USOO7947724B2
`
`(12) United States Patent
`Calderari et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,947,724 B2
`*May 24, 2011
`
`(54) LIQUID PHARMACEUTICAL
`FORMULATIONS 0F PALONOSETRON
`
`.
`.
`.
`_
`(75) Inventors: Giorgio Calderarl, Rancate (CH),
`Danlele Bonad99,VareSe (1T); Roberta
`C annella, Varese (IT); Enrico Braglia,
`PaZZa11°(CH);Ri““d° Brag‘ia’
`Pazzallo (CH); Andrew Miksztal, Palo
`Alto, CA (Us); Thomas Malefyt’
`Carmel Valley, CA (US); Kathleen M.
`Lee, P2110 Alto, CA (US)
`
`(73) Assignees: Helsinn Healthcare S.A., Lugano (CH);
`Roche 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. 154(b) by 0 days.
`This patent is subject to a terminal dis
`claimer.
`
`(21)
`(22)
`(65)
`
`(63)
`
`(60)
`
`(51)
`
`(52)
`(58)
`
`(56)
`
`Appl. No.: 11/186,311
`
`Filed:
`
`Jul. 21, 2005
`
`Prior Publication Data
`
`US 2006/0069114 A1
`
`Mar. 30, 2006
`
`Related US. Application Data
`Continuation
`of
`application
`PCT/EP2004/000888, ?led on Jan. 30, 2004.
`Provisional application No. 60/444,351, ?led on Jan.
`30, 2003.
`
`No.
`
`Int. Cl.
`(2006.01)
`A01N 43/52
`US. Cl. ..................................................... .. 514/397
`
`Field of Classi?cation Search ................. .. 514/397
`See application ?le for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`9/1987 Coates et al. ............... .. 514/397
`4,695,578 A
`6/1988 Tyers et al. ..
`424/10
`4,753,789 A
`4,886,808 A 12/1989 King ...... ..
`514/299
`4,906,755 A
`3/1990 Gittos .... ..
`.. 546/94
`4,929,632 A
`5/1990 Tyers et al.
`514/397
`4,937,247 A
`6/1990 King .......... ..
`514/299
`5,011,846 A
`4/1991 Gittos et al.
`514/294
`5,034,398 A
`7/1991 King .......... ..
`514/299
`5,202,333 A
`4/1993 Berger et a1. ............... .. 514/296
`5,240,954 A
`8/1993 Tyers et al. ................. .. 514/395
`5,272,137 A 12/1993 Blase et a1.
`5,344,658 A
`9/1994 Collin ......................... .. 424/489
`5,578,628 A 11/1996 Tyers et al. ..
`514/397
`5,578,632 A 11/1996 Tyers et al. ................. .. 514/397
`
`4/1997 Collin ......................... .. 424/489
`5,622,720 A
`5,854,270 A * 12/1998 Gambhir
`.. 514/397
`5,922,749 A
`7/1999 Tyers et al.
`.. 514/397
`5,955,488 A
`9/1999 Winterborn
`.. 514/399
`6,063,802 A
`50000 Winterbom
`N 514697
`6,284,749 B1* 9/2001 Castillo etal.
`.. 514/159
`6,287,592 B1 *
`9/2001 Dickinson ..
`.. 424/450
`2003520936333 ii
`35881 lam“
`" iii/533
`ames
`"
`2003/0095926 A1
`5/2003 Dugger, III ................... .. 424/43
`FOREIGN PATENT DOCUMENTS
`W0 03/100091 A 12/2003
`W0
`WO WO-2004/045615 Al * 6/2004
`W0 WO-2004073714 A1 * 6/2004
`WO
`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, 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
`andVomiting Following Laparoscopic Surgery, extracted fromAnes
`thesiology, 1996, vol. 85, No. 3A, p. A21.
`Sorbe, Bengt, 5-HT3 Receptor Antagonists as Antiemetic Agents in
`Cancer Chemotherapy, extracted from Expert Opinion on Investiga
`tional Drugs, 1996, vol. 5, No. 4, pp. 389-407.
`Gaster, Laramie M. and King, Frank D., Serotonin 5-HT3 and 5-HT4
`Receptor Antagonists, extracted from Medicinal Research Reviews,
`1997, vol. 17, No. 2, pp. 163-214.
`Tang, Jun et al., Ef?cacy ofRS-25259, a Novel 5-HT3 Antagonist, in
`the Prevention of Postoperative Nausea and Vomiting After Major
`Gynecologic Surgery, abstract extracted from Anesthesiology, 1997,
`vol. 85, No. 3, suppl. p. A329.
`Tang, Jun et al., The Ef?cacy ofRS-25259, a Long-Acting Selective
`5 -HT3 Receptor Antagonist, for Preventing Postoperative Nausea and
`Vomiting After Hysterectomy Procedures, extracted fromAnesthesia
`andAnalgesia, 1998, vol. 87, pp. 462-467.
`Adis R&D Pro?le, Palonosetron RS 25259, RS 25259 197, extracted
`from Drugs in R&D, Oct. 1999, vol. 2, No. 4, pp. 251-252.
`Piraccini, Gaia et al., An Interesting 5-HT3 Receptor Antagonist
`Antiemetic for Patients Undergoing Chemotherapy-Based Condi
`tioning Regimens?, extracted from Blood, Nov. 16, 2001, vol. 98, No.
`11, part 2, p. 350b, abstract No. 5169.
`(Continued)
`
`Primary Examiner * Brandon J Fetterolf
`Assistant Examiner * Shirley V Gembeh
`(74) Attorney, Agent, or Firm * Amall Golden Gregory
`LLP; Clark G. Sullivan
`
`ABSTRACT
`(57)
`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 particularly useful in the preparation of intravenous and
`oral liquid medicaments.
`
`14 Claims, N0 Drawings
`
`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1010
`
`Exh. 1010
`
`

`
`US 7,947,724 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Stacher, Georg, Palonosetron Helsinn, extracted from Current Opin
`ion in Investigational Drugs, Oct. 2002, vol. 3, No. 10, pp. 1502
`1507.
`Navari, Rudolph M., Pathogenesis-Based Treatment of Chemo
`therapy-Induced Nausea and VomitingiTwo New Agents, extracted
`from Journal of Supportive Oncology, 2003, vol. 1(2), pp. 89-103.
`Oppostion Brief ?led by Dr. Reddy’s Laboratories (UK) Limited,
`opposition to European Patent No. 1601359 B1, Jul. 7, 2009.
`Photolytic and oxidative degradation of an antiemetic agent, RG
`12915 (Won C. M. Et al, International Journal of Pharmaceutics 121
`(1995) 95-105 (1995).
`Palonosetron: a phase II dose ranging study to assess over a 7 day
`period the single dose pharmacokinetic pro?le of palonosetron in
`patients receiving highly emetogenic chemotherapy. Piraccini G et
`al., Proc. Am. Soc. Clin. Onc012002 21 Abs 449 (2002).
`Formulation and administration techniques to minimize injection
`pain and tissue damage associated With parenteral products. LarryA.
`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 Informa Health Care (origi
`nal copyright of 1999 by Interpharma Press), 1999; ISBN
`1574910957, 9781574910957)], p. 401-421.
`Parenteral Dosage Forms. Joanne Broadhead. from Part lliEarly
`drug development, Pharmaceutical preformulation and formulation:
`a practice guide from candidate drug selection to commercial dosage
`form [Edited by Mark Gibson; Published by Interpharma Press,
`2001; ISBN 1574911201, 9781574911206)], p. 331-353.
`Opposition Brief ?led by Tecnimede Sociedade Tecnico-Medicinal
`S.A., opposition to European Patent No. 1601359 B1, Jul. 8, 2009.
`Response brief ?led by Helsinn Healthcare S.A. dated Jul. 13, 2007,
`in response to the communication pursuant to Art. 96(2) EPC of Jan.
`3, 2007 regarding Serial No. 04 706 657.6-2123.
`European Patent Of?ce of?cial communication dated Jul. 19, 2006
`regarding Serial No. 04 706 657.6.
`Response of Helsinn Healthcare S.A. dated Nov. 29, 2006 regarding
`EPO of?cial communication dated Jul. 19, 2006.
`Lachman et al., The Theory and Practice of Industrial Pharmacy,
`1986, third edition, pp. 652-784.
`Opposition Brief ?led by Martin Paul White, opposition to European
`Patent No. 1601359 B1, Jul. 8,2009.
`
`Wong et al. (1995), in British Journal ofPharmacology, vol. 114, pp.
`851-859 and Eglen et al. (1995), in British Journal ofPharmacology,
`vol. 114, pp. 860-866.
`Cover page and pp. 642-644 and 783-784 of The Theory and Practice
`of Industrial Pharmacy, Third Edition, Lea and Febiger (1986).
`Cover page and pp. 514-515 of Modern Pharmaceutics, Second Edi
`tion, Marcel Dekker (1990).
`Cover page and pp. 142-143 of Pharmaceutical Dosage Forms:
`Parenteral Medications vol. 1, Second Edition, Marcel Dekker
`(1992).
`Mitsuo Matsumoto, et al., “Yakuzaigaku Manual”, 1st edition,
`Nanzando Co., Ltd. (1989) 2 pages.
`Michael J. Pikal, “Freeze Drying”, Encyclopedia of Pharmaceutical
`Technology, Third Edition, Jan. 2007, pp. 1 824- 1825, vol. 3, Informa
`Pharmaceuticals & Healthcare.
`Daniele Bonadeo, “Supplemental Declaration of Daniele Bonadeo
`37 C.F.R. 1.132”, U.S. Appl. No. 11/388,270, Jun. 8, 2009.
`Kranke et al. 2007, “Recent advances, trends and economic consid
`erations in .
`.
`. ” Expert Opinion Pharmacother., 8 (18): 3217-3235).
`Morrow et al. 1995, Progress in reducing nausea and emesis. Com
`parisons of ondansetron, granisetron, and tropisetron. Cancer, vol. 76
`No.3 pp. 343-357.
`USPTO Notice of Allowance and Fee Due, U.S. Appl. No.
`11/388,270, ?led Mar. 24, 2006, Date Mailed Jan. 26,2010.
`USPTO Of?ce Action, U.S. Appl. No. 11/129,839, Date Mailed Jan.
`1 5, 20 10.
`Israili, Zafar H., Clinical Pharmacology of Serotonin Receptor
`Type-3 (5-HT3) Antagonists, Curr. Med. Chem.4Central Nervous
`System Agents, 2001, 1, 171-199.
`Barton (Citrate Buffer Calculation), 2000, 2 pages.
`USPTO Of?ce Action, U.S. Appl. No. 11/201,035, Date Mailed Aug.
`19, 2009.
`Response of Helsinn Healthcare to opposition of EP Serial No. 04
`706 657.6 dated Feb. 11, 2010.
`Annex 1 (Statement of Waldo Mossi, Ph.D.) to Response of Helsinn
`Healthcare to opposition ofEP Serial No. 04 706 657.6 dated Feb. 11,
`2010.
`Annex 2 to Response of Helsinn Healthcare to opposition of EP
`Serial No. 04 706 657.6 dated Feb. 11,2010.
`Annex 3 to Response of Helsinn Healthcare to opposition of EP
`Serial No. 04 706 657.6 dated Feb. 11,2010.
`
`* cited by examiner
`
`Exh. 1010
`
`

`
`US 7,947,724 B2
`
`1
`LIQUID PHARMACEUTICAL
`FORMULATIONS OF PALONOSETRON
`
`The present application is a continuation of PCT/EP04/
`000888, ?led Jan. 30, 2004, which claims priority to US.
`Provisional Application 60/444,351, ?led Jan. 30, 2003. The
`content of these applications is incorporated herein by refer
`ence.
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to shelf-life stable liquid for
`mulations of palonosetron that are especially useful in the
`preparation of inj ectable and oral medicaments.
`Emesis is a devastating consequence of cytotoxic therapy,
`radiotherapy, and post-operative environments that drasti
`cally affects the quality of life of people undergoing such
`treatments. In recent years a class 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-HT3 receptor. See DrugsAcZ
`ing on 5-Hydroxylryplamine Receptors: The Lancet Sep. 23,
`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
`cycle of chemotherapy or radiotherapy. In addition, they are
`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 an
`emesis-inhibiting drug such as a 5-HT3 antagonist every day
`until the risk of emesis has substantially subsided. The
`present class of 5-HT3 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 acute emesis. Sabra, K, Choice of a
`5H T 3 ReceptorAnZagonisZ for the Hospital Formulary. EHP,
`October 1996;2 (suppl 1): S 1 9-24.
`Recently, clinical investigations have been made concem
`ing palonosetron, a new 5-HT3 receptor antagonist reported in
`US. 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
`nausea induced by chemotherapeutic agents. However, for
`mulating palonosetron in liquid formulations has not proven
`an easy task, typically due to shelf-stability issues. US. Pat.
`No. 5,202,333 discloses an intravenous formulation of pal
`onosetron in example 13 that contains the following ingredi
`ents:
`
`Ingredient
`
`Palonosetron HCI
`Dextrose Monohydrate
`Citric Acid Monohydrate
`Sodium Hydroxide
`WFJ
`
`Mg
`
`10— 100 mg.
`q.s. to make Isotonic
`1.05 mg.
`0.18 mg.
`To 1.0 ml.
`
`2
`The formulation has a pH of 3.7 and a shelf stability of less
`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 US. 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. Commer
`cially it is distributed by GlaxoSmithKline as Zofran® and is
`indicated for prevention of postoperative nausea and vomit
`ing (PONV), cancer chemotherapy-induced nausea and vom
`iting (CINV), and radiotherapy-induced nausea and vomiting
`(RINV) 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 are disclosed in US. Pat. Nos. 4,886,808, 4,937,247,
`5,034,398 and 6,294,548. Commercially 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 form, oral solution,
`and as an injection.
`Alosetron, its uses, and medicaments made with alosetron
`are disclosed in US. Pat. Nos. 5,360,800 and 6,284,770.
`Commercially it is distributed by GlaxoSmithKline as
`Lotronex®.
`Tropisetron is commercially available as Navoban® (No
`vartis) CAS-89565-68-4 (tropisetron); CAS-105826-92-4
`(tropisetron hydrochloride) and it is indicated for treatment of
`PONV and CINV.
`Dolasetron, its uses, and medicaments made with
`ondansetron are disclosed in US. Pat. Nos. 5,011,846, and
`4,906,755. Commercially it is distributed by Aventis Pharma
`ceuticals Inc. as Anzemet®, indicated for prevention of both
`PONV and CINV, and it is offered in the form of a tablet or an
`intravenous solution.
`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-HT3 receptor antagonist and its phar
`maceutically acceptable carriers that would facilitate making
`a formulation with this increased stability.
`It is an object of the present invention to provide a formu
`lation of Palono setron hydrochloride with increased pharma
`ceutical stability for preventing and/or reducing emesis.
`It is another object of the invention to provide an acceptable
`range of concentrations which will stabilize a formulation
`containing Palono setron hydrochloride.
`It is a further object of the invention to provide a formula
`tion of Palonosetron which would allow for prolonged stor
`age.
`It is also an object of the invention to provide a formulation
`of Palonosetron which would allow terminal sterilization.
`
`SUMMARY OF THE INVENTION
`
`The inventors have made a series of discoveries that sup
`port a surprisingly effective and versatile formulation for the
`treatment and prevention of emesis using palonosetron.
`These formulations are shelf stable forperiods greater than 24
`months at room temperature, and thus can be stored without
`refrigeration, and manufactured using non-aseptic, terminal
`sterilization processes.
`In one aspect, the inventors have discovered that formula
`tions which include the active ingredient palonosetron require
`in some instances only 1/10th the amount of other previously
`known compounds for treating emesis, which surprisingly
`allows the use of concentrations of palonosetron far below
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Exh. 1010
`
`

`
`US 7,947,724 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 mg/mL to about 5 mg/mL palonosetron or a phar
`maceutically acceptable salt thereof; and b) a pharmaceuti
`cally acceptable carrier.
`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.
`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 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/ml palonosetron or a pharmaceu
`tically acceptable salt thereof; from about 10 to about 100
`millimoles citrate buffer; and from about 0.005 to about 1.0
`mg/ml 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 pharmaceutically acceptable carrier, wherein the
`pharmaceutically acceptable carrier comprises a chelating
`agent and mannitol.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`De?nitions
`“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, pre-?lled
`syringes. Vial also means a sealed container of medication
`that is used one time only, and includes breakable and non
`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 (typi
`cally about 5 mls.).
`Throughout this speci?cation the word “comprise,” 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
`[(S)-l-Azabicyclo[2.2.2]oct-3-yl]2,3,3a,4,5,6-hexahydro-l
`oxo-leenZ[de]isoquinoline, and is preferably present as the
`monohydrochloride. Palonosetron monohydrochloride can
`be represented by the following chemical structure:
`
`4
`ConcentrationsiWhen concentrations of palonosetron
`are given herein, the concentration is measured in terms of the
`weight of the free base. Concentrations of all other ingredi
`ents are given 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
`sirable and includes that which is acceptable for veterinary
`use as well as human pharmaceutical use.
`“Pharmaceutically acceptable salts” means salts which are
`pharmaceutically acceptable, as de?ned above, and which
`possess the desired pharmacological activity. Such salts
`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, propionic acid, hexanoic acid, heptanoic acid,
`cyclopentanepropionic 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, cinnamic acid, mandelic acid,
`methanesulfonic acid, ethanesulfonic acid, l,2,-ethanedisul
`fonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic
`acid p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic
`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-l -carboxylic acid),
`3-phenylpropionic acid, trimethylacetic acid, tertiary buty
`lacetic acid, lauryl sulfuric acid, 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.
`Acceptable organic bases include ethanolamine, diethanola
`mine, triethanolamine, tromethamine, N-methylglucamine
`and the like.
`Discussion
`The fact that palonosetron can be formulated in some
`instances at concentrations of only about 1/10’h 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. Thus, in one
`embodiment the invention provides a pharmaceutically stable
`solution for preventing or reducing emesis comprising a)
`from about 0.01 mg/mL to about 5 mg/mL palonosetron or a
`pharmaceutically acceptable salt thereof; and b) a pharma
`ceutically acceptable carrier. Similarly, in another embodi
`ment the invention provides a method of formulating a phar
`maceutically stable solution of palonosetron comprising
`admixing from about 0.01 mg/mL to about 5 mg/mL pal
`onosetron or a pharmaceutically acceptable salt thereof; with
`a pharmaceutically acceptable carrier. In alternative embodi
`ments, the formulation includes palonosetron or a pharma
`ceutically acceptable salt thereof in a concentration from
`about 0.02 mg/mL to about 1.0 mg/mL, from about 0.03
`mg/mL to about 0.2 mg/mL, and most optimally about 0.05
`mg/ml.
`A particular advantage associated with the lower dosages
`of intravenous palonosetron is the ability to administer the
`drug 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
`embodiment the palonosetron is supplied in vials that com
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Exh. 1010
`
`

`
`US 7,947,724 B2
`
`5
`prise 5 ml. of solution, which equates to about 0.25 mg of
`palonosetron at a concentration of about 0.05 mg/ml.
`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.
`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 pH from about 4.0 to about 6.0. Similarly, in
`another embodiment the invention provides a method of for
`mulating a pharmaceutically stable solution of palonosetron
`comprising admixing 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 alternative
`embodiments, the pH is from about 4.5 to about 5.5, and most
`optimally about 5 .0. There are many examples to those of skill
`in the 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
`adjust the pH 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 mg/ml palonosetron
`or a pharmaceutically 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 EDTA. Similarly, in
`another embodiment the invention provides a method of for
`mulating a pharmaceutically stable solution of palonosetron
`comprising admixing from about 0.01 to about 5.0 mg/ml
`palonosetron or a pharmaceutically 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 EDTA. The
`citrate buffer can be in the form of citric acid and/or a salt of
`citric acid such as trisodium citrate. In various embodiments,
`the ranges of one or more of the foregoing ingredients can be
`modi?ed as follows:
`The formulation may comprise palonosetron or a pharma
`ceutically acceptable salt thereof in a concentration from
`about 0.02 mg/mL to about 1.0 mg/mL, from about 0.03
`mg/mL to about 0.2 mg/mL palonosetron hydrochlo
`ride, and most optimally about 0.05 mg/ml.
`The formulation may comprise citrate buffer in a concen
`tration of from about 10 to about 40 millimoles, or 15-30
`millimoles.
`The formulation may comprise EDTA in a concentration of
`from about 0.005 mg/ml to about 1.0 mg/ml, or about 0.3
`to about 0.7 mg/ml, and most optimally about 0.5
`mg/ml.
`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 pharmaceutically acceptable carrier, wherein the
`pharmaceutically acceptable carrier comprises a chelating
`agent and mannitol. Similarly, in another embodiment the
`invention provides a method of formulating a pharmaceuti
`cally stable solution of palonosetron comprising admixing 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. The chelating agent is preferably EDTA,
`and, in various embodiments the chelating agent is present in
`a concentration of from about 0.005 to about 1.0 mg/mL or
`from about 0.05 mg/mL to about 1.0 mg/mL or from about 0.3
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`to about 0.7 mg/ml, or most optimally about 0.5 mg/ml. In
`various embodiments the mannitol is present in a concentra
`tion of from about 10.0 mg/ml to about 80.0 mg/ml, from
`about 20.0 mg/mL to about 60.0 mg/ml, or from about 40.0 to
`about 45.0 mg/ml.
`Injectable formulations are typically formulated as aque
`ous solutions in which water is the primary excipient. Oral
`formulations will differ from injectable formulations gener
`ally by the additional presence of ?avoring agents, coloring
`agents, or viscosity agents. Natural or synthetic sweeteners
`include, among others, mannitol, sorbitol, saccharose, sac
`charine, aspartame, acelsulphame K, or cyclamate. These
`agents are generally present in concentrations in excess of
`100 mg/ml or 250 mg/ml when used as sweetening agents, in
`contrast to the 41.5 mg/ml concentration of mannitol
`described in some of the embodiments of the invention, in
`which mannitol is acting simply as a tonicifying agent.
`The formulations of the present invention are particularly
`suited for use in inj ectable and oral liquid formulations, but it
`will be understood that the solutions may have alternative
`uses. For example, they may be used as intermediates in the
`preparation of other pharmaceutical dosage forms. Similarly,
`they may have other routes of administration including intra
`nasal or inhalation. Inj ectable formulations may take any
`route including intramuscular, intravenous or subcutaneous.
`Still further embodiments relate to improvements in the
`ease with which the palonosetron formulation can be stored
`or manufactured. In particular, the inventors have discovered
`that the formulations of the present invention allow storage of
`the product for extended periods at room temperature. Thus,
`in yet another embodiment the invention provides a method of
`storing one or more containers in which are contained a
`solution of palonosetron or a pharmaceutically acceptable
`salt thereof comprising: a) providing a room comprising said
`one or more containers; b) adjusting or maintaining the tem
`perature of the room at greater than about ten, 15, or 20
`degrees celcius; and c) storing said containers in said room for
`one month, 3 months, 6 months, one year, 18 months, 24
`months or more (but preferably not exceeding 36 months),
`wherein (i) the palonosetron or pharmaceutical salt thereof is
`present in a concentration of from about 0.01 mg/mL to about
`5.0 mg/mL, (ii) the pH of the solution is from about 4.0 to
`about 6.0, (iii) the solution comprises from about 0.01 to
`about 5.0 mg/ml palonosetron or a pharmaceutically accept
`able salt thereof, from about 10 to about 100 millimoles
`citrate buffer and from about 0.005 to about 1 .0 mg/ml EDTA,
`(iv) the solution comprises a chelating agent, or (v) the solu
`tion comprises from about 10 to about 100 milliMoles of a
`citrate buffer.
`The stability of the foregoing formulations also lends itself
`well to terminal sterilization processes in the manufacturing
`process. Therefore, in still another embodiment the invention
`provides a method of ?lling a container in which is contained
`a solution of palonosetron or a pharmaceutically acceptable
`salt thereof comprising: a) providing one or more sterile open
`containers (preferably 5 ml. vials); b) ?lling said containers
`with a solution of palonosetron in a non-aseptic environment;
`c) sealing said ?lled containers; and d) steriliZing said sealed,
`?lled containers, wherein (i) the palonosetron or pharmaceu
`tical salt thereof is present in a concentration of from about
`0.01 mg/mL to about 5 mg/mL, (ii) the pH of the solution is
`from about 4.0 to about 6.0, (iii) the solution comprises from
`about 0.01 to about 5.0 mg/ml palonosetron or a pharmaceu
`tically acceptable salt thereof, from about 10 to about 100
`millimoles citrate buffer and from about 0.005 to about 1.0
`
`Exh. 1010
`
`

`
`7
`mg/ml EDTA, (iv) the solution comprises a chelating agent,
`or (V) the solution comprises from about 10 to about 100
`milliMoles of a citrate buffer.
`
`8
`Example 5
`
`Formulation II
`
`US 7,947,724 B2
`
`EXAMPLES
`
`Example 1
`
`Stabilizing pH
`
`5
`
`The following is a representative pharmaceutical formula
`tion containing palonosetron that is useful for oral formula
`tions, or other liquid formulations of the drug.
`
`A study 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 10.0. The
`results indicated that palonosetron hydrochloride is most
`stable at pH 5.0.
`
`Example 2
`
`Ingredient
`
`Palonosetron Hydrochloride
`Mannitol
`EDTA
`Trisodium citrate
`Citric acid
`WP]
`Sodium hydroxide solution and/or
`hydrochloric acid solution
`Flavoring
`
`mg/mL
`
`0.05*
`150
`0.5
`3.7
`1.5 6
`q.s. to 1 ml
`pH 5.0 r 0.5
`
`q.s.
`
`Stabilizing Concentration Ranges
`
`20
`
`*calculated as a free base
`
`Example 6
`
`25
`
`Stability of Palonosetron without Dexamethasone
`
`The physical and chemical stability of palonosetron HCl
`was studies in concentrations of 5 ug/mL and 30 pg/mL in 5%
`dextrose injection, 0.9% sodium chloride injection 5% dex
`trose in 0.45% sodium chloride injection, and dextrose 5% in
`lactated Ringer’s injection. The admixtures were evaluated
`over 14 days at 4° C. in the dark and for 48 hours at 23° C.
`under ?uorescent light.
`Test samples of palonosetron HCl were prepared in poly
`vinyl chloride (PVC) bags of the infusion solutions at con
`centrations of 5 and 30 ug/mL. Evaluations for physical and
`chemical stability were performed on samples taken initially
`and after 1, 3, 5, 7, and 14 days of storage at 4° C. and after 1,
`4, 24, and 48 hours at 23° C. Physical stability was assessed
`using visual observation in normal room light and using a
`high-intensity monodirectional light beam. In addition, tur
`bidity and particle content were measured electronically.
`Chemical stability of the drug was evaluated by using a sta
`bility-indicating high performance liq