LIQUID PHARMACEUTICAL FORMULATIONS OF P ALONOSETRON
`
`FIELD OF THE INVENTION
`
`5
`
`liquid formulations of
`The present invention relates to shelf-life stable
`palonosetron that are especially useful· in the preparation of injectable and oral ..
`medicaments.
`
`BACKGROUND OF THE INVENTION
`
`10
`
`15
`
`20
`
`25
`
`Emesis is a devastating consequence of cytotoxic therapy, radiotherapy, and post-
`operative environments that drastically affects the quality of life of people undergoing
`In recent years a class of drugs referred to as S-HT3 (5-
`such treatments.
`hydroxytryptamine) receptor antagonists has been developed that treat such emesis by
`antagonizing cerebral functions associated with the S-HT3 receptor. See Drugs Acting on
`5-Hydroxytryptamine Receptors: The Lancet Sep. 23, 1989 and references cited therein~
`Drug~ within this class include ondansetron, granisetron, alosetron, tropisetron~ and
`.
`.
`dolasetron. These S-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 regimen. .
`
`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 S-HT3 antagonist every day until the risk
`of emesis has substantially subsided. The present class of S-HT3 antagonists has not
`proven especially helpful meeting this need, however, because the 5-HT3 receptor
`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
`5HTJ Receptor Antagonist for the Hospital Formulary. EHP, Oct. 1996;2 (suppll):Sl9-
`24.
`
`2
`
`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 1007
`
`Exh. 1007
`
`

`
`Recently, clinical investigations have been made concerning palonosetron,.a new
`5-HTJ receptor antagonist reported in U.S. Patent 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, formulating
`· palonose:tron 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
`palonosetron in example 13 that contains the following ingredients:
`
`5
`
`Palonoset~on HCI
`
`Dextrose Monohydrate
`
`Citric Acid Monohydrate
`
`..
`
`Sodium Hydroxide
`
`.... WFJ
`
`10
`
`10-lOOmg.
`
`q.s. to make Isotonic
`
`1.05 mg .
`
`0.18 mg.
`
`To 1.0 ml.
`
`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.
`
`15
`
`Ondansetron, its uses, and medicaments made with ondansetron are disclosed in
`U.S. Patent Numbers 4,695,578, 4,753,789, 4,929,632, 5,240,954, 5,344,658, 5,5.78,628, .
`5,578,632, 5,922,749, 5,622,720, 5,955,488, and 6,063,802. Commercially it is ·
`distributed by GlaxoSmithK.line as Zofran® and is indicated for prevention . of
`postoperative nausea and vomiting (PONV), cancer chemotherapy-induced nausea and
`vomiting (CINV), and radiotherapy-induced nausea and vomiting (RINV) and it is
`available as an injection, tablets and solution, and as Zofran ODT® ( ondansetron) Orally
`20 Disintegrating Tablets.
`
`Granisetron, its uses, and medicaments made with granisetron are disclosed . in
`U.S. Patent Numbers 4,886,808, 4,937,247, 5,034,398 and 6,294,548. Commercially it is
`
`3
`
`Exh. 1007
`
`

`
`distributed by Roche Laboratories Inc. as Kytril®, indicated for the prevention of nausea
`and vomiting associated with chemotherapy or radiation therapy, and is offered in tablet
`form, oral solution, and as an injection.
`
`5
`
`Alosetron, its. uses, and medicaments made with alosetron are disclosed in U.S.
`Patent Numbers 5,360,800 and 6,284,770.
`Commercially it is 'distributed by
`GiaxoSinithKiine as totronex®.
`
`Tropisetron is commercially available as Navoban® (Novartis) CAS- 89565-68-4
`(tropisetron); CAS - 105826-92-4 (tropisetron hydrochloride) and it is indicated for
`treatment ofPONV and CINV.
`
`Dolasetron, its uses, and medicaments made with ondansetron are disclosed in
`U.S. Patent Numbers 5,01l,846, and 4,906,755. Commercially it is distributed by
`A ventis Pharmaceuticals 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 formulation with increased
`'stability and thereby increased shelf life. There also exists a need for .an appropriate .
`range of concentrations for both the 5-HTJ receptor antagonist and its pharmaceutically
`acceptable carriers that would facilitate making a formulation with this increased ,
`stability.
`
`10
`
`15
`
`20
`
`It is an objec~ of the present invention to provide a formulation of Palonosetron ·
`hydrochloride with increased pharmaceutical 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 Palonosetron hydrochloride.
`
`. It is a further object of the invention to provide a formulation of Palonosetron
`·25 · which would allow for prolonged storage.
`
`It is also an object of the invention to provide a formulation of Palonosetron
`which would allow terminal sterilization.
`
`4
`
`Exh. 1007
`
`

`
`SUMMARY OF THE INVENTION
`
`The inventors have made a series of discoveries that support a surprisingly
`effective and versatile formulation for the treatment and prevention of emesis using
`palonosetron. These formulations are shelf stable for periods greater than 18 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 formulations which include the
`active ingredient palonosetron require in some instances only 1/101h the amount qf other
`previously known compounds for treating emesis, which surprisingly 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 mglmL
`palonosetron or a pharmace.utically acceptable salt thereof; and b) a pharmaceutically
`acceptable carrier .
`
`5
`
`10
`
`• • • • • : 'I
`
`. .... . , 15
`
`The inventors have further discovered that by adjusting the formulation's pH
`and/or excipient concentrations it is possible 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 pharmaceutically
`acceptable salt thereof; from about 10 to about 100 millimoles citrate buffer; and from
`about 0.005 to about 1.0 mg/ml EDT A.
`
`20
`
`25
`
`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
`
`5
`
`Exh. 1007
`
`

`
`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
`
`5
`
`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, pre-
`,
`filled 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,
`10 miniature screw-top jars, and any other type of container of a size capable of holding only
`one unit dose ofpalonosetron (typically about 5 mls.).
`
`Throughout this specification the word ."comprise," or variations such as
`'\~omprises" or "comprising," will be ~ders~ood .to. imply the inclusion of a stated
`element, integer or step, or group of elemen~s, integers or steps, but not the exclusion of
`any other element, integer or step, or group of elements, integers or steps
`
`(3aS)-2,3,3a,4,5,6-Hexahydro-2-[ (S)-1-
`means
`. "Palonosetron"
`Azabicyclo[2.2.2]oct-3-yl]2,3,3a,4,5,6-hexahydro-1-oxo-l.Hbenz[ de ]isoquinoline, and ·is
`preferably present as the monohydrochloride. Palonosetron monohydrochloride can be
`represented by the_ following chemical structure:
`
`IS
`
`20
`
`Concentrations -- When concentrations of palonosetron are given herein, the
`concentration is measured in terms of the weight of the free base. Concentrations of all
`
`6
`
`Exh. 1007
`
`

`
`other ingredients are given based on the weight of ingredient added to the solution.
`(PLEASE CONFIRM]
`
`"Pharmaceutically acceptable" means that which is useful in preparing a
`pharmaceutical composition that is generally safe, non-toxic and neither biologically nor
`otherwise undesirable an.d includes that which is acceptable for veterinary use as well as
`human pharmaceutical use.
`
`"Pharmaceutically acceptable salts" means salts which are pharmaceutically
`acceptable, as defined 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, lactic acid, ·.malonic acid,
`succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
`o-( 4-hydroxybenzoyl)benzoic acid, .cinnruni~, acid, mandelic acid, methanesulfonic. acid,
`ethanesulfonic
`acid,
`1,2,-ethanedjsul:fon.ic , .acid, 2-hydroxyethanesulfonic·. •acid,
`benzenesulfonic acid p-chlorobenze~~s~lfo!riG ~cid, 2-naphthalenesulfonic acid, p-
`toluenesulfonic
`acid,
`camphorsulfonic
`acid,
`4-methylbicyclo[2.2.2]oct-2-ene-I-
`carboxylic acid, glucoheptonic acid, 4,4' -methylenebis(3-hydroxy-~-ene-l-carboxylic
`acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic 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, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and
`the like.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`DISCUSSION
`
`The fact that palonosetron can be formulated in some instances at concentrations
`of only about 1/1 oth the amount of other previously known compounds for treating
`
`30
`
`7
`
`Exh. 1007
`
`

`
`emesis, surprisingly allows the use of concentrations of palonosetron far below those that ·
`would ordinarily be expected. Thus, in one embodiment the invention provides a
`,. p~armaceutically stable solution for preventing or reducing emesis comprising a) from
`about 0.01 mg/mL to about 5 mg/mL palonosetr~n or a pharmaceutically acceptable salt '
`thereof; ~d b) a pharmaceutically acce~table carrier. In alternative embodiments, the
`formulation includes palonosetron or a pharmaceutically acceptable salt. thereof in a...:.
`concentra~ion 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 mglml.
`
`5
`
`JO
`
`.•.
`
`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 lO·to 30 seconds.
`In one particular embodiment the palonosetron is supplied in vials that comprise 5 ml. of ~
`solution, which equates to apout 0.2~ mg ofpalonosetron at a concentration of about 0.05 ·
`.
`:-
`=-·~ ..... ':''i.'
`15 mg/ml.
`· .' .... .
`
`·. ~
`
`.. i
`
`.
`
`20
`
`The inventors have furthef·discovered that by adjusting the fonnulation's pH ·
`and/or excipient concentrations "it is possible 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 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 formulation. :
`Two exemplary solutions are sodium hydroxide and hydrochloric acid solution, either of
`25 which could be used to adjust the pH of the formulation.
`
`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 pharmaceutically acceptable salt thereof; from about I 0 to about I 00
`millimoles citrate buffer; and from about 0.005 to about l.O mg/ml EDT A. The citrate
`buffer can be in the form of citric acid and/or a salt of citric acid such as trisodium citrate.
`
`30
`
`8
`
`Exh. 1007
`
`

`
`In various embodiments, the ranges of one or more of the foregoing ingredients can be
`modified as follows:
`
`The formulation may comprise palonosetron or a pharmaceutically
`•
`acceptable salt thereof in a concentration from about 0.02 mglmL to about l.O
`mglmL, from about 0.03 mglmL to about 0.2 mg/mL palonosetron hydrochJ_oride,
`and most optimally about 0. OS mg/ml.
`
`The formulation may comprise citrate buffer in a concentration 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 mglml, or about 0.3 to about 0.7 mg/ml, and most
`optimally about 0.5 mg/ml.
`
`5
`
`10
`
`15
`
`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 embodim~nt the . invention provides a pharmaceutically stable solution for
`preventing or reducing. ~mesis . comprising a) palonosetron or a pharmaceutically
`...... •, .. ··.. .
`.
`·.
`acceptable salt thereof an:d p) a phannaceutical.ly acceptable carrier, wherein the
`p~armaceutically acceptable· carrier comprises a chelating agent and mannitol. The
`chelating agent is preferably EDT A, and, in vari~us embodiments the chelating agent is
`present in a concentration of from about 0.005 to about 1.0 mglmL or from about 0.05
`20 mg/mL to about 1.0 mg/mL or from about 0.3 to about 0.7 mg/ml, or most optimally
`about 0.5. mg/ml. In various embodiments the mannitol is present in a concentration 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 mglml.
`
`Injectable formulations are typically formulated as aqueous solutions in . which
`25 water is the primary excipient. Oral formulations will differ from injectable formulations
`generally by the additional presence of flavoring agents, coloring agents, or viscosity
`agents. Natural or synthetic sweeteners include, among others, mannitol, sorbitol,
`saccharose, saccharine, 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
`
`30
`
`9
`
`: .·.
`
`' \ , .
`
`Exh. 1007
`
`

`
`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
`injectable 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. Siniilarly, they may have other routes of :·
`a~inistration including intranasal or inhalation. Injectable 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 ~anufactured. In particular, the inventors have
`discovered that the formulations ~f 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·, <.:. ·. •:
`temperature· of the. room at greater than about ten, 15, or 20 degrees celcius; and -c)
`, ·. ' ...
`storing said containers in said rooin for one month,· 3 months, 6 months, one year, 18
`-· '
`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
`to about 5.0 mg/ml palonosetron or a
`solution comprises from about 0.01
`pharmaceutically acceptable 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 solution 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 filling 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 mi. vials); b) filling said
`
`5
`
`10
`
`15
`
`· 20
`
`25
`
`30
`
`10
`
`Exh. 1007
`
`

`
`5
`
`10
`
`15
`
`20
`
`containers with a solution of palonosetron in a non·aseptic environment; c) sealing said·
`filled containers; and d) sterilizing said sealed, filled containers, wherein (i). . the
`palonosetron or pharmaceutical salt thereof is present in a concentration of from about
`0.01 mg/mL to about 5 mg/mL, {i~) the pH of tpe solution is from about 4.0 to about 6.0,
`(i~i) the solution comprises from about 0.01 to about 5.0 mg/ml palonosetron or a
`pharmaceutically acceptable salt thereof, from about 10 to about . .1 00 millimoles .citrate
`.
`.
`buffer and from about 0.005 to ~bout 1.0 mg/ml EDT A, (iv) the solution comprises a
`chelating agent, or (v) the solution comprises from about 10 to about 100 milliMoles of a
`citrate buffer.
`
`EXAMPLES
`
`EXAMPLE 1: STABILIZING PH
`. · A :stu~Y. was conducted to determine the effect of pH on formulations cont~ning
`palonose~on hydrochloride, measuring th¥ stability at 80°C at pH 2.0, 5.0,7.4;.and.lO.Q.
`The results indicated that palonosetronhydrochloride is most stable at pH 5.0.
`
`EXAMPLE 2: STABILIZING CONCENTRATION RANGES
`
`A formulation optimization study was performed using an experimental design
`software. Twenty-four lots of drug product were analyzed to investigate the appropriate
`concentration ranges for palonosetron hydrochloride (0.05 mg/mL to 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 on the optimal fo~ulation, which was shown to be formulated with
`EDTA 0.05% and 20 mM citrate buffer at pH 5.0. The results of this study indicated that
`palonosetron concentration was also a critical factor in chemical stability, with greatest
`stability seen at the lowest palonosetron concentrations.
`
`25
`
`EXAMPLE 3: TONICIFYING AGENT
`
`Formulations ofpalonosetron hydrochloride in citrate buffer were prepared
`including either a) sodium chloride or b) mannitol. The palonosetron hydrochloride
`
`11
`
`Exh. 1007
`
`

`
`formulation including mannitol showed superior stability. The optimum level of
`mannitol required for an isotonic solution was found to be 4.15%.
`
`EXAMPLE 4: FORMULATION I
`
`- 5
`
`is a. representative pharmaceutical formulation containing
`The following
`palonosetron that is useful fo.r intravenous fonnulations, or other liquid formulations of
`the drug.
`
`Ingredient
`Palonosetron Hydrochloride
`Mannitol
`EDTA
`Trisodium citrate
`· • = · · • '· · • Citric acid
`'WFJ
`·.; .. ;!
`
`Sodium hydroxide solution and/or
`hydrochloric acid solution· ·
`
`mg/mL
`
`I
`•• , • : , ' •
`
`' I '
`
`0.05
`41.5
`0.5
`3.7
`1.56
`1.0
`pH5.0±0.5
`
`· 10
`
`EXAMPLE 5: FORMULATION II
`The following is a representative pharmaceutical formulation containing
`palonosetron that is useful for oral formulations, or other liquid formulations of the drug.
`
`mg/mL
`
`lng~edient
`Palonosetron Hydrochloride
`Mannitol
`EDTA
`Trisodium citrate
`Citric acid
`
`0.05
`150
`0.5
`3.7
`1.56
`
`12
`
`Exh. 1007
`
`

`
`' .
`
`WFJ
`Sodium hydroxide solution and/or
`hydrochloric acid solution
`Flavoring
`
`1.0
`pH 5.0±0.5
`
`q.s.
`
`This invention has been described with reference to its preferred embodiments.
`Variations and modifications of the invention will be obvious to those skilled in the art
`from the foregoing detailed description of the invention.
`
`5
`
`13
`
`Exh. 1007
`
`

`
`What is claimed is:
`
`CLAIMS
`
`1)
`
`A pharmaceutically stable solution for preventing or reducing emesis comprising:
`
`· 5
`
`a)
`
`to about 5 mg/mL palonosetron. or a
`from about 0.01 mg/mL
`.. pharmaceutically acceptable salt the:t~Qf; and
`
`10
`
`15
`
`2)
`
`3)
`
`4)
`
`S)
`
`6)
`
`7)
`
`8)
`
`9)
`
`b)
`
`a pharmaceutically acceptable carrier.
`
`The solution of claim 1 wherein the palonosetron or pharmaceutically acceptable ·
`salt thereofis in a concentration from about 0.02 mg/mL to about 1.0 mg/:rnL.
`
`The solution of claim 1 wherein the palonosetron or pharmaceutically acceptable
`salt thereof is in a concentration from about 0.03 mg/mL to about 0.2 mg/mL.
`
`The solution of claim 1 wherein the palonosetron or pharmaceutically acceptable
`salt thereof is in a concentration of about 0.05 mg/mL.
`
`The solution of claim 1 comprising palonosetron·hydrochloride.
`
`The solution of claim 1 wherein the pH is from about 4.0 to about 6.0.
`
`The solution of claim 1 wherein the pH is from about 4.5 to about 5.5.
`
`The solution of claim 1 wherein the pharmaceutically acceptable carrier
`comprises a chelating agent.
`
`The solution of claim 1 wherein the pharmaceutically acceptable :carrier
`comprises :from about 0.005 mg/ml to about 1.0 mg/ml EDTA.
`
`20
`
`10)
`
`The solution of claim 1 wherein the pharmaceutically acceptable .:carrier
`comprises mannitol.
`
`11)
`
`12)
`
`13)
`
`25
`
`The solution of claim 1 wherein the pharmaceutically acceptable ·carrier
`comprises :from about 10 to about 100 milliMoles of a citrate buffer.
`
`The solution of claim I adapted for intravenous administration.
`
`The solution of claim 1 adapted for oral administration.
`
`14) A pharmaceutically stable solution for preventing or reducing emesis comprising:
`
`14
`
`Exh. 1007
`
`

`
`a)
`
`b)
`
`palonosetron or a pharmaceutically acceptable salt thereof; and
`
`a pharmaceutically acceptable carrier,
`
`. at a pH from about 4.0 to about 6.0.
`
`15)
`
`The solution of claim 14 wherein the pH is from about 4.5 to about 5.5.
`
`5
`
`16) The solution ofclaim 14 wherein the pH is about 5.0;
`
`17)
`
`18)
`
`The solution of claim 14 wherein the palonosetron or pharmaceutically acceptable
`salt thereof is in a concentration from about 0.01 mglmL to about 5:0 mglmL.
`
`The solution of claim 14 wherein the palonosetron or pharmaceutically acceptable
`salt thereof is in a concentration of about 0.05 mglmL.
`
`10
`
`19)
`
`The solution of claim 14 wherein the pharmaceutically acceptable carrier
`· comprises a chelating agent.
`
`20)
`
`21)
`
`2~)
`
`23)
`
`24)
`
`25)
`
`26)
`
`The solution of claim 14 wherein the ·pharmaceutically acceptable carrier
`comprises from about 0.005 mglml to about 1.0 mg/ml EDT A.
`
`The solution of claim 14 wherein the pharmaceutically acceptable ·carrier
`comprises mannitol. ·
`
`I
`
`The solution of claim 14 wherein the pharmaceutically acceptable carrier
`comprises from about 10 to about 100 milliMoles of a citrate buffer ..
`
`The solution of claim 14 comprising palonosetron hydrochloride.
`
`.
`
`The solution of claim 14 further comprising sodium hydroxide or hydrochloric
`acid.
`
`The solution of claim 14 adapted for intravenous administration.
`
`The solution of claim 14 adapted for oral administration.
`
`27) A pharmaceutically stable solution for preventing or reducing emesis comprising
`
`a)
`
`from about 0.01 to about 5.0 mg/ml palonosetron or a pharmaceutically
`acceptable salt thereof;
`
`b)
`
`from about 1 0 to about 100 millimoles citrate buffer; and
`
`15
`
`20
`
`25
`
`15
`
`Exh. 1007
`
`

`
`5
`
`.10
`
`.
`
`15
`
`28)
`
`29)
`
`30)
`
`31)
`
`32)
`
`33)
`
`34)
`
`35)
`
`36)
`
`37)
`
`c)
`
`from about 0.005 to about 1.0 mg/ml EDTA.
`
`The solution of claim 27 comprising about 0.05 mg/ml to of palonosetron
`hydrochloride.
`
`The solution of claim 27 c9mprising from about 1 0 to about 40 milliMoles citrate
`buffer.
`
`The solution of claim 27 comprising from about 0.3 to about 0.7 mg/ml of EDT A.
`
`The solution of claim 27 adapted for intravenous administration.
`
`The solution of claim 27 adapted for oral administration.
`
`A pharmaceutically stable solution for preventing or reducing emesis comprising
`
`a)
`
`b)
`
`palonosetron or a pharmaceutically acceptable salt thereof and
`
`a pharmaceutically acceptable carrier,
`
`wherein the pharmaceutically acceptable carrier comprises a chelating agent. ..
`
`•
`
`•
`
`•
`
`1 •• :· •• .'1
`
`, ... '
`
`•
`
`The solution of claim 33 wherein the chelating agent is EDTA .
`..
`The solution of claim 33 wherei~· th~ chelating agent is present in an amount from
`about 0.005 mg/ml to about 1.0 mg/ml.
`
`The solution of claim 33 wherein the chelating agent is present in an amount from
`about 0.3 mg/ml to about 0.7 mg/ml.
`
`The solution of claim 33 wherein the palonosetron or pharmaceutically acceptable
`salt thereof is in a concentration from about 0.01 mg/mL to about 5.0 mg/mL.
`
`20
`
`38)
`
`The solution of claim 33 wherein the palonosetron or pharmaceutically acceptable
`salt thereof is in a concentration of about 0.05 mg/mL.
`
`39)
`
`40)
`
`25
`
`The solution of claim 33 wherein the pharmaceutically acceptable carrier
`comprises mannitol.
`
`The solution of claim 33 wherein the pharmaceutically acceptable carrier
`comprises from about 10 to about 100 milliMoles of a citrate buffer.
`
`41)
`
`The solution of claim 33 comprising palonosetron hydrochloride.
`
`16
`
`Exh. 1007
`
`

`
`I
`I -
`I
`
`42)
`
`43)
`
`44)
`
`45)
`
`The solution of claim 33 wherein the pH is from about 4.0 to about 6.0.
`
`The solution of claim 33 wherein the pH is from about 4.5 to about 5.5.
`
`The solution of claim 33 adapted for intravenous administration.
`
`The solution of claim 33 adapted for oral administration.
`
`S
`
`46) A pharmaceutically stable solution for preventing or reducing emesis comprising ·
`
`a)
`
`b)
`
`palonosetron or a pharmaceutically acceptable salt thereof and
`
`a pharmaceutically acceptable carrier,
`
`wherein the pharmaceutically acceptable carrier comprises mannitol.
`
`The solution of claim 46 wherein the mannitol is in a concentration from.about
`10.0 mg/ml to about 80.0 mg/ml.
`
`The solution of claim 46 wherein the mannitol is in a concentration from about
`40.0 mg/ml to about 45.0 :rpg/ml..
`
`The solution of claim 46 wherein .the palonosetron or pharmaceutically acceptable
`salt thereof is in a concentration .from about 0.01 mg/mL to about 5.0 mg/mL.
`.
`.
`The solution of claim 46 wherein the palonosetron or pharmaceutically acceptable
`salt thereof is in a concentration Qf about 0.05 mg/m.L.
`
`The solution of claim 46 wherein the pharmaceutically acceptable carrier
`comprises a chelating agent.
`
`The solution of claim 46 wherein the pharmaceutically acceptable carrier
`comprises from about 0.005 mg/ml to about 1.0 mg/ml EDTA.
`
`The solution of claim 46 wherein the pharmaceutically acceptable carrier
`comprises from about 10 to about 100 milliMoles of a citrate buffer.
`
`The solution of claim 46 comprising palonosetron hydrochloride.
`
`The solution of claim 46 wherein the pH is from about 4.0 to about 6.0.
`
`The solution of claim 46 wherein the pH is from about 4.5 to about 5.5.
`
`The solution of claim 46 adapted for intravenous administration.
`
`10
`
`47)
`
`48)
`
`49)
`
`15
`
`50)
`
`51)
`
`52)
`
`53)
`
`54)
`
`55)
`
`56)
`
`57)
`
`20
`
`25
`
`17
`
`Exh. 1007
`
`

`
`58)
`
`The solution of claim 46 adapted for oral administration.
`
`59) A: pharmaceutically stable solution for preventing or reducing· drug induced
`emesis comprising
`
`a)
`
`b)
`
`·5
`
`palonosetron or a pharmaceutically acceptable salt thereof and
`
`a phannaceutically acceptable carrier,
`
`wherein the pharmaceutically acceptable carrier comprises from about 10 to about
`100 milliMoles of a citrate buffer.
`
`60)
`
`The solution of claim 59 wherein the pharmaceutically acceptable carrier ·
`comprises from about 10 to about 70 milliMoles of a citrate buffer.
`
`10
`
`61)
`
`The solution of claim 59 wherein the pharmaceutically acceptable carrier
`comprises from about 10 to about 40 milliMoles of a citrate buffer.
`
`15
`
`62)
`
`63)
`
`64)
`
`65)
`
`The solution of claim 59 wherein the palonosetron or pharmaceutically acceptable
`, ..... .
`salt thereof is in a conc:entration from about 0.01 mg/mL to about 5.0 mg/mL.
`
`The solution of'd~iin 59' wherein the palonosetron or pharmaceutically acceptable
`salt thereof is in a concentration of about 0.05 mg/mL.
`
`The solution of claim 59 wherein the pharmaceutically acceptable carrier
`comprises a chelating agent.
`
`The solution of claim 59 wherein the pharmaceutically acceptable carrier .
`comprises from about 0.005 mg/ml to about 1.0 mg/ml EDT A.
`
`20
`
`66)
`
`The solution of claim 59 wherein the pharmaceutically acceptable carrier
`comprises mannitol.
`
`67)
`
`68)
`
`69)
`
`70)
`
`71)
`
`25
`
`The solution of claim 59 comprising palonosetron hydrochloride.
`
`The solution of claim 59 wherein the pH is from about 4.0 to about 6.0.
`
`The solution of claim 59 wherein the pH is from about 4.5 to about 5.5.
`
`The solution of claim 59 adapted for intravenous administration.
`
`The solution of claim 59 adapted for oral administration.
`
`18
`
`Exh. 1007
`
`

`
`r--
`1-
`
`72) A method of storing one or more containers in which are contained a solution of
`palonosetron or a pharmaceutically acceptable salt thereof comprising:
`
`a)
`
`b)
`
`providing a room comprising said one or more containers;
`
`adjusting or maintaining the temperature of the room at greater than about
`ten degrees celcius;
`
`c)
`
`storing said containers in said room for one month or more,
`
`wherein (i) the palonosetron or pharn1aceutical 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 acceptable 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 mannitol or a