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`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`
`US007947724B2
`
`(12) United States Patent
`Calderari et al.
`
`(JO) Patent No.:
`(45) Date of Patent:
`
`US 7,947,724 B2
`*May 24, 2011
`
`(54) LIQUID PHARMACEUTICAL
`FORMULATIONS OF PALONOSETRON
`
`(75)
`
`Inventors: G iorgio C alderari, Rancate (CH);
`Daniele Bonadeo, Varese (1T); Roberta
`C annella, Varese (IT); Enrico Braglia,
`Pazzallo (CH); Riccardo Braglia,
`Pazzallo (CH); Andrew M iksztal, Palo
`Alto, CA (US); Thomas 1.\'(alefyt,
`Carmel Valley, CA (US); Kathleen M.
`Lee, Palo Alto, CA (US)
`
`(73) Assignees: Helsinn Bealthcare S.A., L ugano (CH);
`Roche Palo Alto LLC , Palo Alto, CA
`(US)
`
`( *) Notice:
`
`Subject to any disclaimer, t he term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is subject to a terminal dis-
`claimer.
`
`(21) A ppl. No.: 11/186,311
`
`(22) Filed:
`
`.Jul. 21, 2005
`
`(65)
`
`Prior Publication Data
`
`US 2006/00691 14 A 1
`
`Mar. 30, 2006
`
`Related U.S. Application Data
`(63) Continuation
`of
`application
`P CT/EP2004/000888, filed on Jan. 30, 2004.
`(60) Provisional application No. 60/444,351 , filed on Jan.
`30, 2003.
`
`No.
`
`(51)
`
`Int. C J.
`AOJN 43152
`(2006.01)
`(52) U.S. C l. . ....................................................... 514/397
`(58) F ield of C lassification Search ................... 514/397
`See application file for complete search history.
`
`(56)
`
`References C ited
`
`U.S. PATENT DOCUMENTS
`.. ........ 514/397
`Coates et al.
`4,695,578 A
`9/1987
`4,753,789 A
`Tyers et aL . ...... ............. 424/10
`6/1988
`4,886,808 A
`12/1989
`King . ... .... . .. .. .... ........... 514/299
`4,906,755 A
`Gittos ............................ 546/94
`3/1990
`4,929,632 A
`Tyers et aL . ................. 514/397
`5/1990
`4,937,247 A
`King ................. ........... 514/299
`6/ 1990
`5,011,846 A
`Gittos et aL .................. 514/294
`411991
`5,034,398 A
`7/1991
`King . ... .... . .. .. .... ........... 514/299
`Berger et al. .. .... ........... 514/296
`5,202,333 A
`4/1993
`Tyers et aL ....... ........... 514/395
`5,140,954 A
`8/1993
`Blaseetal.
`5,272,.137 A
`12/1993
`9/1994
`5,344,658 A
`Collin .......................... 424/489
`Tyers et at
`................. 514/397
`5,578,628 A
`1111996
`Tyers et aL ....... ........... 514/397
`5,578,632 A
`11/1996
`
`wo
`WO
`WO wo
`
`4/1997 Collin ........................... 424/489
`5,622,720 A
`5,854,270 A *
`12/1998 Gambhir ....................... 514/397
`7/1999 Tyersetal .................... 514/397
`5,922,749 A
`9/1999 Wintcrbom ................... 5141399
`5,955,488 A
`5/2000 Winterbom ................... 514/397
`6,063,802 A
`6,284,749 Bl •
`912001 CastilloetaL ................ 514/159
`912001 Dickinson ..................... 424/450
`6,287,592 B1 •
`9/2001 James
`.............. 514/299
`6,294,548 Bl
`9/2001 James ........................... 514/299
`200110020029 AI
`5/2003 Dugger, III ..................... 424/43
`2003/0095926 AI
`FOREIGN PATENT DOCUMENTS
`WO 03/ 100091 A
`12/2003
`W0-2004/045615 AI *
`6/2004
`W0-2004073714 AI *
`6/2004
`2004067005
`8/2004
`OTHER PUBLICATIONS
`Chaitow, 1990, 3 pages.*
`Eglen, R M. et al., Pharmacological Characterization of RS 25259-
`197, a Novel and Selective 5-HT3 Receptor Antagonist, i.n vivo,
`extracted from BritishJoumal of Pharmacology, 1995, voL 114, No.
`4,pp.860-866
`Chelly, Jacques et al., Oral RS-25259 Prevents Postoperative !\au sea
`and Vomiting Following Lapa.roscopic Surgery, extracted fromAnes-
`thesiology, 1996, vol. 85, ~o. 3A, p. A21.
`Sorbe, Bengl, 5-HT3 Receptor Antagonists as Antiemetic Agents in
`Cancer Chemotherapy, extracted from Expert Opinion on Investiga-
`tional Drugs, !996, vol. 5. No. 4, pp. 389-407.
`Gasler, umunie M. and King, F..ank D., Serotonin 5-rlT3 and 5-HT 4
`Receptor Antagonists, extracted from Medicinal Research Reviews,
`1997, vol. 17, No.2, pp. 163-214.
`Tang, Jun et al., Efficacy ofRS-25259, a Novei 5-HT3 Antagonist, in
`the Prevention of Postoperative Nausea and Vomiting After Major
`Gynecologic Surgery, abstract extracted from Anesthesiology, !997,
`vol. 85, No.3, suppl. p. A329.
`Tang, Jun et al., The Efficacy ofRS-25259, a Long-Acting Selective
`5-HT3 Receptor Antagonisl, for Prevenling Postoperative 1auseaand
`Vomiting After Hysterectomy Procedures, exlracted from Anesthesia
`and Analgesia, 1998, vol. 87, pp. 462-467.
`Adis R&D Profile, Palonosetron RS 25259, RS 25259 197, extracted
`from Dmgs in R&D, Oct. 1999, vol. 2, o. 4, pp. 251-252.
`Piraccini, Gaia et at., An Interesting 5-HT3 Receptor Antagonist
`Antiemetic for Palienls Undergoing Chemo!'herapy-Rased Condi-
`tioning Regimens?, extracted from Blood, Nov. 16, 200 I , vol. 98, No.
`11, part 2, p. 350b, abslract No. 5169.
`
`(Continued)
`
`Primary Examiner - Brandon J Fetterolf
`Assistant Examiner - Shirley V Gembeh
`(7 4) Attorney, Agent, or Firm - Arnall Golden Gregory
`LLP; Clark G. Sullivan
`
`(57)
`ABSTRAC T
`The presem invention relates to shelf-stable liquid formula-
`tions of palonosctron for rcd\tcing chemotherapy and radio-
`therapy induced emesis w ith palonosetron. The formulations
`are particularly useful in the preparation of intravenous and
`ordl liy_uid m.:uicarnt:nts.
`
`14 C lairns, No Drawi.ngs
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1002
`
`Exh. 1002
`
`

`
`US 7,947,724 B2
`Page 2
`
`OTHER PUBLICATIONS
`Stacher. Georg, Palonosetron Helsim1. c.xtracted from Curre/11 Opin-
`ion in Investigational Dmgs, Oct. 2002, vol. 3. l'o. 10, pp. 1502-
`1507.
`'avari, Rudolph M., Pathogenesis-Based Treatment of Chemo-
`therapy-lnduced ausea and Vomiting- Two New Agents, extracted
`from Joumal ofSupponive Oncology, 2003, vol. 1(2), pp. 89-!03.
`Oppostion Brief filed by Dr. Reddy's Laboratories (UK) Limited,
`opposition to European Patent No. 1601359 81, Jul. 7, 2009.
`Photolytic and oxidat ivc degradation of an antiemetic agent, RG
`12915 ( Won C. M. Et at, International Journal o fPhannaceutics 121
`(1995)95-.105 ( 1995).
`Palonosclron: a phase II dose ranging study to assess over a 7 day
`period the s ingle dose phannacokinetic profile of palonosetron in
`patients receiving highly omctogenic chemotherapy. Piraccini G et
`al., Proc. Am. Soc. Clin. Oncol 2002 2 1 Abs 449 (2002).
`Formulation and administration techniques to minimize injection
`pain and tissue da.mage associated with parentera.l products. Larry A.
`Gatlin; Carol A Brister Gatlin, from Injectable Drug Development:
`Techniq ues to Reduce Pain and Irritation [Edited by Pramod K.
`Gupla, Gayle A. Bra.zeau; Published by lnfonna Hea.lth Care (origi·
`na.l copyright of 1999 by lnterphanna Press), !999; ISBN
`15749 10957, 978 1574910957)], p. 401-421.
`Parenteral Dosage Fonns. Joanne Broadhead. from Part 11- Early
`dn•g development, Phanmceutica.l prefonnulation and formulation:
`a practice guide from candidate dmg selection to commercial dosage
`fonu [Edited by Mark Gibson; Published by lnterphanna Press.
`2001; ISBN 1574911201, 9781574911206)]. p. 331-353.
`Opposirion Rrief filed hy Tccnimede Socierlade Tecnico-Medicinal
`S.A~ opposition to European Patent 'o. 1601359 Bl, Jul. 8. 2009.
`Response brief filed by llelsinn Health care S.A. dated Jul. 13, 2007,
`in response to the eommunicruion pursuant to Art. 96(2) EPC of Jan.
`3, 2007 regarding Serial 1 o. 04 706 657.6-2123.
`European Patent Office official communication dated Jul. 19, 2006
`regarding Serial No. 04 706 657.6.
`.
`Response oflielsinn Hca.lthcare S.A. dated Nov. 29, 2006 regardmg
`EJ>O otlicial communication dated Jul. 19, 2006.
`Lachman et at., The Theory and Practice of Indu stria.! Pharmacy,
`1986, third edition, pp. 652-784.
`Opposition Brief filed by Mattin Paul White, opposition to European
`Patent No. 160 1359 B 1, Jul. 8, 2009.
`
`Wongel al. (1995). in British Jouma.l ofPhannacology, vol. 114, pp.
`851-859 and Eglcn et 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
`of lndustrial Pharmacy, Third Edition, Lea and Febiger (1986).
`Cover page and pp. 514-5 15 of Modem Phannaceutics, Second Edi-
`tion. Marcel Dekker ( 1990).
`Cover page and pp. 142-143 of Phannaceutical Dosage Fonns:
`Parenteral Medications vol. I, Second Edition, Marcel Dekker
`( 1992).
`Mitsuo Matsumoto, et at., "Ya.kuzaigaku Manual", 1st edition,
`Nanzando Co., Lid. ( 1989) 2 pages.
`Michael J. Pika.l, "Frcc'lc Drying", Encyclopedia of Phannaceutical
`Technology, Third Edition, Jan . 2007, pp. 1824-1825, vol. 3, In forma
`Pharmaceuticals & Healthcarc.
`Daniele l3onadeo, "Supplemental Declaration of Daniele Bonadeo
`37 C.F.R. 1.132", U.S. Appl. No. 1.1/388,270, Jun. 8, 2009.
`Kranke e t at. 2007, "Recent advances, trends and economic consid·
`erations in ... " Expert Opinio n Pharmacorher., 8 (1 8): 3217-3235).
`Morrow ct at. J 995, Progress in reducing nausea and emesis. Com·
`pari sons of ondansetron, granisctron, and tropisetron. Cancer, vol. 76
`No.3 pp. 343-357.
`USPTO
`otice of Allowance and Fee Due, U.S. Appl. No.
`J J/388,270. filed Mnr. 24, 2006, Date Mailed Jan. 26, 2010.
`USPTO Office Action, U.S. Appl. No. 11/129.839, Date Mailed Jan.
`15,20 10.
`lsraili. Zafar H .. Clinical Phannacology of Serotonin Receptor
`Type-3 (5-HT3) Antagonists, Curr. Med. Chem.--Central :\fervous
`SystemA.gents,2001, I, 171-199.
`Barton (Citrate Buffer Calculation). 2000. 2 pages.
`USPTOOfficcA<:tion, U.S.Appl. o. 111201,035. Date Mailed Aug.
`19,2009.
`Response of llelsinn llealthca.re to opposition of EP Serial No. 04
`706 657.6 dated Feb. II , 20 10.
`Annc.x 1 (Statement of Waldo Mossi, Ph.D.) to ResponseofHelsinn
`llealthcare to opposition ofEP Serial No. 04 706 657.6 dated Feb. II ,
`2010.
`Annex 2 to Response of llelsinn Healthcare to opposition of EP
`Seria.l 'o. 04 706 657.6 dated Feb. II, 2010
`Annex 3 to Response of llelsinn Healthcare to opposition of EP
`Seria.l No. 04 706 657.6 dated Feb. II , 2010.
`* cited by examiner
`
`Exh. 1002
`
`

`
`US 7,947,724 B2
`
`1
`LIQUID PIIAR.I\1ACEUTICAL
`FORMULATIONS OF PALO~OSETRO~
`
`The present application is a continuation of PCTIEP04/
`000888, filed Jan. 30, 2004, which claims priority to U.S.
`Provisional Application60/444,351. filed Jan. 30,2003. The
`content of these applications is incorporated herein by refer-
`ence.
`
`BACKGROUND OF THE INVENTION
`
`2
`The fommlation has a pi I of3.7 and a shelf stability ofless
`than the 1-2 year time period required by health amhorities in
`various countries.
`Ondansctron, its uses, and medicaments made with
`5 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, 5,955,4KK, and 6,063,802. Commer-
`cially it js distributed by G laxoSmitbKJine as Zofran® and is
`indicated for prevention of postoperative nausea and vomit-
`to ing (PO NV), cancer chemotherapy-induced nausea and vom-
`iting (ClNV), and radiotherapy-induced nausea and vomiting
`(RJNV) and it is available as an injection, tablets and solution,
`and as Zofran ODT® (ondansetron) Orally Disintegrating
`Tablets.
`Granisetron, its uses, and medicaments made with granis-
`etron arc disclosed in U.S. Pat. Nos. 4,886,808, 4,937,247,
`5,034,398 and 6,294,548. Commercially it is distributed by
`Roche Laboratories lnc. as Kytril®, indicated for the preven-
`tion of nausea and vomiting associated with chemotherapy or
`20 radiation therapy, and is offered in tablet fom1, oral solution,
`and as an injection.
`Alosctron, 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 GlaxoS.mithK.line as
`25 Lotronex®.
`Tropisetron is commercially available as Navoban® (No-
`vartis) CAS-89565-68-4 (tropisetron); CAS-I 05826-92-4
`(tropisetron hydrochloride) and it is indicated for treatment of
`PONV and CJNV.
`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 Aventis Pharma-
`ceutical!' Inc. :~s An7.emet®, indicated for prevention of hoth
`PONY and CINV, and it is offered in the fonn of a tablet or an
`35 intravenous solurion.
`Therefore, there exists a need for a palonosetron formula-
`tion with increased stability and thereby increased shelf life.
`There also exists a need for an appropriate range of concen-
`trations for both the 5-HT 3 receptor antagonist and its phar-
`40 maccutically acceptable carriers that would facilitate making
`a formulation with this increased stability.
`lt is an object of the present invention to provide a formu-
`lation ofPalonosetron hydrochloride with increased phanna-
`ceutical stability for preve11ting and/or reducing emesis.
`It is another object of the invention to provide an acceptable
`range of concentrations which will stabilize a formulation
`containing Palonosctron hydrochloride.
`It is a further objt.'Ct of the invention to provide a formula-
`tion ofPalonosctron which would allow for prolonged stor-
`50 age.
`It is also an object of the invention to provide a fom1ulation
`ofPalonosetron which would allow terminal sterilization.
`
`15
`
`"llie present invention relates to shelf-life stable liquid for-
`mulations of palonosetron that are especially useful in the
`preparation of injectable and oral medicaments.
`Emesis is a devastating consequence of cytotoxic therapy,
`radiutht:n1py, and pust-up~::rative envirunments that drasti-
`cally alfects the quality of life of people undergoing such
`treatments. In r~.--cent ye<Jrs <1 cl<JSS of drugs referred to as
`5-HT3 (5-hydroxytryptamine) receptor antagonists has been
`developed that treat such emesis by antagonizing cerebral
`functions associated with the 5-HT 3 receptor. See Drugs Act-
`ing on 5-Hydroxytryptamine Receptors: Tbe Lancet Sep. 23,
`1989 and references cited therein. Drugs within this class
`include ondansctron, granisetron, alosetron, tropisetron, and
`dolasctron. These 5-IIT3 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
`often supplied as tablets or oral elixirs to either supplement an 30
`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
`administcredonlyonce, it would bedesirableto administer an
`emesis-inhibiting dn1g such as a 5-HT3 antagonist every day
`until the risk of emesis has substantially subsided. The
`present class of 5-JIT 3 antagonists has not proven especially
`hclpliJn meeting this need, however, because tlhe 5-BT3 recep-
`tor antagonists currently marketed have proven to be less
`effective in controlling delayed nausea and vomiting than
`they are at controlling acute emesis. Sabra, K, Choice of a
`5HT3 Receptor Antagonist for the HospiLal Formulary. EHP,
`October 1996;2 (suppiJ):SJ9-24.
`Recently, clinical investigations have been made concem-
`ing palonosetron, a new 5-JIT, receptor antagonist reported in
`U.S. Pat. No. 5.202,333. These investigations have shown
`that the dntg 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
`nausea induced by chemotherapeutic agents. However, for-
`mulating palonosetron in liquid formulations has not proven
`an easy task, typically due to shelf-stability issues. U.S. Pat.
`No. 5,202,333 discloses an intravenous formulation of pal- 55
`onosctron in example 13 that contains the following ingredi-
`cots:
`
`45
`
`!Jtgrediem
`
`PnJonosctron I!CI
`Dextrose Monohydrlllc
`Citric Acid Monohydrate
`Sodiwn Hydroxide
`WFJ
`
`Mg
`
`10-100 mg.
`q.s. to male Isotonic
`1.05 mg.
`0.18 mg.
`To 1.0 mi.
`
`SUMMARY OF THE INVENTION
`
`The inventors have made a series of discoveries that sup-
`port a surprisingly effective and versati Je formulation for the
`treatment and prevention of emesis using palonosetron.
`These formulations are shelf stable for periods greater than 24
`60 months at room temperature, and thus cao be stored without
`refrigeration, and manufactltred using non-aseptic, terminal
`sterilization processes.
`ln one aspect, the inventors have discovered that formula-
`tions which include the active ingredient palonosetron require
`65 in some instances only 1/lo'" the amount of other previously
`known compounds for treating emesis, which surprisingly
`allows the usc of concentrations of palonosetron far below
`
`Exh. 1002
`
`

`
`US 7,947,724 B2
`
`5
`
`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-
`maceutically acceptable salt thereof; and b) a pharmaceuti-
`cally acceptable carrier.
`111e 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.
`Therefore, in another embodiment, the invention provides a 10
`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 pH from about 4.0 to about 6.0. In another 15
`embodiment the invention provides a pharmaceutically stable
`solution for preventing or reducing emesis comprising from
`about 0.01 to about 5.0 mglml palouosetron or a phamlaceu-
`tically acceptable salt thereof; from about 10 to about 100
`millimoles citrate buffer; and from about 0.005 to about 1.0 20
`mglml EDTA.
`The inventors have further discovered that the addition of
`mannitol and a chelating agent can increase the stability of
`palonosetron formulations. Therefore,
`in still 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 phannaceuticalny acceptable carrier, wherein the
`pharmaceutically acceptable carrier comprises a chelating
`agent and mannitol.
`
`4
`Concentrations- When concentrations of palonosetron
`are given herein, tbe<.;on<.;entmtiun i~ mea~ured in term~uftbe
`weight o f the free base. Concentrations of all other ingredi-
`ents are given based on the weight of ingrediei:ilt added to the
`solution.
`"Pharmaceutically acceptable" means that which is useful
`in preparing a pharmaceutkal composition that is generally
`safe, non-toxic and neither biologically nor otherwise unde-
`sirable and includes that which is acceptable for veterinary
`use as well as human pharmaceutical use.
`"Pharmaceutically acceptable salts" means salts which are
`pbannaceutically acceptable, as defined above, and which
`possess the desired pharmacological activity. Such salts
`include acid addition salts fonned with inorganic acids such
`as hydrocl1loric acid, hydrobromic acid, sul.fi.•ric acid, tlit·ric
`acid, phosphoric acid, and tbe like; or with organic acids such
`as acetic acid, propionic acid, hexanoic acid, heptanoic acid,
`cyclopeutanepropionic acid, glycolic acid, pyruvic 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, citU1amic acid, mandelic acid,
`methanesulfonic acid, ethanesulfo•1ic acid, 1 ,2,-ethanedisul-
`fonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic
`acid p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic
`25 acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-meth-
`ylbicyclo[2.2.2]oct-2-ene-l -carboxylic acid, glucoheptonic
`acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),
`3-phenylpropiouic acid, trimethylacetic acid, tertiary buty-
`lacetic acid, Iaury! su!Jhric acid, gluconic acid, glutamic acid,
`30 hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
`acid, and the like.
`Jn addition, pbannaceutically 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, sodimn carbonate, potassium
`hydroxide, aluminum hydroxide and calcium hydroxide.
`Acceptable organic bases include ethanolamine, diethanola-
`mine, triethanolamine, tromethamine, N-methylglucamine
`and the like.
`Discussion
`The fact that palonosetron can be fommlated in some
`instances at concentrations of only about 1/w'" the amount of
`other previously known compounds for treating emesis, sur-
`prisingly allows the use of concentrations of pa lonosetron far
`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 about 5 mglmL palonosetron or a
`pharmaceutically acceptable salt thereof; and b) a pharma-
`ceutically acceptable carrier. Similarly, in another embodi-
`ment the invention provides a method offormulating a phar-
`maceutically stable solution of palonosetron comprising
`admixing from about 0.01 mglmL to about 5 mglmL pal-
`onosetron or a phannaceutically acceptable salt thereof; with
`a pharmaceutically acceptable carrier. In alternative embodi-
`ments, t11e formulation includes palonosetron or a phanna-
`ceutically acceptable salt thereof in a concentration from
`about 0.02 mglmL to abot1t 1.0 mglmL, from about 0.03
`mglmL to about 0.2 mglmL, and most optimally about 0.05
`mglrnl.
`A particular advantage associated with the lower dosages
`of intravenous palonosetron is the ability to administer the
`dmg in a single intravenous bolus over a short, discrete time
`period. This time period generally extends from about 10 to
`65 about 60 seconds, or about 10 to about 40 seco·nds, and most
`preferably is about 10 to 30 seconds. In one particular
`embodiment the palonosetron is supplied in vials that com-
`
`DETAJLED DESCRJPTJON OF THE JNVENTJON
`
`Definitions
`''Vial" means a small glass container sealed with the most 35
`suitable stopper and seal, other suitable primary containers
`may be used, for instance, but not limited to, pre-filled
`syringes. Vial also means a sealed container of medication
`that is used one time only, and includes bre<lkable and non-
`breakable glass vials, breakable plastic vials, miniature 40
`screw-top jars, and any other type of container of a size
`capable of holding only one unit dose of palonosetron (typi-
`cally about 5 mls.).
`TI1roughout this specification the word "comprise," or
`variations such as "comprises" or "comprising," will be 45
`understood to imply the inclusion of a stated element, integer
`or step, or group of elements, integers or steps, hut not the
`exclusion of any other element, integer or step, or group of
`elements, integers or steps
`"Pal.onosetron" means (3aS)-2,3,3a,4,5,6-Hexahydro-2- 50
`[(S)-l-Azabicyclo[2 .2.2]oct-3-yl]2,3,3a,4,5,6-bexabydro-l-
`oxo-l Hbenz[de]isoquinoline, and is preferably present as the
`monobydrocllloride. Palonosetron monohydrochJoride can
`be represented by the following chemical structure:
`
`55
`
`60
`
`0
`
`• HCI
`
`N'"f5J
`
`H
`
`Exh. 1002
`
`

`
`US 7,947,724 B2
`
`6
`5
`to about 0.7 mglml, or most optimally about 0.5 mgfml. ln
`prise 5 mi. of solution, which equates to about 0.25 mg of
`various embodiments the maJmitol is presem in a concentra-
`palunosetron at a cmu;t:nlratiun of about 0.05 mg/ml.
`tion of from about 10.0 mglml to about 80.0 mglml, from
`11Je inventors have further discovered that by adjusting the
`formulation's pH and/or excipient concentrations it is pos-
`about20.0 mglmL to about60.0 mglml, or from about 40.0 to
`sible to increase the stability of palonosetron formulations. 5 about 45.0 mglml.
`Therefore, in another embodiment, the invention provides a
`Injectable formulations are typically formulated as aque-
`pharmaceutically stable solution for preventing or reducing
`ous solutions in which water is the primary excipient. Oral
`emesis comprising a) palonosetron or a phannaceutically
`formulations will differ from injectable formulations gener-
`acceptable salt thereof; an.d b) a phannaceutically acceptable
`ally by the additional presence of flavoring agents, coloring
`carrier, at a pH from about 4.0 to about 6.0. Similarly, in 10 agents, or viscosity agents. Namral or synthetic sweeteners
`another embodiment the invention provides a method of for-
`include, among others, mannitol, sorbitol, saccharose, sac-
`mulating a pharmaceutically stable solution of palonosetron
`charine, aspartame, acelsulphame K, or cydamate. These
`comprising admixing a) palonosetron or a pbannaceutically
`agents are generally present in concentrations in excess of
`acceptable salt thereof; and b) a phannaceutically acceptable
`carrier, at a pH from about 4.0 to about 6.0. ln alternative 15 I 00 mglml or 250 mglml when used as sweetening agents, in
`embodiments, the pH is from about 4.5 to abm1t 5.5, and most
`contrast to the 41.5 mglml concentration of mannitol
`optimally about 5.0. There are many examples to those of skill
`described in some of the embodiments of the invention, in
`in the art of suitable solutions to adjust the pH of a formula-
`which mam1itol is acting simply as a tonicifying agent.
`tion. Two exemplary solutions are sodium hydroxide and
`TI1e fonnulations of the present invention are particularly
`hydrochloric acid solution, either of which could be used to 20 suited for use in injectable and oral liquid formulations, but it
`adjust the pH of the fonnulation.
`will be lmderstood that the solutions may have altemative
`In another embodiment the invention provides a pham1a-
`uses. For example, they may be used as intermediates in the
`cemically stable solution for preventing or reducing emesis
`preparation of other phannaceutical dosage forms. Similarly,
`comprising from about 0.0 I to about 5.0 mglml palonosetron
`they may have other routes of administration including intra-
`or a pharmaceutically acceptable salt thereof and (i) from 25 nasal or inhalation. Il~ectable fonnulations may take any
`about 10 to about 100 millimoles citrate buffer, and/or (ii)
`route including intramuscular, intravenous or subcutaneous.
`from about 0.005 to about 1.0 mglml EDTA. Similarly, in
`Still further embodiments relate to improvements in the
`another embodiment the invention provides a method of for-
`ease with which the palonosetron formulation can be stored
`mulating a pharmaceutically stable solution of palonosetron
`or manufactured. In particular, the inventors have discovered
`comprising admixing from about 0.01 to about 5.0 mglml 30 that the formulations of the present invention allow storage of
`palonosetron or a pharmaceutically acceptable salt thereof
`the product for extended periods at room temperantre. Thus,
`and (i) from about 10 to about 100 millimoles citrate buffer,
`i1J yet another embodiment t.be invention provides a method of
`and/or (ii) from about 0.005 to about 1.0 mg/ml EDTA. The
`citrate buffer can be in the foml of citric acid and/or a salt of
`storing one or more containers in which are contained a
`citric acid such as trisoditun citrate. In various embodiments, 35 solution of palonosetron or a pharmaceutically acceptable
`the ranges of one or more of the foregoing ingredients can be
`salt thereof comprising: a) providing a room comprising said
`modified as follows:
`one or more containers; b) adjusti11g or maintaining the tem-
`11Je formulation may comprise palonosetron or a phamJa-
`perature of the room at greater than about ten, 15, or 20
`ceutically acceptable salt thereof in a concentration from
`degrees celcius; and c) storing said containers in said room for
`about 0.02 mglmL to about 1.0 mglmL, from about 0.03 40 one month, 3 months, 6 months, one year, 1 8 months, 24
`mg/mL to about 0.2 mglmL palonosetron hydrochlo-
`months or more (but preferably not exceeding 36 months),
`ride, and most optimally about 0.05 mglml.
`wherein (i) the palonosetron or pharmaceutical salt thereof is
`1l1e formulation may comprise citrate buffer in a concen-
`present in a concentration o:ffrom about 0.0.1 mg/mL to about
`tration offrom about 10 to about 40 millimoles, or 15-30
`5.0 mgfmL, (ii) the pH of the solution is from about 4.0 to
`millimoles.
`45 about 6.0, (iii) the solution comprises from about 0.01 to
`The formulation may comprise EDTA in a concentration of
`about 5.0 mglml palonosetron or a pharmaceutically accept-
`from about 0.005 mglml to about 1.0 mglml, or about 0.3
`able salt thereof, from about I 0 to about 100 millimoles
`to about 0.7 mglml, and most optimally about 0.5
`citrate buffer and from about 0.005 to about 1.0 mglml EDTA,
`mglml.
`(iv) the solution comprises a chelating agent, or (v) the solu-
`llle inventors have further discovered that the addition of 50 tion comprises from about 10 to about I 00 milliMoles of a
`mannitol and a chelating agent can increase the stability of
`citrate buffer.
`palonosetron formulatioillS. Therefore, in still another
`The stability of the foregoing formulations also lends itself
`embodiment the invention provides a pharmaceutically stable
`well to terminal sterilization processes in the manufacturing
`solution for preventing or reducing emesis comprising a)
`process. TI1erefore, in still another embodiment the invention
`palonosetron or a pharmaceutically acceptable salt thereof 55 provides a method of filling a container in which is contained
`and b) a phanuaceuticalny acceptable carrier, wherein t:he
`a solution of palouoset:ron or a pharmaceutically acceptable
`pharmaceutically acceptable carrier comprises a chelating
`salt thereof comprising: a) providing one or more sterile open
`agent and mannitol. Similarly, in another embodiment the
`containers (preferably 5 ml. vials); b) filling said containers
`invention provides a method of fonuulating a pham1aceuti-
`with a solution ofpalonosetron in a non-aseptic enviromnent;
`cally stable solution ofpalonosetron comprising admixing a) 60 c) sealing said filled containers; and d) sterilizing said sealed,
`filled containers, wherein (i) the palonosetron or pharmaceu-
`palonosetron or a pharmaceutically acceptable salt thereof
`and b) a pharmaceuticalEy acceptable carrier, wherein the
`tical salt thereof is present in a concentration of from about
`0.01 mglmL to about 5 mglmL, (ii) the pH of the solution is
`pharmaceutically acceptable carrier comprises a chelating
`agent and mannitol. The chelating agent is preferably EDTA,
`from about 4.0 to about 6.0, (iii) the solution comprises from
`and, i11 various embodiments the chelating agent is present in 65 about 0.0 I to about 5.0 mglml palonosetron or a pharmaceu-
`a concentration of from about 0.005 to about 1.0 mglmL or
`l'ically acceptable salt thereof, from about 10 to about 100
`from about 0.05mglmL to about 1.0 mglmL or from about0.3
`millimoles citrate buffer and from about 0.005 to about 1.0
`
`Exh. 1002
`
`

`
`7
`mg/ml EDTA, (iv) the solution comprises a chelal'ing agent,
`or (v) tht: ~olution com prist:~ from about 10 to about 100
`milliMoles of a citrate buffer.
`
`US 7,947,724 B2
`
`8
`Example 5
`
`Fonnulation 11
`
`EXAMPLES
`
`Example I
`
`Stabilizing pH
`
`5
`
`The following is a repres·entative phannaceutical formula-
`tion containing palonosetron that is useful for oral formula-
`tions, or other liquid formulations of the drug.
`
`10
`
`A sntdy was conducted to determine the effect of pH on
`formulations containing palonosetron hydrochloride, mea-
`suring the stability at 80° C. at pH 2.0, 5.0, 7.4, and 1 0.0. The
`results indicated that palonosetron hydrochloride is most 15
`stable at pH 5.0.
`
`Example 2
`
`Ingredient
`
`Palonosetron Hydrochloride
`Mannitol
`EDTA
`Trisodium cit:rste
`Citric acid
`WFJ
`Sodiwn hydroxide solution and/or
`hydrochJoric acid solution
`Flavoring
`
`mglmL
`o.o5•
`150
`0.5
`3.7
`.1.56
`q.s. to JmJ
`pA 5.0 "' 0.5
`
`q.s.
`
`Stabilizing Concentration Ranges
`
`20
`
`•ca lculated as a free ba;;e
`
`A fonnulation optimization study was perfonned using an
`experimental design software. Twenty-four lots of dmg prod-
`uct were analyzed to investigate the appropriate concentra-
`tion ranges for palonosetron hydrochloride (0.05 mg/mL to 25
`5.0 mg/mL), citrate buffer (0 to 80 mM) and EDTA (0 to
`0.10%). The level ofEDTA and citrate buffer were selected
`based o n the optimal formulation, which was shown to be
`formulated with EDTA 0.05% and 20 mM citrate buffer at pH
`5.0. The results of this s tudy indicated that palonosetron 30
`concentration was also a critical factor i