Patent Application
`
`entitled
`
`BENDAMUSTINE PHARMACEUTICAL COMPOSITIONS
`
`Inventors;
`
`Jason Edward Brittain
`1580 Chiswick Ct.
`
`El Cajon, CA 92020
`
`Gary T. Elliott
`12433 Kingspine Ave.
`San Diego, CA 92131
`
`Joe Craig Franklin -
`11519 Kirby Place
`San Diego, CA92126
`
`CERTIFICATE OF MAILILNG BY “EXPRESS MAIL”
`“EXPRESS MAIL” Label Number: EU882120300US
`
`DATE OF DEPOSIT: Januag 14, 2005
`
`I hereby certify that this paper or fee is being deposited with the United States Postal Service “Express
`
`Mail-Post Office to Addressee” service under 37 C.F.R.§ 1.10 on the date indicated above and is addressed
`
`to : Mail Stop Provisional Patent Application, Commissioner for Patents, P.O. Box 1450, Alexandria, VA
`22313-1450.
`
`flmfw./Dd
`
`Robert W. Prince
`
`Number of Drawings: 6 (on 6 pages)
`Docket No.: O32PRV
`
`AGILA ET AL - EXHIBIT 1018 I
`0001
`
`0001
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`AGILA ET AL - EXHIBIT 1018
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`

`
`FIELD OF THE INVENTION
`
`The present invention pertains to the field of pharmaceutical compositions for the
`
`treatment of various disease states, especially neoplastic diseases and autoimmune
`
`diseases. Particularly, it relates to pharmaceutical formulations comprising nitrogen
`
`mustards, particularly the nitrogen mustard bendamustine, e.g., bendamustine HCI.
`
`BACKGROUND OF THE INVENTION
`
`The following description includes information that may be useful in understanding the
`
`present invention. It is not an admission that any such information is prior art, or
`
`relevant, to the presently claimed inventions, or that any publication specifically or
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`implicitly referenced is prior art.
`
`Because of their high reactivity in aqueous solutions, nitrogen mustards are difficultito
`
`formulate as pharmaceuticals and are ofien supplied for administration in a lyophilized
`
`form that requires reconstitution, usually in water, by skilled hospital personal prior to
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`administration. Once in aqueous solution, nitrogen mustards are subject to degradation
`
`by hydrolysis, thus, the reconstituted product should be administered to a patient as soon
`
`as possible after its reconstitution.
`
`Bendamustine, (4-{5-[Bis(2-chloroethy])amino]—1-methyl-2-benzimidazolyl} butyric
`
`acid, is an atypical structure with a benzimidazole ring, whose structure includes an
`
`active nitrogen mustard (see Formula. 1, which shows bendamustine hydrochloride).
`
`* CI/H
`I
`J/NWLiEN‘>—\_O>~OH -HCI
`'1
`
`Cl
`
`Formula I
`
`Bendamustine was initially synthesized in 1963 in the German Democratic Republic
`
`(GDR) and was available from 1971 to 1992 in that location under the name
`
`Cytostasan®. Since that time, it has been marketed in Germany under the tradename
`
`Ribomustin®. It has been widely used in Germany to treat chronic lymphocytic
`
`leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma, and breast
`
`cancer.
`
`0002
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`0002
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`

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`Due to its degradation in aqueous solutions (like other nitrogen mustards), bendamustine
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`is supplied as a lyophilized product. The current lyophilized formulation of
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`bendamustine (Ribomustin®) contains bendamustine hydrochloride and mannitol in a
`
`sterile lyophilized form as a white powder for intravenous use following reconstitution.
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`The finished lyophilisate is unstable when exposed to light. Therefore, the product is
`
`stored in brown or amber—colored glass bottles. The current lyophilized formulation of
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`bendamustine contains degradation products that may occur during manufacturing of the
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`drug substance and/or during the lyophilization process to make the finished drug
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`product.
`
`Currently bendamustine is formulated as a lyophilized powder for injection with 100 mg
`
`of drug per 50 mL Vial or 25 mg of drug per 20 mL vial. The vials are opened and
`
`reconstituted as close to the time of patient administration as possible. The product is
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`reconstituted with 40 mL (for the 100 mg presentation) or 10 mL (for the 25 mg
`
`presentation) of Sterile Water for Injection. The reconstituted product is further diluted
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`into 500 mL, q.s., 0.9% Sodium Chloride for Injection. The route of administration is by
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`intravenous infusion over 30 to 60 minutes.
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`Following reconstitution with 40 mL Sterile Water for Injection, vials of bendamustine
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`are stable for a period of 7 hours under room temperature storage or for 6 days upon
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`storage at 2—8°C. The 500 mL admixture solution must be administered to the patient
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`within 7 hours of vial reconstitution (assuming room temperature storage of the
`
`admixture).
`
`The reconstitution of the present bendamustine lyophilized powder is difficult. Reports
`
`from the clinic indicate that reconstitution can require at least fifteen minutes and may
`
`require as long as thirty minutes. Besides being burdensome and time-consuming for the
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`healthcare professional responsible for reconstituting the product, the lengthy exposure of
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`bendamustine to water during the reconstitution process increases the potential for loss of
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`potency and impurity formation due to the hydrolysis of the product by water.
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`0003
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`0003
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`

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`Thus, a need exists for lyophilized formulations of bendamustine that are easier to
`
`reconstitute and which have a better impurity profile than the current lyophilate
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`(lyophilized powder) fonnulations of bendamustine.
`
`German (GDR) Patent No. 34727 discloses a method of preparing (o-[5-bis-(B-
`
`chloroethyl)-amino-benzimidazolyl-(2)]-alkane carboxylic acids substituted in the 1-
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`position.
`
`German (GDR) Patent No. 80967 discloses an injectable preparation of y-[1-methyl-5-
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`bis-([3-chloroethyl)-amino-benzimaidazolyl-(2)]-butric acid hydrochloride.
`
`Gennan (GDR) Patent No. 159877 discloses a method for preparing 4-[1 —methyl-5—bis
`
`(2-chloroethyl) amino-benzimidazolyl-2)-butyric acid.
`
`German (GDR) Patent No. 159289 discloses an injectable solution of bendamustine.
`
`Ribomustin® bendamustine Product monograph (updated 1/2002)
`
`http://www.ribosepharm.de/pdf/ribomustin bendamustin/productmonographpdf provides
`
`information about Ribomustin® including product description.
`
`Ni et al. report that the nitrosourea SarCNU was more stable in pure tertiary butanol than
`
`in pure acetic acid, dimethyl sulfoxide, methylhydroxy, water or in TBA/water mixtures 0
`
`(Ni et al. (2001) Int]. J. Phamaceutics 226239-46).
`
`Lyophilized cyclophoshamide is known in the alt see e.g., US Patent Nos. 5,418,223;
`
`5,413,995; 5,268,368; 5,227,374; 5,130,305; 4,659,699; 4,537,883; and 5,066,647.
`
`The lyophilized nitrogen mustard Ifosfamide is disclosed in International Publication No.
`
`WO 2003/066027; US Pat. Nos. 6,613,927; 5,750,131; 5,972,912; 5,227,373; and
`
`5,204,335.
`
`Teagarden et al. disclose lyophilized formulations of prostaglandin E-1 made by
`
`dissolving PGE-1 in a solution of lactose and tertiary butyl alcohol (US Pat. No.
`
`5,770,230).
`
`0004
`
`0004
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`

`
`SUMMARY OF THE INVENTION
`
`The present invention is directed to stable pharmaceutical compositions of nitrogen
`
`mustards, in particular lyophilized bendamustine and its use in treatment of various
`
`disease states, especially neoplastic diseases and autoimmune diseases.
`
`An embodiment of the invention is a pharmaceutical composition of bendamustine
`
`containing not more than about 0.5% to about 0.9% (area percent of bendamustine) HP1,
`
`as shown in Formula II, where the HP1 is the amount of HP] present at time zero after
`
`reconstitution of a lyophilized pharmaceutical composition of bendamustine as described
`
`herein.
`
`HO/\L
`N
`O
`Clf \(:[N:>_\_>_OH Formula 11.
`
`Another embodiment of the invention is a lyophilized preparation of bendamustine
`
`containing not more than about 0.1 % to about 0.3% bendamustine dimer as shown in
`
`Formula III at time zero after reconstitution.
`
`Ho’fi
`Ho’\/N
`
`HO
`
`0
`N
`7:
`I Ii>LN:*\_>‘°“
`
`\
`
`Formula III
`
`Yet another embodiment of the invention is a lyophilized preparation of bendamustine
`
`containing not more than about 0.5% to about 0.15% bendamustine ethylester, as shown
`
`in Formula IV at time zero after reconstitution
`
`C|
`
`%
`
`COOCH2CH3
`
`Formula IV.
`
`0005
`
`0005
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`

`
`Still another embodiment of the invention is a lyophilized preparation of bendamustine
`
`containing not more than about 0.5 % to about 0.9% (area percent of bendamustine) HP1
`
`at the time of drug product release. An aspect of this embodiment is lyophilized
`
`preparations of bendamustine containing not more than about 0.5 % to about 0.9% (area
`
`percent of bendamustine) HP1 at the time of release of drug product where the
`
`lyophilized preparation is packaged in a vial or other pharmaceutically acceptable
`
`container.
`
`In yet another aspect of the invention, the lyophilized preparations of bendamustine are
`
`stable with respect to the amount of HP1 for at least about 6 months to about 36 months
`
`i or greater when stored at about 2° to about 30°. Preferred temperatures for storage are
`
`about 5° C and about room temperature.
`
`Another embodiment of the invention is a pharmaceutical dosage form that includes a
`
`pharmaceutical composition of bendamustine containing not more than about 0.5% to
`
`about 0.9% HP1 where the HP1 is the amount of HP1 present at time zero afier
`
`reconstitution of a lyophilized preparation of bendamustine of the present invention. In
`
`preferred aspects of the invention, the dosage form can be about 5 to about 500 mg of
`bendamustine, about 10 to about 300 mg of bendamustine, about 25 mg of bendamustine,
`
`about 100 mg of bendamustine, and about 200 mg of bendamustine.
`
`Yet another embodiment of the invention is a pharmaceutical dosage form that includes a
`
`lyophilized preparation of bendamustine containing not more than about 0.5% to about
`
`0.9% HP1. Preferred dosage forms can be about 5 to about 500 mg of bendamustine,
`
`about 10 to about 300 mg of bendamustine, about 25 mg of bendamustine, about 100 mg
`
`of bendamustine, and about 200 mg of bendamustine.
`
`In still another embodiment, the invention includes a pharmaceutical composition of
`
`bendamustine including bendamustine containing not more than about 0.5%‘to about
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`0.9% HP1 (area percent of bendamustine) and a trace amount of one or more organic
`
`solvents, wherein said HP] is the amount of HP1 present at time zero after reconstitution
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`of a lyophilized pharmaceutical composition of bendamustine as disclosed herein.
`
`In
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`different aspects of this embodiment, the organic solvent is selected from one or more of
`
`tertiary butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol, acetone, ethyl
`
`0006
`
`0006
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`

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`acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl
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`isobutyl ketone, l-pentanol, methyl acetate, carbon tetrachloride, dimethyl sulfoxide,
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`hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, and cyclohexane.
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`Preferred organic solvents include one or more of ethanol, methanol, propanol, butanol,
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`isopropanol, and tertiary butanol. A more preferred organic solvent is tertiary butanol,
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`also known as TBA, and t-butanol.
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`The present invention involves a method for obtaining agency approval for a
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`bendamustine product, the improvement which includes setting a release specification for
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`bendamustine degradants at about 2.0 % to about 5.5 % (area percent bendamustine) or
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`otherwise to achieve the pharmaceutical compositions described herein.
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`Another embodiment is a method for obtaining agency approval for a bendamustine
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`product, the improvement which includes setting a shelf-life specification for
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`bendamustine degradants at about 5.0% to about 8.0% (area percent bendamustine)
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`where the product is stored at about 2°C to about 30°C. Preferred temperatures for
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`storage are about 5°C and about room temperature.
`
`Another embodiment of the invention is a process for manufacturing a lyophilized
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`preparation of bendamustine which includes controlling for the concentration of
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`bendamustine degradants in the final product, such that the concentration of
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`bendamustine degradants is no more than about 5.5 % to about 2.0 % (area percent of
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`bendamustine) at release or otherwise to achieve the pharmaceutical compositions
`
`described herein.
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`The present invention discloses a process for manufacturing a lyophilized preparation of
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`bendamustine which includes controlling for the concentration of bendamustine
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`degradants in the final product, such that the concentration of bendamustine degradants is
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`no more than about 8.0% to about 5.0% at the time of product expiration; wherein said
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`product is stored at about 2°C to about 30°C.
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`Another embodiment of the invention is a bendamustine pre-lyophilization solution or
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`dispersion comprising one or more organic solvents where the solution or dispersions
`
`include at least one stabilizing concentration of an organic solvent which reduces the
`
`level of degradation of bendamustine so that the amount of HP1 produced during
`
`0007
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`0007
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`

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`lyophilization from about 0 to 24 hours does not exceed about 0.5% to about 0.9% (area
`
`percent bendamustine). An aspect of this embodiment is the lyophilized powder
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`produced from the pre-lyophilization solution or dispersion.
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`Still another embodiment of the invention is a bendamustine pre-lyophilization solution
`
`or dispersion comprising one or more organic solvents where the solution or dispersions
`
`include at least one stabilizing concentration of an organic solvent which reduces the
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`level of degradation of bendamustine so that the amount of bendamustine dimer produced
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`during lyophilization from about 0 to 24 hours does not exceed about 0.5% to about 0.9%
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`(area percent bendamustine). An aspect of this embodiment is the lyophilized powder
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`produced from the pre-lyophilization solution or dispersion.
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`The invention also discloses methods for preparing a bendamustine lyophilized
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`preparation that includes dissolving bendamustine in a stabilizing concentration of an
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`alcohol solvent of between about 5% to about 100% (v/v) alcohol; and lyophilizing the
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`mixture wherein the bendamustine lyophilized preparation made from such methods
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`contains not more than about 0.5% to about 0.9% (area percent of bendamustine) HP1 as
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`shown in Formula II, wherein said HP1 is the amount of HP] present at time zero afier
`
`reconstitution of the lyophilized pharmaceutical composition of bendamustine. Other
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`alcohol concentrations include about 5% to about 99.9%, about 3% to about 70%, about
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`5% to about 60%, about 3% to about 50%, about 3% to about 40%, about 20% to about
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`35%. Preferred concentrations of alcohol are from about 20% to about 30%. Preferred
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`alcohols include one or more of methanol, ethanol, propanol, iso-propanol, butanol, and
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`tertiary-butanol. A more preferred alcohol is tertiary-butanol. A preferred concentration
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`of tertiary-butanol is about 20% to about 30%. An aspect of this embodiment is the
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`addition of an excipient before lyophilization. A preferred excipient is mannitol.
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`Preferred concentrations of bendamustine are from about 2 mg/mL to about 50 mg/mL.
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`An aspect of this embodiment includes the lyophilized powder obtained from the
`
`methods of preparation disclosed herein.
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`The invention also involves bendamustine formulations for lyophilization that include an
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`excipient and a stabilizing concentration of an organic solvent. A preferred formulation
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`includes bendamustine at a concentration of about 15 mg/mL, mannitol at a concentration
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`0008
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`0008
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`

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`of about 25.5 mg/mL, tertiary-butyl alcohol at a concentration of about 30% (v/v) and
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`water. Included in this embodiment of the invention are the lyophilized preparations
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`made from such bendamustine formulations.
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`Included in the inventions are methods of treating a medical condition in a patient that
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`involve administering a therapeutically effective amount of a pharmaceutical composition
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`of the invention where the condition is amenable to treatment with said pharmaceutical
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`composition. Some conditions amenable to treatment with the compositons of the
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`invention include chronic lymphocytic leukemia (CLL), Hodgkin’s disease, non-
`
`Hodgkin’s lymphoma (NHL), multiple myeloma (MM), breast cancer, small cell lung
`cancer, hyperproliferative disorders, and an autoimmune disease. Preferred conditions
`
`include NHL, CLL, brest cancer, and MM. Preferred autoimmune diseases include
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`rheumatoid arthritis, multiple sclerosis or lupus.
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`Also included in the invention are methods of treating in which the pharmaceutical
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`compositions of the invention are in combination with one or more anti-neoplastic agents
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`where the antineoplastic agent is given prior, concurrently, or subsequent to the
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`administration of the pharmaceutical composition of the invention. Preferred
`antineoplastic agents are antibodies specific for CD20.
`
`Another embodiment of the invention is a lyophilization cycle for producing lyophilized
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`bendamustine preparations of the invention. A preferred lyophilization cycle includes a)
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`freezing to about -50°C over about 8 hours; b) holding at -50°C for about 4 hours; c)
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`ramping to -25°C over about 3 hours; d) holding at -10°C for 30 hours; e) ramping to
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`between about 25°C and about 40°C or higher for about 3 hours; t) holding between
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`about 25°C and about 40°C for about 25 hours; g) ramping to about 20°C in 1 hour; h)
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`unloading at about 20°C, at a pressure of 13.5 psi in a pharrnaceutically acceptable
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`container that is hermetically sealed; wherein the pressure is about 150 microns
`
`throughout primary drying and 50 microns throughout secondary drying. An aspect of
`
`this cycle involves step (e) which is ramped to about 30-35°C for 3 hours and then
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`ramped to 40°C for 5 hours. Another aspect of this embodiment is the lyophilized
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`powered prepared from such lyophilization cycles.
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`0009
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`0009
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`

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`The invention also encompasses a pharmaceutical dosage form of bendamustine
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`containing not more than about 0.5 % to about 0.9% HP1 (area percent of bendamustine)
`
`wherein said dosage form comprises a vial or other pharmaceutically acceptable
`
`container, wherein said HP1 is the amount of HP1 present pre-reconstitution or at time
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`zero after reconstitution of said dosage form. Preferred concentrations of bendamustine
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`include about 120 to about 500 mg/container, about 100 mg/container, about 5 mg to about
`
`2 g/container and about 170 mg/container.
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`Another aspect of the invention is a lyophilized preparation of bendamustine that can be
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`reconstituted in water at room temperature in under about 10 minutes to about 5 minutes.
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`Another embodiment of the invention is a method for reducing the formation of
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`bendamustine degradants in a lyophilized preparation by preparing a pre-lyophilization
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`solution or dispersion of one or more organic solvents, wherein said solution comprises at
`least one stabilizing concentration of an organic solvent which reduces the level of
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`degradation of bendamustine so that the amount of HP] produced during lyophilization
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`from about 1 to 24 hours does not exceed about 0.5% to about 0.9% (area percent
`
`bendamustine) and said pre-lyophilization solution or dispersion is prepared using one or
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`more means to reduce free radical production. Such means can include one or more of
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`the following: 1) making the pre-lyophilization solution or dispersion at temperatures
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`below about 40°C; 2) adding an antioxidant such as an excipient that has antioxidant
`
`properties, including mannitol; 3) preparing the pre-lyophilization or dispersion under
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`gas; preparing the pre-lyophilization solution or dispersion under conditions devoid of
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`ultraviolet light; and 4) the pre-lyophilization solution or dispersion in a container that
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`blocks or reduces ultraviolet light.
`
`The present invention also includes pre-lyophilized pharmaceutical compositions of
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`bendamustine. A preferred pre-lyophilized composition includes bendamustine HC1
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`about 15 mg/mL, mannitol about 25.5 mg/mL, about 30% (v/v) tertiary-butyl alcohol,
`
`and water.
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`These and other embodiments of the invention are described hereinbelow or are evident
`
`to persons of ordinary skill in the art based on the following disclosures.
`
`10
`
`0010
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`0010
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`

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`BRIEF DESCRIPTION OF THE DRAWINGS
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`Fig. 1 shows the solubility of bendamustine at various temperatures for two different
`
`solutions of bendamustine in tertiary butanol.
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`Fig. 2 shows the purity results of an HPLC analysis after incubating bendamustine in
`
`various alcohols for 24 hours at 5°C. Results are presented as the area percent of the
`
`bendamustine peak.
`
`Fig. 3 shows HP1 (Formula II) formation after 24 hours in various alcohol/water co-
`
`solvents at 5°C
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`Fig 4 shows dimer (Formula III) formation after 24 hours in various alcohol/water co-
`
`solvents at 5°C
`
`Fig. 5- shows a lyophilization cycle for bendamustine using a TBA/water cosolvent.
`
`Fig. 6 shows a chromatogram for Ribomustin® using HPLC method No.-1.
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`DETAILED DESCRIPTION OF THE INVENTION
`
`Definitions:
`
`As used herein, the terms “formulate” refers to the preparation of a drug, e.g.,
`
`bendamustine, in a form suitable for administration to a mammalian patient, preferably a
`
`human. Thus, "formulation" can include the addition of pharmaceutically acceptable
`
`excipients, diluents, or carriers.
`
`Asused herein, the term “lyophilized powder” or “lyophilized preparation” refers to any
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`solid material obtained by lyophilization, i.e., freeze-drying of an aqueous solution. The
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`aqueous solution may contain a non-aqueous solvent and/or a solution composed of an
`
`aqueous and non-aqueous solvent(s).
`
`By “stable pharmaceutical composition” is meant any phannaceutical composition
`
`having sufficient stability to have utility as a pharmaceutical product. Preferably, a stable
`
`11
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`0011
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`0011
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`

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`pharmaceutical composition has sufficient stability to allow storage at a convenient
`
`temperature, preferably between -20°C and 40°C, more preferably about 2°C to about
`
`30°C, for a reasonable period of time, e.g., the shelf-life of the product which can be as
`
`short as one month but is typically six months or longer, more preferably one year or
`
`longer even more preferably twenty-four months or longer, and even more preferably
`
`thirty-six months or longer. The shelf-life or expiration can be that amount of time where
`
`the active ingredient degrades to a point below 90% purity. For purposes of the present
`
`invention stable pharmaceutical composition includes reference to pharmaceutical
`
`compositions with specific ranges of impurities asdescribed herein. Preferably, a stable
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`pharmaceutical composition is one which has minimal degradation of the active
`
`ingredient, e.g., it retains at least about 85 % of undegraded active, preferably at least
`
`about 90 %, and more preferably at least about 95%, after storage at 2-30°C for a 2-3 year
`
`period of time.
`
`By “degraded” is meant that the active has undergone a change in chemical structure.
`
`The term "therapeutically effective amount" as used herein refers to that amount of the
`
`compound being administered that will relieve to some extent one or more of the
`
`symptoms of the disorder being treated. In reference to the treatment of neoplasms, a
`
`therapeutically effective amount refers to that amount which has the effect of (1)
`
`reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably
`
`stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent,
`
`preferably stopping) tumor growth, and/or, (4) relieving to some extent (or, preferably,
`
`eliminating) one or more symptoms associated with the cancer. Therapeutically effective
`
`amount can also mean preventing the disease from occurring in an animal that may be
`
`predisposed to the disease but does not yet experience or exhibit symptoms of the disease
`
`(prophylactic treatment). Further, therapeutically effective amount can be that amount
`
`that increases the life expectancy of a patient afflicted with a terminal disorder. Typical
`
`therapeutically effective doses for bendamustine for the treatment of non-Hodgkin’s
`
`lymphoma can be from about 60-120 mg/m2 given as a single dose on two consecutive
`
`days. The cycle can be repeated about every three to four weeks. For the treatment of
`
`chronic lymphocytic leukemia (CLL) bendamustine can be given at about 80-100 mg/m2
`
`on days 1 and 2. The cycle can be repeated afier about 4 weeks. For the treatment of
`
`12
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`0012
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`0012
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`

`
`Hodgkin’s disease (stages II-IV), bendamustine can be given in the “DBVBe regimen”
`
`with daunorubicin 25 mg/m2 on days 1 and 15, bleomycin 10 mg/m2 on days 1 and 15,
`
`vincristine 1.4 mg/m2 on days 1 and 15, and bendamustine 50 mg/m2 on days 1-5 with
`
`repetition of the cycle about every 4 weeks. For breast cancer, bendamustine (120
`
`mg/m2) on days 1 and 8 can be given in combination with methotrexate 40 mg/m2 on
`
`days 1 and 8, and 5-fluorouracil 600 mg/m2 on days 1 and 8 with repetition of the cycle
`
`about every 4 weeks. Asa second-line of therapy for breast cancer, bendamustine can be
`
`given at about 100-150 mg/m2 on days 1 and 2 with repetition of the cycle about every 4
`
`weeks.
`
`As used herein "neoplastic" refers to a neoplasm, which is an abnormal growth, such
`
`growth occurring because of a proliferation of cells not subject to the usual limitations of
`
`growth. As used herein, "anti-neoplastic agent" is any compound, composition,
`
`admixture, co-mixture, or blend which inhibits, eliminates, retards, or reverses the
`
`neoplastic phenotype of a cell.
`
`As used herein "hyperproliferation" is the overproduction of cells in response to a
`
`particular growth factor. "Hyperproliferative disorders" are diseases in which the cells
`
`overproduce in response to a particular growth factor. Examples of such
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`"hyperproliferative disorders" include diabetic retinopathy, psoriasis, endometriosis,
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`cancer, macular degenerative disorders and benign growth disorders such as prostate
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`enlargement.
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`As used herein, the term “vial” refers to any walled container, whether rigid or flexible.
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`"Controlling" as used herein means putting process controls in place to facilitate
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`achievement of the thing being controlled. For example, in a given case, "controlling"
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`can mean testing samples of each lot or a number of lots regularly or randomly; setting
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`the concentration of degradants as a release specification; selecting process conditions,
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`e.g., use of alcohols and/or other organic solvents in the pre-lyophilization solution or
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`dispersion, so as to assure that the concentration of degradants of the active ingredient is
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`not unacceptably high; etc. Controlling for degradants by setting release specifications .
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`for the amount of degradants can be used to facilitate regulatory approval of a
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`pharmaceutical product by a regulatory agency, such as the U.S. Food and Drug
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`Administration and similar agencies in other countries or regions ("agency").
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`The term "pharmaceutically acceptable” as used herein means that the thing that is
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`pharmaceutically acceptable, e.g., components, including containers, of a pharmaceutical
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`composition, does not cause unacceptable loss of pharmacological activity or
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`unacceptable adverse side effects. Examples of pharmaceutically acceptable components
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`are provided in The United States Pharmacopeia (USP), The National Formulary (NF),
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`adopted at the United States Pharmacopeial Convention, held in Rockville, Md. in 1990
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`and FDA Inactive Ingredient Guide 1990, 1996 issued by the U.S. Food and Drug
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`Administration (both are hereby incorporated by reference herein, including any
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`drawings). Other grades of solutions or components that meet necessary limits and/or
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`specifications that are outside of the USP/NF may also be used.
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`The term “pharmaceutical composition” as used herein shall mean a composition that is
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`made under conditions such that it is suitable for administration to humans, e.g., it is
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`made under GMP conditions and contains pharmaceutically acceptable excipients, e.g.,
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`without limitation, stabilizers, bulking agents, buffers,_ carriers, diluents, vehicles,
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`solubilizers, and binders. As used herein pharmaceutical composition includes but is not
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`limited to a pre-lyophilization solution or dispersion as well as a liquid form ready for
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`injection or infusion.
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`A “pharmaceutical dosage form” as used herein means the pharmaceutical compositions
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`disclosed herein being in a container and in an amount suitable for reconstitution and
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`administration of one or more doses, typically about 1-2, 1-3, 1-4, 1-5, 1-6, 1-10, or about
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`1-20 doses. A “pharmaceutical dosage form” -as used herein also means a lyophilized
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`pharmaceutical composition disclosed herein in a container and in an amount suitable for
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`reconstitution and delivery of one or more doses, typically about 1-2, 1-3, 1-4, 1-5, 1-6,
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`1-10, or about 1-20 doses. The pharmaceutical dosage form can comprise a vial or
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`syringe or other suitable pharmaceutically acceptable container. The pharmaceutical
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`dosage form suitable for injection or infusion use can include sterile aqueous solutions or
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`dispersions or sterile powders comprising an active ingredient which are adapted for the
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`extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In
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`all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions
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`of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid
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`dispersion medium comprising, for example, water, ethanol, a polyol such as glycerol,
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`propylene glycol, or liquid polyethylene glycols and the like, vegetable oils, nontoxic
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`glyceryl esters, and suitable mixtures thereof. The prevention of the growth of
`microorganisms can be accomplished by various antibacterial and antifungal agents, for
`
`example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
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`As used herein, the term "excipient" means the substances used to formulate active
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`pharmaceutical ingredients (API) into pharmaceutical formulations; in a preferred
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`embodiment, an excipient does not lower or interfere with the primary therapeutic effect
`
`of the API. Preferably, an excipient is therapeutically inert. The term "excipient"
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`encompasses carriers, diluents, vehicles, solubilizers, stabilize_rs, bulking agents, and
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`binders. Excipients can also be those substances present in a pharmaceutical formulation
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`as an indirect or unintended result of the manufacturing process. Preferably, excipients
`
`are approved for or considered to be safe for human and animal administration, i.e.,
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`GRAS substances (generally regarded as safe). GRAS substances are listed by the Food
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`and Drug administration in the Code of Federal Regulations (CFR) at 21 CFR § 182 and
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`21 CFR § 184, incorporated herein by reference. Preferred excipents include, but are not
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`limited to, hexitols, including mannitol and the like.
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`As used herein “a stabilizing concentration of an organic solvent” or “a stabilizing
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`concentration of an alcohol” means that amount of an organic solvent or alcohol that
`
`reduces the level of degradation of bendamustine to achieve a specified level of
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`degradants in the final drug product. For example, with respect to the degradant HP1, a
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`stabilizing concentration of an organic solvent is that amount which results in an HP1
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`concentration (area percent of bendamustine) of less than about 0.9 %, preferably less
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`than 0.8 %, more preferably less than 0.7 % and even more preferably less than 0.6 %.
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`With respect to the overall degradant concentration of the final drug product, a stabilizing
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`concentration of an organic solvent is that amount that results in a total degradant
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`concentration (at the time of drug product release) of less than about 8% (area percent
`
`bendamustine), preferably less than about 7 %, more preferably less than about 6%, and
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`even more preferably less than about 5.5 %. By "area percent of bendamustine" is meant
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`the amount of a specified degradant, e.g., HPI , relative to the amount of bendamustine as
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`determined, e.g., by HPLC.
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`The term “organic solvent” means an organic material, usually a liquid, capable of
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`dissolving other substances.
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`As used herein, “trace amount of an organic solvent” means an amount of solvent that is
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`equal to or below recommended levels for pharmaceutical products, for example, as
`
`recommended by ICH guidelines (International Conferences on Harmonization,
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`Impurities-- Guidelines for Residual Solvents. Q3C. Federal Register.
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`l997;62(247):67377). The lower limit is the lowest amount that can be detected.
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`The term “at release” means the drug product has met the release specifications and can
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`be used for its intended pharmaceutical purpose.
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`A. General
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`The invention provides stable, pharmaceutically acceptable compositions prepared from
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`bendamustine. In particular, the invention provides formulations for the lyophilization of
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`bendamustine HCl. The lyophilizedpowder obtained from such formulations is more
`
`easily reconstituted than the presently available lyophilized powder of bendamustine.
`
`F