WO2014170769A2 - Compositions pharmaceutiques de bendamustine lyophilisée - Google Patents

Compositions pharmaceutiques de bendamustine lyophilisée Download PDF

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Publication number
WO2014170769A2
WO2014170769A2 PCT/IB2014/059778 IB2014059778W WO2014170769A2 WO 2014170769 A2 WO2014170769 A2 WO 2014170769A2 IB 2014059778 W IB2014059778 W IB 2014059778W WO 2014170769 A2 WO2014170769 A2 WO 2014170769A2
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Prior art keywords
bendamustine
lyophilized
hydrochloride monohydrate
mannitol
bendamustine hydrochloride
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Ceased
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PCT/IB2014/059778
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WO2014170769A3 (fr
Inventor
Pradeep SHIVAKUMAR
Shivamurthy RAMAKRISHNAIAH
Badrinath ALAMPALLI
Akshaykant CHATURVEDI
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Shilpa Medicare Ltd
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Shilpa Medicare Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to lyophilized pharmaceutical compositions comprising nitrogen mustards, particularly the nitrogen mustard is bendamustine.
  • the invention also relates to the use of lyophilized pharmaceutical compositions of Bendamustine for the treatment of neoplastic diseases.
  • Bendamustine also known as (4- ⁇ 5- [Bis (2-chloroethyl) amino] -1-methy 1-2- benzimidazolyl ⁇ butyric acid, is an active nitrogen mustard (see Formula I, which shows bendamustine hydrochloride).
  • 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 trade name 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.
  • GDR German Democratic Republic
  • bendamustine Due to its degradation in aqueous solutions (like other nitrogen mustards), bendamustine is supplied as a lyophilized product.
  • the lyophilized formulation of bendamustine contains bendamustine hydrochloride and mannitol in a sterile lyophilized form as a white powder for intravenous use following reconstitution.
  • 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 bendamustine contains degradation products that may occur during manufacturing of the drug substance and/or during the lyophilization process to make the finished drug product.
  • the bendamustine product is sold in the United States by Cephalon, Inc. as TREANDA ® for injection, a lyophilized powder in a single-use vial indicated for the treatment of patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin's lymphoma.
  • a 25 mg dose vial contains 25 mg of bendamustine hydrochloride and 42.5 mg of mannitol, and a 100 mg dose vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol.
  • TREANDA ® is intended for intravenous infusion only after reconstitution with sterile water for injection USP, and then further dilution with either 0.9% Sodium Chloride injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride injection, USP.
  • the pH of the reconstituted solution is 2.5-3.5.
  • TREANDA ® is supplied as a sterile non- pyrogenic white to off-white lyophilized powder, in a single-use vial.
  • Bendamustine hydrochloride is very unstable in an aqueous solution.
  • the bis-2- chloroethylamino bond is found labile to get hydrolyzed in weak acid, neutral, or alkaline solution.
  • Monohydroxy-bendamustine [HP-1] is formed as a hydrolyzed product rapidly in the presence of water.
  • BM1EE Another compound- Bendamustine ethyl ester
  • BM1EE is also known to be formed when bendamustine reacts with ethyl alcohol, where ethanol was utilized in penultimate steps of either API or formulation.
  • BM1EE can be formed during drug substance manufacturing, e.g., during recrystalization and/or purification processes.
  • BM1EE is reported to be one of the potential cytotoxic compound than bendamustine.
  • vials of bendamustine are stable for a period of 7 hours under room temperature storage or for 6 days upon storage at 2-8°C.
  • the 500 mL admixture solution must be administered to the patient within 7 hours of vial reconstitution (assuming room temperature storage of the admixture). 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 healthcare professional responsible for reconstituting the product, the lengthy exposure of bendamustine to water during the reconstitution process increases the potential for loss of potency and impurity formation due to the hydrolysis of the product by water.
  • German (GDR) Patent No. 80967 discloses an injectable preparation of y-[l-methyl-5-bis- (P-chloroethyl)-amino-benzimaidazolyl-(2)-]-butric acid hydrochloride.
  • German (GDR) Patent No. 159289 discloses an injectable solution of bendamustine.
  • Ribomustin ® bendamustine Product monograph (updated January 2002) http://www.ribosepharm.de/pdf/ribomustin_bendamustin/productmonogra-ph.pdf provides information about Ribomustin ® including product description.
  • Teagarden et al. disclose lyophilized formulations of prostaglandin E-l made by dissolving PGE-1 in a solution of lactose and tertiary butyl alcohol (U.S. Pat. No. 5,770,230).
  • U.S Publication No. 2006/0159713 discloses a lyophilized pharmaceutical composition comprising bendamustine or bendamustine HC1, mannitol, tertiary-butyl alcohol and water.
  • the said lyophilized pharmaceutical composition contains not more than about 0.5% bendamustine ethylester.
  • U.S. Patent No. 8,461,350 discloses a pharmaceutical composition comprising bendamustine or bendamustine hydrochloride, mannitol, water, and a list of plethora solvents selected from ethanol, n-propanol, n-butanol, isopropanol, methanol, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, acetone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, or a combination thereof.
  • solvents selected from ethanol, n-propanol, n-butanol, isopropanol, methanol, ethyl a
  • Chandrasekhar etal in WO2012/103226 A2 discloses a lyophilized pharmaceutical formulation of bendamustine, comprising not more than about 0.4% by weight of HP-1 compound, based on the bendamustine content, of a compound having the structure:
  • the formulation being prepared by lyophilizing a solution that does not contain tertiary-butyl alcohol or ethanol.
  • the lyophilized pharmaceutical formulation being prepared by lyophilizing a solution containing necessarily water and at least one organic solvent or a mixture thereof.
  • Palepu Nagesh R etal in US 2011/0184036 discloses long term storage stable bendamustine - containing solution compositions.
  • the compositions include bendamustine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable fluid which can include in some embodiments PEG, PG or mixtures thereof and an antioxidant or chloride ion source.
  • the bendamustine-containing compositions have less than about 5% total impurities, on a normalized peak area response ("PAR") basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after at least about 15 months of storage at a temperature of from about 5°C to about 25°C.
  • PAR normalized peak area response
  • HPLC high performance liquid chromatography
  • Drager Anthony et al in US8344006 discloses a stable, non-aqueous liquid, pharmaceutical formulation comprising from about 5 mg/ml to about 120 mg/mL of bendamustine, or a pharmaceutically acceptable salt thereof, solubilized in about 66% (v/v) of dimethylacetamide and about 34% (v/v) of propylene glycol, wherein said formulation, following dilution with a pharmaceutically acceptable diluent, is suitable for injection into a patient without lyophilization.
  • bendamustine hydrochloride is preferred to be supplied in lyophilized form. Also it is well-known that bendamustine hydrochloride is hygroscopic in nature; it is always preferred to select diluents as sugar alcohols like mannitol, for preparing such lyophilized bendamustine compositions.
  • Bendamustine or bendamustine hydrochloride, and mannitol are insoluble in few organic solvent-water mixtures like dimethyl carbonate, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone methyl acetate, carbon tetrachloride, hexafluoroacetone, chlorobutanol, dimethyl sulfone, cyclohexane, or a combination thereof.
  • organic solvent-water mixtures like dimethyl carbonate, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone methyl acetate, carbon tetrachloride, hexafluoroacetone, chlorobutanol, dimethyl sulfone, cyclohexane, or a combination thereof.
  • lyophilized bendamustine products also require reconstitution in water for injection, by skilled hospital personal prior to administration, and it is always needed to ensure quicker reconstitution time of bendamustine lyophilized cakes in water.
  • the present invention is directed to a lyophilized bendamustine composition
  • a lyophilized bendamustine composition comprising bendamustine and its salts like bendamustine hydrochloride, and mannitol, derived from dimethyl sulfoxide.
  • the present invention is directed to a pre-lyophilized bendamustine composition
  • a pre-lyophilized bendamustine composition comprising of bendamustine hydrochloride monohydrate, bulking agent, and dimethyl sulfoxide; wherein the composition is devoid of water.
  • the present invention is directed to a pre-lyophilized bendamustine composition consisting of bendamustine hydrochloride monohydrate, mannitol, and dimethyl sulfoxide.
  • the present invention is directed to a process for preparing a lyophilized pharmaceutical composition comprising:
  • the present invention is directed to a pre-lyophilized composition
  • a pre-lyophilized composition comprising bendamustine hydrochloride monohydrate crystalline Form-SM characterized by X-ray powder diffraction pattern comprising atleast 7 characteristic peaks selected from the XRPD 2 theta degrees peaks at 7.42, 10.60, 11.17, 16.43, 17.94, 22.89, 26.33, 28.77, 30.28, 31.92, 40.89 ⁇ 0.1 2 ⁇ 0 .
  • the present invention is directed to a pre-lyophilized composition comprising bendamustine hydrochloride monohydrate crystalline Form II.
  • the present invention is directed to a lyophilized pharmaceutical composition comprising of bendamustine hydrochloride monohydrate, and mannitol, derived from dimethyl sulfoxide.
  • the present invention is directed to a lyophilized pharmaceutical composition comprising of bendamustine hydrochloride monohydrate, and mannitol, derived from dimethyl sulfoxide, wherein the pre-lyophilization solution contains bendamustine hydrochloride monohydrate at a concentration of about 5 to 50 mg/ml, and mannitol at a concentration of about 10 to 80 mg/ml.
  • the present invention is directed to a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising of bendamustine hydrochloride monohydrate, and mannitol, derived from dimethyl sulfoxide, wherein the pre-lyophilization solution contains bendamustine hydrochloride monohydrate at a concentration of about 5 to 50 mg/ml, and mannitol at a concentration of about 10 to 80 mg/ml, contains not more than about 0.2% (area percent of bendamustine) HP1 as shown in Formula II, wherein amount of HP1 present at release.
  • the present invention is directed to a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising of bendamustine hydrochloride monohydrate, and mannitol, derived from dimethyl sulfoxide, wherein the pre-lyophilization solution contains bendamustine hydrochloride monohydrate at a concentration of about 5 to 50 mg/ml, and mannitol at a concentration of about 10 to 80 mg/ml, containing no detected levels of bendamustine ethylester present at release.
  • the present invention is directed to a lyophilized pharmaceutical composition of bendamustine hydrochloride monohydrate, and mannitol, derived from dimethyl sulfoxide, wherein the pre-lyophilization solution contains no detected levels of bendamustine ethylester present at release.
  • the present invention is directed to a method of treating a medical condition selected from chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, breast cancer, small cell lung cancer, and an autoimmune disease, by administering therapeutically effective amount of the dissolved preparation of lyophilized pharmaceutical composition of bendamustine hydrochloride monohydrate, and mannitol, derived from dimethyl sulfoxide.
  • a medical condition selected from chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, breast cancer, small cell lung cancer, and an autoimmune disease
  • Bendamustine hydrochloride Monohydrate Form-SM characterized by X-ray powder diffraction pattern comprising atleast 7 characteristic peaks selected from the XRPD 2 theta degrees peaks at 7.42, 10.60, 11.17, 16.43, 17.94, 22.89, 26.33, 28.77, 30.28, 31.92, 40.89 ⁇ 0.1 20°
  • Bendamustine hydrochloride Form II disclosed under US20120071532
  • various other crystalline forms of Bendamustine hydrochloride, mentioned under prior art, can be included here for preparing the invention lyophilized compositions.
  • Fig. l is illustration of X-ray powder diffraction (XRPD) pattern of Bendamustine hydrochloride monohydrate Form-SM, disclosed under WO2012059935.
  • emboidment of the present invention provides a pre-lyophilized bendamustine composition
  • a pre-lyophilized bendamustine composition comprising of bendamustine hydrochloride monohydrate, bulking agent, and dimethyl sulfoxide; wherein the composition is devoid of water.
  • emboidment of the present invention provides a pre-lyophilized bendamustine composition consisting of bendamustine hydrochloride monohydrate, mannitol, and dimethyl sulfoxide.
  • a pre-lyophilized bendamustine composition consisting of bendamustine hydrochloride monohydrate Form- SM, mannitol, and dimethyl sulfoxide.
  • emboidment of the present invention provides a process for preparing a lyophilized pharmaceutical composition comprising: a) Dissolving bendamustine hydrochloride monohydrate, and mannitol, in dimethyl sulfoxide; and
  • a process for preparing a lyophilized pharmaceutical composition comprising:
  • emboidment of the present invention provides a pre- lyophilized composition
  • bendamustine hydrochloride monohydrate crystalline Form-SM characterized by X-ray powder diffraction pattern comprising atleast 7 characteristic peaks selected from the XRPD 2 theta degrees peaks at 7.42, 10.60, 11.17, 16.43, 17.94, 22.89, 26.33, 28.77, 30.28, 31.92, 40.89 ⁇ 0.1 20°.
  • emboidment of the present invention provides a pre- lyophilized composition comprising bendamustine hydrochloride monohydrate crystalline Form II.
  • emboidment of the present invention provides a lyophilized pharmaceutical composition comprising of bendamustine hydrochloride monohydrate, and mannitol, derived from dimethyl sulfoxide.
  • emboidment of the present invention provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising of bendamustine hydrochloride monohydrate, and mannitol, derived from dimethyl sulfoxide, wherein the pre-lyophilization solution contains bendamustine hydrochloride monohydrate at a concentration of about 5 to 50 mg/ml, and mannitol at a concentration of about 10 to 80 mg/ml.
  • emboidment of the present invention provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising of bendamustine hydrochloride monohydrate, and mannitol, derived from dimethyl sulfoxide, wherein the pre-lyophilization solution contains bendamustine hydrochloride monohydrate at a concentration of about 5 to 50 mg/ml, and mannitol at a concentration of about 10 to 80 mg/ml, contains not more than about 0.2% (area percent of bendamustine) HP1 as shown in Formula II, wherein amount of HP1 present at release.
  • a lyophilized pharmaceutical composition comprising of bendamustine hydrochloride monohydrate Form-SM, and mannitol, derived from dimethyl sulfoxide, wherein the pre-lyophilization solution contains bendamustine hydrochloride monohydrate at a concentration of about 5 to 50 mg/ml, and mannitol at a concentration of about 10 to 80 mg/ml, contains not more than about 0.2% (area percent of bendamustine) HP1 as shown in Formula II, wherein amount of HP1 present at release.
  • emboidment of the present invention provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising of bendamustine hydrochloride monohydrate, and mannitol, derived from dimethyl sulfoxide, wherein the pre-lyophilization solution contains bendamustine hydrochloride monohydrate at a concentration of about 5 to 50 mg/ml, and mannitol at a concentration of about 10 to 80 mg/ml, containing no detected levels of bendamustine ethylester present at release.
  • a lyophilized pharmaceutical composition comprising of bendamustine hydrochloride monohydrate Form-SM, and mannitol, derived from dimethyl sulfoxide, wherein the pre-lyophilization solution contains bendamustine hydrochloride monohydrate at a concentration of about 5 to 50 mg/ml, and mannitol at a concentration of about 10 to 80 mg/ml, containing no detected levels of bendamustine ethylester present at release.
  • emboidment of the present invention provides a method of treating a medical condition selected from chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, breast cancer, small cell lung cancer, and an autoimmune disease, by administering therapeutically effective amount of the dissolved preparation of lyophilized pharmaceutical composition of bendamustine hydrochloride monohydrate, and mannitol, derived from dimethyl sulfoxide.
  • a medical condition selected from chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, breast cancer, small cell lung cancer, and an autoimmune disease
  • the term "bendamustine” includes the compound bendamustine, pharmaceutically acceptable salts of bendamustine, isomers, solvates, complexes and hydrates, anhydrous forms thereof, and any polymorphic or amorphous forms or combinations thereof.
  • the salt bendamustine hydrochloride monohydrate will be discussed herein as a representative of any of these, although the disclosure is not limited to the use of only this salt.
  • formulation refers to preparing a drug, e.g., bendamustine, in a form suitable for administration to a patient, such as a human.
  • a “formulation” can include pharmaceutically acceptable excipients, including diluents or carriers.
  • excipient means the substances used to formulate active pharmaceutical ingredients (API) into pharmaceutical formulations; in a preferred embodiment, an excipient does not lower or interfere with the primary therapeutic effect of the API. Preferably, an excipient is therapeutically inert.
  • excipient encompasses carriers, diluents, vehicles, solubilizers, stabilizers, bulking agents, and binders. Excipients can also be those substances present in a pharmaceutical formulation 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., GRAS substances (generally regarded as safe).
  • GRAS substances are listed by the Food and Drug administration in the Code of Federal Regulations (CFR) at 21 CFR section 182 and 21 CFR section 184, incorporated herein by reference.
  • Preferred bulking agents include, but are not limited to, hexitols, including mannitol and the Others include Lactose, Trehalose, Sorbitol, Glucose, Raffinose, Glycine, Histidine, PVP (K40).
  • organic solvent means an organic material, usually a liquid, capable of dissolving other substances.
  • pharmaceutically acceptable describes substances or components that do not cause unacceptable losses of pharmacological activity or unacceptable adverse side effects.
  • examples of pharmaceutically acceptable ingredients are those having monographs in United States Pharmacopeia (USP 29) and National Formulary (NF 24), United States Pharmacopeial Convention, Inc, Rockville, Maryland, 2005 (“USP/NF”), or a more recent edition, and the components listed in the continuously updated Inactive Ingredient Search online database of the FDA.
  • USP/NF United States Pharmacopeia
  • Other useful components that are not described in the USP/NF, etc. may also be used.
  • composition as used herein shall mean a composition that is made under conditions such that it is suitable for administration to humans, e.g., it is made under GMP conditions and contains pharmaceutically acceptable excipients, e.g., without limitation, stabilizers, bulking agents, buffers, carriers, diluents, vehicles, solubilizers, and binders.
  • pharmaceutical composition includes but is not limited to a pre- lyophilization solution or dispersion as well as a liquid form ready for injection or infusion after reconstitution of a lyophilized preparation.
  • lyophilized composition or "lyophilized bendamustine pharmaceutical composition”; can be used interchangeably, and refers to any solid material obtained by lyophilization i.e., freeze-drying of non-aqueous solution.
  • No n- aqueous solution refers to a solution composed of one or more non-aqueous solvent(s).
  • a lyophilized preparation is one in which the solid material is obtained by freeze-drying a solution composed of Dimethyl sulfoxide.
  • degradation or “degradation” is meant that the active has undergone a change in chemical structure.
  • a therapeutically effective amount 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.
  • 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/m given as a single dose on two consecutive days. The cycle can be repeated about every three to four weeks.
  • CLL chronic lymphocytic leukemia
  • bendamustine can be given at about 80-100 mg/m on days 1 and 2. The cycle can be repeated after about 4 weeks.
  • bendamustine For the treatment of Hodgkin's disease (stages II-IV), bendamustine can be given in the "DBVBe regimen" with daunorubicin 25 mg/m on days 1 and 15, bleomycin 10 mg/m 2 on days 1 and 15, vincristine 1.4 mg/m 2 on days 1 and 15, and bendamustine 50 mg/m on days 1-5 with repetition of the cycle about every 4 weeks.
  • bendamustine (120 mg/m ) on days 1 and 8 can be given in combination with methotrexate 40 mg/m 2 on days 1 and 8, and 5-fluorouracil 600 mg/m 2 on days 1 and 8 with repetition of the cycle about every 4 weeks.
  • bendamustine As a second-line of therapy for breast cancer, bendamustine can be given at about 100-150 mg/m on days 1 and 2 with repetition of the cycle about every 4 weeks.
  • vial refers to any walled container, whether rigid or flexible.
  • trace amount of an organic solvent means an amount of solvent that is equal to or below recommended levels for pharmaceutical products, for example, as recommended by ICH guidelines (International Conferences on Harmonization, Impurities- Guidelines for Residual Solvents. Q3C. Federal Register. 1997; 62(247):67377). The lower limit is the lowest amount that can be detected.
  • release or "at release” means the drug product has met the release specifications and can be used for its intended pharmaceutical purpose.
  • ND or “Not detected” or “No detected limits of means the drug or drug product has no detected content of a particular impurity as compared to bendamustine content. Sometimes the same can also be referred with the term “BDL” meaning below the level of detection.
  • Impurity- A Monohydroxy Bendamustine or BND- HP1. ForrauJa TI
  • Impurity-B Bendamustine Dimer.
  • Impurity-C Isopropyl 4-(5-(bis (2-chIoroethyl) amino)-l-methyl-l H-benzo[d]imidazol-2-yl) butanoate (Formula V).
  • Lyophilization recipe is as follows:
  • Lyophilized cakes obtained in example 1 is characterized for cake appearance & solution clarity, after dissolving in WFI to get 5mg/mL concentration of bendamustine.
  • 100 mg/vial lyophilized cake of example 1 is characterized by HPLC for assay & related substances.
  • Buffer preparation Weigh and transfer 3.85g of ammonium acetate in lOOOmL of water, dissolve and add lmL of triethylamine, adjust pH 4.7 with dilute glacial acetic acid. Filter and degas.
  • Mobile phase A Transfer 580mL of buffer solution 420mL of acetonitrile into a lOOOmL of beaker and mix and degas.
  • Mobile Phase B Acetonitrile, filter and degas.
  • Sample preparation for lOOmg/Vial Take 2 vials and reconstitute each vial with 5ml of diluent and transfer into 100ml of volumetric flask, mix well and dilute to volume with diluent. Further, transfer 1ml of the above solution into 50ml volumetric flask and dilute to volume with diluent.
  • the Tailing factor for Bendamustine peak is NMT 2.0.
  • the relative standard deviation (RSD) for 5 injections of standard preparation is NMT 2.0%.
  • Buffer Preparation Transferred 1ml of Trifluro acetic acid in 1000ml volumetric flask containing 500ml water, mixed well and diluted with water.
  • Mobile phase A Prepared a mixture of Buffer solution & Acetonitrile in the ratio of 90: 10.
  • Mobile Phase B Prepared a mixture of Buffer solution & Acetonitrile in the ratio of 50:50.
  • Sample preparation for 100 mg/Vial Take 1 vial and reconstitute with 20 ml of diluent and transfer into 50ml volumetric flask and dilute to volume with diluent.
  • the Tailing factor for Bendamustine HCl peak is NMT 2.0.
  • the relative standard deviation (%RSD) for 6 injections of standard preparation is NMT 5.0%.
  • Example 1 formulation is subjected to accelerated stability 40°C/75%RH (1,2,3 and 6 M) and real time stability 25°C/60%RH (3 and 6M).
  • Ethyl ester impurity is in BDL in the Example- 1 lyophilized composition of bendamustine hydrochloride.

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Abstract

La présente invention concerne des compositions pharmaceutiques lyophilisées comprenant des moutardes azotées, en particulier la moutarde azotée étant de la bendamustine, par exemple, de l'hydrochlorure de bendamustine. La présente invention concerne également l'utilisation de compositions pharmaceutiques lyophilisées pour le traitement de divers états pathologiques, notamment de maladies néoplastiques et de maladies auto-immunes.
PCT/IB2014/059778 2013-04-15 2014-03-14 Compositions pharmaceutiques de bendamustine lyophilisée Ceased WO2014170769A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1665CH2013 2013-04-15
IN1665/CHE/2013 2013-04-15

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WO2014170769A2 true WO2014170769A2 (fr) 2014-10-23
WO2014170769A3 WO2014170769A3 (fr) 2015-04-02

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA037673B1 (ru) * 2018-07-04 2021-04-29 Тютор С.А.С.И.Ф.И.А. Способ получения фармацевтической композиции, содержащей бендамустин, фармацевтическая композиция бендамустина

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US8436190B2 (en) * 2005-01-14 2013-05-07 Cephalon, Inc. Bendamustine pharmaceutical compositions
AR072777A1 (es) * 2008-03-26 2010-09-22 Cephalon Inc Formas solidas de clorhidrato de bendamustina

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA037673B1 (ru) * 2018-07-04 2021-04-29 Тютор С.А.С.И.Ф.И.А. Способ получения фармацевтической композиции, содержащей бендамустин, фармацевтическая композиция бендамустина

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