UNITED PATENT NON-PROVISIONAL PATENT APPLICATION
`
`LIQUID PHARMACEUTICAL FORMULATIONS OF P ALONOSETRON
`
`FoR
`
`BY
`
`GIORGIO CALDERARI
`
`DANIELE BONADEO
`
`ROBERTA CANNELLA
`
`ALBERTO MACCIOCCHI
`
`ANDREW MIKSZTAL
`
`THOMAS MALEFYT
`
`KATHLEEN M. LEE
`
`CARMINE P ANUCCIO
`
`5579776vl
`
`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 1025
`
`Exh. 1025, Page 1 of 20
`
`

`
`LIQUID PHARMACEUTICAL FORMULATIONS OF P ALONOSETRON
`
`FIELD OF THE INVENTION
`
`The present invention relates to shelf-life stable liquid formulations of
`palonosetron that are especially useful in the preparation of injectable and oral
`5 medicaments.
`
`BACKGROUND OF THE INVENTION
`
`Emesis is a devastating consequence of cytotoxic therapy, radiotherapy,
`and post-operative environments that drastically 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-HT 3
`receptor. See Drugs Acting on 5-Hydroxytryptamine Receptors: The Lancet Sep.
`23, 1989 and references cited therein. Drugs within this class include
`ondansetron, granisetron, alosetron, tropisetron, and dolasetron. These 5-HT 3
`antagonists are often administered intravenously shortly before chemotherapy or
`/radiotherapy is initiated, and can be ad1ninistered 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 chetnotherapeutic
`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 5-HT3 antagonist
`every day until the risk of etnesis has substantially subsided. The present class of
`5-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
`
`10
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`15
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`20
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`25
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`5579776vl 2
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`Exh. 1025, Page 2 of 20
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`

`
`acute emesis. Sabra, K, Choice of a SHT3 Receptor Antagonist for the Hospital
`Formula1y. EHP, Oct. 1996;2 (suppll):S19-24.
`
`5
`
`Recently, clinical investigations have been made concerning palonosetron,
`a new 5-HT3 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
`However,
`fonnulating palonosetron
`in
`liquid
`chemotherapeutic agents.
`formulations has not proven an easy task, typically due to shelf- stability issues.
`10 U.S. Pat. No. 5,202,333 discloses an intravenous formulation of palonosetron in
`example 13 that contains the following ingredients:
`
`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.
`
`. - --·--·-·--·--······
`
`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 tnade with ondansetron are
`disclosed in U.S. Patent Numbers 4,695,578, 4,753,789, 4,929,632, 5,240,954,
`5,344,658, 5,578,628, 5,578,632, 5,922,749, 5,622,720, 5,955,488, and 6,063,802.
`Cmnmercially it is distributed by GlaxoSmithKline as Zofran® and is indicated
`for prevention of postoperative nausea and vomiting
`(PONY), cancer
`5579776vl 3
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`20
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`Exh. 1025, Page 3 of 20
`
`

`
`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 Disintegrating Tablets.
`
`5
`
`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.
`Comtnercially it is 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.
`
`Alosetron, its uses, and medicaments made with alosetron are disclosed in
`10 U.S. Patent Numbers 5,360,800 and 6,284,770. Commercially it is distributed by
`GlaxoSmithKline as Lotronex®.
`
`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.
`
`15
`
`20
`
`Dolasetron, its uses, and medicaments made with ondansetron are
`disclosed in U.S. Patent Numbers 5,011,846, 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-HT 3 receptor antagonist and its
`pharmaceutically acceptable carriers that would facilitate making a formulation
`with this increased stability.
`
`25
`
`It is an object of the present invention to provide a fonnulation of
`Palonosetron hydrochloride with increased pharmaceutical stability for preventing
`and/or reducing emesis.
`
`5579776vl 4
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`Exh. 1025, Page 4 of 20
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`

`
`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 which would allow for prolonged storage.
`
`5
`
`It is also an object of the invention to provide a formulation of
`Palonosetron which would allow terminal sterilization.
`
`SUMMARY OF THE INVENTION
`
`10
`
`15
`
`20
`
`25
`
`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
`24 months at room tetnperature, 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 irlstances only 111 oth
`the amount of 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 mg/tnL palonosetron or a pharmaceutically
`acceptable salt thereof; and b) a pharmaceutically acceptable canier.
`
`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
`
`5579776vl 5
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`Exh. 1025, Page 5 of 20
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`

`
`another emboditnent the invention provides a pharmaceutically stable solution for
`preventing or reducing emesis cmnprising from about 0.01 to about 5.0 mg/ml
`palonosetron or a phannaceutically acceptable salt thereof; from about 10 to about
`100 millitnoles citrate buffer; and from about 0.005 to about 1.0 mg/ml EDTA.
`
`5
`
`10
`
`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
`
`DEFINITIONS
`
`15
`
`"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, 1niniature screw-top jars, and any other type of container
`of a size capable of holding only one unit dose of palonosetron (typically about 5
`20 mls.).
`
`Throughout this specification 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
`
`25
`
`means
`"Palonosetron"
`(3aS)-2,3,3a,4,5,6-Hexahydro-2-[(S)-l-
`Azabicyclo[2.2.2]oct -3-yl]2,3,3 a,4,5,6-hexahydro-l-oxo-1Hbenz[ de ]isoquinoline,
`
`5579776vl 6
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`Exh. 1025, Page 6 of 20
`
`

`
`the monohydrochloride.
`1s preferably present as
`and
`Palonosetron
`monohydrochloride can be represented by the following chemical structure:
`
`5
`
`10
`
`15
`
`Concentrations -- When concentrations of palonosetron are given herein,
`the concentration is measured in terms of the weight of the free base.
`Concentrations of all other ingredients 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 undesirable and includes that which is acceptable for
`veterinary use as well as human pharmaceutical use.
`
`are
`salts which
`salts" means
`acceptable
`"Pharmaceutically
`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, hydrobrotnic 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, 1nalic acid,
`maleic acid, fumaric acid,
`tartaric acid, citric acid, benzoic acid, o-( 4-
`5579776vl 7
`
`Exh. 1025, Page 7 of 20
`
`

`
`5
`
`10
`
`hydroxybenzoyl)benzoic acid, cinnrunic acid, mandelic acid, methanesulfonic
`acid, ethanesulfonic acid, 1 ,2,-ethanedisulfonic acid, 2-hydroxyethanesulfonic
`acid, benzenesulfonic acid p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic
`acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-
`ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-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
`organrc
`bases
`include
`ethanolrunine,
`diethanolrunine,
`triethanolrunine,
`tromethrunine, N-methylglucamine and the like.
`
`15
`
`DISCUSSION
`
`The fact nhat palonosetron can be formulated in some instances at
`concentrations of only about 1/10th the runount of other previously known
`compounds for treating emesis, surprisingly allows the use of concentrations of
`palonosetron far below those that would ordinarily be expected. Thus, in one
`emboditnent the invention provides a pharmaceutically stable solution for
`preventing or reducing emesis cotnprising a) from about 0.01 mg/mL to about 5
`mg/mL palonosetron or a pharmaceutically acceptable salt thereof; and b) a
`pharmaceutically acceptable carrier.
`Similarly, in another embodiment the
`invention provides a method of formulating a pharmaceutically stable solution of
`palonosetron comprising admixing frmn about 0.01 mg/mL to about 5 mg/mL
`palonosetron or a pharmaceutically acceptable
`salt
`thereof; with a
`pharmaceutically acceptable canier. In alternative etnbodiments, the formulation
`includes palonosetron or a phannaceutically acceptable salt thereof in a
`
`20
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`25
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`5579776vl 8
`
`Exh. 1025, Page 8 of 20
`
`

`
`5
`
`10
`
`15
`
`20
`
`25
`
`concentration from about 0.02 tng/mL to about 1.0 mg/tnL, 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
`1 0 to about 60 seconds, or about 1 0 to about 40 seconds, and most preferably is
`about 10 to 30 seconds.
`In one particular embodiment the palonosetron is
`supplied in vials that comprise 5 ml. of solution, which equates to about 0.25 mg
`ofpalonosetron 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 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 phannaceutically 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 formulating
`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 emboditnents, the pH is from about 4.5 to about 5.5, and most
`optitnally about 5.0. There are tnany 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 which could be used
`to adjust the pH of the formulation.
`
`In another embodi1nent 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 and (i) frotn
`about 10 to about 100 millimoles citrate buffer, and/or (ii) from about 0.005 to
`5579776vl 9
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`Exh. 1025, Page 9 of 20
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`

`
`about 1.0 mghnl EDTA. Similarly, in another etnbodiment the invention provides
`a 1nethod of fonnulating 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
`5 millimoles citrate buffer, and/or (ii) from about 0.005 to about 1.0 1ng/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. In various embodiments, the ranges of one or more of the
`foregoing ingredients can be modified as follows:
`
`10
`
`15
`
`20
`
`25
`
`formulation may comprise palonosetron or a
`The
`•
`pharmaceutically acceptable salt thereof in a concentration from about
`0.02 mg/tnL to about 1.0 mg/mL, from about 0.03 mg/mL to about 0.2
`mg/mL palonosetron hydrochloride, and most optimally about 0.05
`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 mg/ml, or about 0.3 to about 0.7
`mg/ml, and most optilnally about 0.5 n1g/ml.
`
`The inventors have further discovered that the addition of mannitol and a
`chelating agent can increase the stability of palonosetron fom1ulations. 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 pham1aceutically acceptable
`carrier, wherein the pharmaceutically acceptable carrier comprises a chelating
`agent and tnannitol. Similarly, in another etnbodiment the invention provides a
`method of formulating a pharmaceutically stable solution of palonosetron
`comprising admixing a) palonosetron or a pharmaceutically acceptable salt
`5579776v I 1 0
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`Exh. 1025, Page 10 of 20
`
`

`
`the
`earner, wherein
`acceptable
`a pharmaceutically
`thereof and b)
`pharmaceutically acceptable carrier comprises a chelating agent and mannitol.
`The chelating agent is preferably EDT A, and, in various embodiments the
`chelating agent is present in a concentration of from about 0.005 to about 1.0
`5 mg/mL or from about 0.05 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/tnL to about 60.0 mg/ml, or from about 40.0 to about
`45.0mg/ml.
`
`10
`
`15
`
`20
`
`25
`
`Injectable formulations are typically formulated as aqueous solutions in
`which 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/n1l 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
`injectable and oral liquid formulations, but it will be understood that the solutions
`tnay have alternative uses. For example, they may be used as intermediates in the
`preparation of other pharmaceutical dosage forms. Similarly, they tnay have
`Injectable
`other routes of administration including intranasal or inhalation.
`formulations may take any route including intramuscular, intravenous or
`subcutaneous.
`
`Still further etnbodiments relate to improvetnents in the ease with which
`the palonosetron formulation can be stored or manufactured. In particular, the
`5579776vl 11
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`Exh. 1025, Page 11 of 20
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`

`
`5
`
`inventors have discovered that the formulations of the present invention allow
`storage of the product for extended periods at room tetnperature. Thus, in yet
`another e1nbodiment the invention provides a method of storing one or 1nore
`containers
`in which are contained a solution of palonosetron or a
`pharmaceutically acceptable salt thereof cmnprising: 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 room for one month, 3 months, 6 months, one
`year, 18 months, 24 months or 11_1ore (but preferably not exceeding 36 months),
`10 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 frmn 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 a chelating agent, or
`(v) the solution comprises from about 10 to about 100 milliMoles of a citrate
`buffer.
`
`15
`
`20
`
`25
`
`The stability of the foregoing fonnulations 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 ml. vials); b) filling said 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 phannaceutical salt
`thereof is present in a concentration of from about 0.01 mg/mL to about 5 mghnL,
`(ii) the pH of the solution is frmn about 4.0 to about 6.0, (iii) the solution
`comprises frmn about 0.01 to about 5.0 1ng/ml palonosetron or a pharmaceutically
`acceptable salt thereof, from about 1 0 to about 1 00 millimoles citrate buffer and
`5579776vl 12
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`Exh. 1025, Page 12 of 20
`
`

`
`frmn 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.
`
`5
`
`10
`
`15
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`20
`
`25
`
`EXAMPLES
`
`EXAMPLE 1: STABILIZING PH
`
`A study was conducted to determine the effect of pH on formulations
`containing palonosetron hydrochloride, measuring 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: 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 of
`EDT A and citrate buffer were selected based on the opthnal formulation, 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.
`
`EXAMPLE 3: TONICIFYING AGENT
`
`Formulations of palonosetron hydrochloride In citrate buffer were
`prepared including either a) sodium chloride or b) mannitol. The palonosetron
`hydrochloride formulation including mannitol showed superior stability. The
`optimum level of n1annitol required for an isotonic solution was found to be
`4.15%.
`
`5579776v1 13
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`Exh. 1025, Page 13 of 20
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`

`
`EXAMPLE 4: FORMULATION I
`
`The following is a representative pharmaceutical formulation containing
`is useful for intravenous formulations, or other liquid
`palonosetron that
`formulations of the drug.
`
`Ingredient
`P alonosetron Hydrochloride
`Mannitol
`EDTA
`Trisodium citrate
`Citric acid
`WFJ
`Sodium hydroxide solution and/ or
`hydrochloric acid solution
`* calculated as a free base
`
`5
`
`mg/mL
`
`0.05*
`41.5
`0.5
`3.7
`1.56
`q.s. to 1 m1
`pH 5.0 ±0.5
`
`EXAMPLE 5: FORMULATION II
`
`The following is a representative phannaceutical formulation containing
`palonosetron that is useful for oral fonnulations, or other liquid formulations of
`the drug.
`
`10
`
`··--
`
`Ingredient
`··-· ··----------··· ··-----------~-·-- --········--·-··
`Palonosetron Hydrochloride
`Mannitol
`EDTA
`Trisodium citrate
`Citric acid
`WFJ
`5579776vl 14
`
`mg/mL
`..... --- --····-···· -··-·-·--··-·----·-··--····-·····
`0.05*
`150
`0.5
`3.7
`1.56
`q.s. to l1nl
`
`--·---------
`
`Exh. 1025, Page 14 of 20
`
`

`
`Sodium hydroxide solution and/or
`!hydrochloric acid solution
`Flavoring
`*calculated as a free base
`
`pH 5.0 ± 0.5
`
`q.s.
`
`5
`
`10
`
`15
`
`20
`
`EXAMPLE 6- STABILITY OF P ALONOSETRON WITHOUT DEXAMETHASONE
`
`The physical and chemical stability of palonosetron HCl was studies in
`concentrations of 5 J..Lg/mL and 30 J..Lg/mL in 5% dextrose injection, 0.9% sodium
`chloride injection, 5% dextrose in 0.45% sodium chloride injection, and dextrose
`5% in lactated Ringer's injection. The admixtures were evaluated over 14 days at
`4 oc in the dark and for 48 hours at 23 °C under fluorescent light.
`Test samples of palonosetron HCl were prepared in polyvinyl chloride
`(PVC) bags of the infusion solutions at concentrations of 5 and 30 Jlg/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, turbidity and particle content were tneasured electronically. Chemical
`stability of the drug was evaluated by using a stability-indicating high
`performance liquid chromatographic (HPLC) analytical technique.
`
`All samples were physically stable throughout the study. The solution
`remained clear, and little or no change in particulate burden and haze level were
`found. Additionally, little or no loss of palonosetron HCl occurred in any of the
`smnples at either tetnperature throughout the entire study period.
`
`EXAMPLE 7- STABILITY OF P ALONOSETRON WITH DEXAMETHASONE
`
`The physical and chemical stability of palonosetron HCl 0.25 mg admixed
`with dexmnethasone (as sodium phosphate) 10 mg or 20 mg in 5% dextrose
`injection or 0.9% sodiu1n chloride injection in polyvinyl chloride (PVC)
`
`5579776vl 15
`
`Exh. 1025, Page 15 of 20
`
`

`
`minibags, and also admixed with dexatnethasone (as sodiutn phosphate) 3.3 tng in
`5% dextrose injection or 0.9% sodium chloride injection in polypropylene
`syringes at 4 oc in the dark for 14 days and at 23 oc exposed to normal laboratory
`fluorescent light over 48 hours, was studied.
`
`Test samples of palonosetron HCl 5 J.Lg/mL with dexamethasone (as
`sodium phosphate) 0.2 mg/mL and also 0.4 mg/mL were prepared in polyvinyl
`chloride (PVC) minibags of each infusion solution. Additionally, palonosetron
`HCl 25 J.Lg/mL with dexatnethasone (as sodium phosphate) 0.33 mg/mL in each
`infusion solution were prepared as 10 mL of test solution in 20-mL polypropylene
`syringes. Evaluations for physical and chemical stability were performed on
`satnples taken initially and after 1, 3, 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 monodirectionallight
`beatn. In addition, turbidity and particle content were measured electronically.
`Chemical stability of the drug was evaluated by using a stability-indicating high
`performance liquid chromatographic (HPLC) analytical technique.
`
`All satnples were physically compatible throughout the study. The
`solutions remained clear, and little or no change in particulate burden and haze
`level were found. Additionally, little or no loss of palonosetron HCl and
`dexamethasone occurred in any of the samples at either temperature throughout
`the entire study period.
`
`5
`
`10
`
`15
`
`20
`
`EXAMPLE 8: FORMULATION Ill
`
`is a representative pharmaceutical formulation and
`The following
`container closure for palonosetron that is useful for intravenous infusion
`formulations.
`
`25
`
`Ingredient
`
`..1
`
`Amount (mg)
`
`5579776vl 16
`
`Exh. 1025, Page 16 of 20
`
`

`
`---·-
`
`-·-
`
`-·-
`
`.... ----·--·------·--··
`. - -·--·· -.. ·--··
`Palonosetron Hydrochloride
`Sodium Chloride
`EDTA
`Sodium citrate
`Citric acid monohydrate
`WFJ
`Sodium hydroxide solution and/or
`hydrochloric acid solution
`Container closure system
`
`. ··,-·· .....
`
`·-
`
`.... 0.75a)
`
`·····-- . .... ··-·····---··--···---··-·---··--
`
`450.0
`2.5
`18.5
`7.8
`q.s. to 50mL
`pH 4.8 ± 0.5
`
`plastic containerbJ
`plus rubber stopperc)
`
`a) Calculated based on the we1ght of free base.
`b) Polyethylene multilayer film infusion bag.
`c) Isoprene rubber stopper.
`
`5
`
`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 :fr01n the foregoing detailed description of the invention.
`
`5579776vl 17
`
`Exh. 1025, Page 17 of 20
`
`

`
`What is claimed is:
`
`CLAIMS
`
`1. A pharmaceutical single-use, unit-dose formulation for intravenous
`administration to a human to reduce the likelihood of cancer chemotherapy-
`induced nausea and vomiting, comprising a 5 mL sterile aqueous isotonic
`solution, said solution comprising:
`
`5
`
`palonosetron hydrochloride in an amount of 0.25 mg based on the weight
`of its free base;
`
`from 0.005 mg/mL to 1.0 mg/mL EDTA; and
`
`10
`
`from 10 mg/mL to 80 mg/mL mannitol,
`
`wherein said formulation is stable at 24 months when stored at room
`temperature.
`
`2. The pharmaceutical formulation of claim 1, wherein said EDT A is in
`an atnount of 0.5 mg/mL.
`
`15
`
`3. The pharmaceutical fonnulation of claim 1, wherein said mannitol is in
`an amount of 41.5 mg/mL.
`
`4. The pharmaceutical formulation of claim 1, wherein said solution
`further cotnprises a citrate buffer.
`
`5. The pharmaceutical formulation of claim 4, wherein said citrate buffer
`is at a concentration of 20 millimolar.
`
`20
`
`6. The pharmaceutical formulation of claim 1, wherein said solution is
`buffered at a pH of 5.0 ± 0.5.
`
`7. The phannaceutical formulation of claim 1, wherein said EDTA is in
`an an1ount of 0.5 mg/mL, wherein said mannitol is in an amount of 41.5 mg/mL,
`
`5579776vl 18
`
`Exh. 1025, Page 18 of 20
`
`

`
`wherein said solution further comprises a citrate buffer at a concentration of 20
`tnillitnolar, and wherein said solution is buffered at a pH of 5.0 ± 0.5.
`
`8. A pharmaceutical single-use, unit-dose formulation for intravenous
`administration to a human to reduce the likelihood of cancer chemotherapy-
`induced nausea and vomiting, comprising a 5 mL sterile aqueous isotonic
`solution, said solution comprising:
`
`5
`
`palonosetron hydrochloride in an amount of 0.25 mg based on the weight
`of its free base;
`
`from 0.005 mg/mL to 1.0 mg/mL EDTA; and
`
`10 .
`
`from 10 mg/mL to 80 mg/mL mannitol, wherein said formulation is stable
`at 18 months when stored at room temperature.
`
`9. A pharmaceutical single-use, unit-dose formulation for intravenous
`adtninistration to a human to reduce the likelihood of cancer chemotherapy-
`induced nausea and vomiting, comprising a 50 mL sterile isotonic solution
`buffered at a pH of 4.8 ± 0.5 comprising:
`
`15
`
`palonosetron hydrochloride in an amount of 0. 75 mg based on the weight
`of its free base;
`
`450.0 mg sodium chloride;
`
`2.5 mgEDTA;
`
`20
`
`18.5 mg sodium citrate; and
`
`7.8 mg citric acid monohydrate,
`
`wherein said formulation is contained in a polyethylene n1ultilayer film infusion
`bag comprising an isoprene rubber stopper.
`
`5579776vl 19
`
`Exh. 1025, Page 19 of 20
`
`

`
`ABSTRACT
`
`The present invention relates to shelf-stable liquid formulations of
`palonosetron for reducing chemotherapy and radiotherapy induced emesis with
`palonosetron. The formulations are particularly useful in the preparation of
`intravenous and oral liquid medicaments.
`
`5
`
`5579776vl 20
`
`Exh. 1025, Page 20 of 20