological activity. Such salts
`t5 include acid addition salts formed with inorganic acids such
`as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
`acid, phosphoric acid, and the like; or with organic acids such
`as acetic acid, propioiuc acid, hexanoic acid, hcptanoic acid,
`cyclopeutanepropionic acid, glycolic acid, pymvic acid, lac-
`20 tic acid, malonic acid, succinic acid, malic acid, maleic acid,
`fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-
`hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
`methanesulfonic acid, etbane sulfonic acid, I ,2, el banedisul-
`fou.ic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic
`25 acid p-chlorobenr.enesulfonic acid, 2-naphthalenesulfonic
`acid, p-toluenesu11onic acid, camphorsulfonic acid, 4-meth-
`ylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic
`acid, 4,4' -methylenehis(:'-hydroxy-2-ene-1-carho"Xylicacid),
`3-phenylpropionic acid, trimethylacetic acid, ter:tiary buty-
`30 !acetic acid, Iaury! sulfuric acjd, glucortic 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
`35 with inorganic or organic bases. Acceptable inorganic bases
`include sodium hydroxide, sodium carbonate, potassium
`hydroxide, aluminum hydroxide and calcium hydroxide.
`Acceptable organic bases include ethanolamine, diethanola-
`mioe, triethanolamine, tromethanine, N-methyJglucamine
`40 and the like.
`Discussion
`The fact that palonosetron can be formulated in some
`insane at concentrations of only about Yio'" the amount of
`other previously known compounds for treating emesis, sur-
`prisingly allows the use of concentrations of palonosetron far
`below those that would ordinarily be expected. Tims, in one
`embodiment tbe invention provides a pharmaceutically stable
`solution for preventing or reducing emesis comprising a)
`from about 0.01 mglmL to about 5 mglmL palonoserron or a
`pharmaceutically acceptable salt thereof and b) a pharmaceu-
`tically acceptable carrier. Sim ilarly, in another embodiment
`the invention provides a met bod of formulating a pbannaceu-
`tically stable solution of palo nosetron comprising admixing
`from about 0.01 mglmL to about 5 mglmL palonosetron or a
`55 pharmaceutically acceptable salt thereof with a phamJaccu-
`tically acceptable carrier. ln altemative embodiments, the
`formulation includes palonosetron or a phannaceutically
`acceptable salt thereof in a concentration from about 0.02
`mglmL to about 1.0 mgllllL, from about0.03 mgimL to about
`60 0.2 mglmL, and most optimally about 0.05 mglml.
`A parricular advantage associated with the lower dosages
`of intravenous palonosetron is the ability to adll!lirtister the
`c.lrug in a sing,lt: intnwt:nous bolus ovt:r <1 short, dis~.;rt:te time
`period. This time period generally extends from about 10 to
`65 about GO seconds, or about I 0 to about 40 seconds, and most
`preferably is about 10 to 30 seconds. In one particular
`embodiment the palonosctron is supplied in vials that com-
`
`50
`
`Definitions
`"Vial" 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, pie filled
`syringes. Vial also means a sealed container of medication
`that is used one time only, and includes breakable and nco-
`breakable glass 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 (lypi-
`cally about 5 mls.).
`lbroughout tlus specification the word! "comprise," or
`variations such as "comprises" or "Comprising;• will be 45
`understood to imply the iuclusion of a stated clement, integer
`or step, or group of elements, integers or s.teps, but not the
`exclusion of any other e lement, integer or step, or group of
`elements, integers or steps
`"Palonosetron" means (3aS)-2,3,3a,4,5,6-Hexahydro-2-
`[(S)-1-Azabicyclo[2 .2.2]oct-3-yl)2,3,3a.4,5 ,6-hexahydro-1-
`oxo-J Hbeoz[ de ]isoquinoline, and is preferably present as the
`monobydrochloride. Pa lonosetron monobydrocbloride cao
`be I"epresentec.l by the following, ~:hemic<1l structure;
`
`•HCt
`
`Exh. 1003
`
`

`
`US 7,947,725 B2
`
`5
`prise 5 mi. of solution, which equates to about 025 mg of
`palonosetron at a concentration of about 0.05 mglml.
`The inventors have further discovered that by adjusting the
`formulation's pH and/or excipient concentrations it is pos-
`sible to increase the stability of palonosetron formulations. 5
`Therefore, in another embodiment the invention provides a
`pharmaceutically stable solution for preventing or reducing
`emesis comprising a) palonosetron or a pharmaceutically
`acceptable salt thereof and b) a pharmaceutically acceptable
`carrier. at a pll firm about 4.0 to about 6.0. Similarly, in 10
`another embodiment the invention provides a method of for-
`mulating a pharmaceutically stable solution of palonosetron
`comprising admixing a) palonose::tron or a pham1aceutically
`acceptable salt thereof; and b) a pham1aceut.ically acceptable
`catTier, at a pH from a bout 4.0 to about 6.0. In altemative 15
`embodiments, the pH is from about4.5 to about 5.5, and most
`optimally about 5.0. There are many examples to those of skill
`in tihe art of suitable solutions to adjust the pH of a formula-
`tion. Two exemplary solutions are sodium hydroxide and
`hydrochloric acid solution, either of which could be used to 20
`adjust the pl-1 of the formulation.
`In another embodiment the invention provides a pharma-
`ceutically stable solution for preventing or reducing emesis
`comprising from about 0 .01 to about 5.0 mgJmJ palonosetron
`or a phannaceutically acceptable salt thereof and (i) from 25
`about 10 to about 100 millimoles citrate bulfer, and/or (ii)
`frol!ll about 0.005 to about I .0 mglml EDlA. Similarly, in
`another embodiment the invention provide~ a method of for-
`mulating a pharmaceutically stable solution of palonosetroo
`comprising admixing from abom 0.01 to about 5.0 mglml 30
`palonosetroo or a pharmaceutically acceptable salt thereof
`and (i) from about 10 to about 100 millimoles citrate buiTer,
`and/or(ii) from about 0.005 to about l.Omg ED'IAThecitrate
`buffer can be in the forn1 of citric acid at1d/or a salt of citric
`acid such as trisoditun citrate. ln various embodiments, the 35
`rru1gcs of one or more of the foregoing ingredients can be
`modified as follows:
`'lbe formulation may comprise palonosetron or a pharma-
`ceutically acceptable saltthereofin a concentration from
`about 0.02 mglrnL to about I .0 mglmL, from about 0.03
`mglmL to about 0.2 mglmL palooosetron hydrochlo-
`ride;
`and most optimally about 0.05 mglmL.
`1l1e fommlation may comprise citrate buffer in a concen-
`tration of from about lO to about 40 millimoles, or 15-30
`millimoles.
`The fonnulation may comprise EDTA in a concentration of
`from about0.005 mglml to about 1.0 mglml, or about 0.3
`to about 0.7 mglml, and most optimally about 0.5
`mglml.
`l l1e inventors have further discovered tbat tbe addition of
`mam1itol and a chelating agent can increase the stability of
`paJonosetron fommlations. TI1erefore,
`in still another
`embodiment the invention provides a pharmaceutically stable
`solution for preventing or reducing emesis comprising a)
`p1llonosetron or 1l pharm1lceutically acceptable salt thereof
`and