US20120003309A1 - Solid Dosage Forms Of Bendamustine - Google Patents

Solid Dosage Forms Of Bendamustine Download PDF

Info

Publication number
US20120003309A1
US20120003309A1 US13/132,343 US200913132343A US2012003309A1 US 20120003309 A1 US20120003309 A1 US 20120003309A1 US 200913132343 A US200913132343 A US 200913132343A US 2012003309 A1 US2012003309 A1 US 2012003309A1
Authority
US
United States
Prior art keywords
bendamustine
tablets
saccharide
tablet
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/132,343
Other languages
English (en)
Inventor
Jeffrey Colledge
Thomas Alfred Profitlich
Ulrich Patzak
Taoufik Ouatas
Margaretha Olthoff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astellas Deutschland GmbH
Original Assignee
Astellas Deutschland GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astellas Deutschland GmbH filed Critical Astellas Deutschland GmbH
Assigned to ASTELLAS DEUTSCHLAND GMBH reassignment ASTELLAS DEUTSCHLAND GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: COLLEDGE, JEFFREY, PROFITLICH, THOMAS ALFRED, PATZAK, ULRICH, OLTHOFF, MARGARETHA, OUATAS, TAOUFIK
Publication of US20120003309A1 publication Critical patent/US20120003309A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Bendamustine(4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazo-2-yl]butanoic acid, a nitrogen mustard) is an alkylating agent with bifunctional alkylating activity. It corresponds to the following formula I:
  • Bendamustine appears to be free of any cross-resistance with other alkylating agents, which offers advantages in terms of chemotherapy for patients who have already received treatment with an alkylating agent.
  • Bendamustine was initially synthesized in the German Democratic Republic (GDR).
  • GDR German Democratic Republic
  • the hydrochloric acid of bendamustine was the active ingredient in a commercial product available from 1971 to 1992 under the trade name Cytostasan®. Since that time, it has been marketed in Germany under the trade name Ribomustin® and has been widely used to treat chronic lymphocytic leukemia, non-Hodgkin's lymphoma and multiple myeloma.
  • the marketed product contains a lyophilized powder of bendamustine hydrochloride which is reconstituted with water for injection yielding a concentrate. This is subsequently diluted with an aqueous solution of 0.9% sodium chloride resulting in the final solution for infusion. This final solution is administered to the patient by intravenous infusion over a period of about 30 to 60 minutes.
  • US 2006/0128777 A1 describes methods for treating cancers, characterised by death-resistant cells and bendamustine-containing compositions in general.
  • oral solid dosage forms which are capsules, tablets, pills, powders or granules, wherein the active compound may be admixed with at least one inert excipient, such as sucrose, lactose or starch.
  • inert excipient such as sucrose, lactose or starch.
  • specific compositions were not exemplified.
  • compositions are suitable for oral administration and comprise bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, which compositions have an improved dissolution profile.
  • FIG. 1 shows the mean plasma concentration (tablets versus capsule) vs. time curve obtained after administering bendamustine hydrochloride in the form of prior art capsules and the tablet formulations of Examples 6 to 8 (Tablets 1-3) and example 9 (formulation 3) (Tablet 4) to dogs. It is apparent from FIG. 1 that the tablet formulations provide for higher maximum concentrations of bendamustine, as compared to the prior art capsule.
  • FIG. 2 shows a flow sheet of wet granulation manufacturing trials.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable ester, salt or a solvate thereof as an active ingredient and at least one pharmaceutically acceptable excipient selected from monosaccharides, disaccharides, oligosaccharides, cyclic oligosaccharides, a polysaccharide and saccharide alcohols.
  • the ratio by weight between the active ingredient and excipient is in the range of 1 to 1-5, preferably 1 to 2-5, more preferably a ratio selected from 1:5 and 1:2.
  • the present invention relates to a pharmaceutical composition in a solid dosage form for oral administration, the composition comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, which is a pharmaceutically acceptable saccharide selected from the group consisting of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a saccharide alcohol, wherein the ratio by weight of the active ingredient to the excipient is in the range of 1:1.
  • a pharmaceutically acceptable saccharide selected from the group consisting of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a saccharide alcohol, wherein the ratio by weight of the active ingredient to the excipient is in the range of 1:1.
  • the present invention relates to a pharmaceutical composition in a solid dosage form suitable for oral administration, the composition comprising bendamustine or pharmaceutically acceptable ester, salts or solvates thereof as an active ingredient and at least one pharmaceutically acceptable excipient which is a pharmaceutically acceptable saccharide selected from the group consisting of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a saccharide alcohol, wherein the ratio by weight of the active ingredient to the saccharide excipient(s) is in the range of 1:2-5 and which composition shows a dissolution of the bendamustine of at least 60% in 20 minutes, 70% in 40 minutes and 80% in 60 minutes as measured with a paddle apparatus at 50 rpm according to the European Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5.
  • a pharmaceutically acceptable excipient which is a pharmaceutically acceptable saccharide selected from the group
  • compositions wherein the pharmaceutically acceptable saccharide is selected from the group consisting of one or more of a monosaccharide, a disaccharide and an oligosaccharide, wherein the ratio by weight of the active ingredient to the saccharide excipient(s) is in the range of 1:2-5 and which composition shows a dissolution of the bendamustine of at least 60% in 20 minutes, 70% in 40 minutes and 80% in 60 minutes as measured with a paddle apparatus at 50 rpm according to the European Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5.
  • the pharmaceutically acceptable saccharide is selected from the group consisting of one or more of a monosaccharide, a disaccharide and an oligosaccharide, wherein the ratio by weight of the active ingredient to the saccharide excipient(s) is in the range of 1:2-5 and which composition shows a dissolution of the bendamustine of at least 60% in 20 minutes, 70% in 40 minutes and 80% in 60 minutes as measured
  • the present invention is based, inter alia, on the surprising discovery that a specific and desirable dissolution profile can be reached by incorporating a certain amount of pharmaceutically acceptable saccharides into the pharmaceutical composition.
  • a pharmaceutically acceptable saccharide selected from the group consisting of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide or a saccharide alcohol and preferably selected from the group consisting of one or more of a monosaccharide, a disaccharide and an oligosaccharide is used as an excipient in a pharmaceutical composition comprising bendamustine or pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, a particularly favourable profile of the composition as regards stability, tabletting properties, dissolution and impurity formation is achieved.
  • the above saccharides result in a composition which shows a dissolution of the bendamustine of at least 60% in 20 minutes, 70% in 40 minutes and 80% in 60 minutes as measured with a paddle apparatus at 50 rpm according to the European Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5.
  • any combination of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a saccharide alcohol may be used.
  • saccharides are associated with a particularly favourable profile of a pharmaceutical composition as regards stability and dissolution.
  • Preferred saccharides of the composition according to the present invention are dextrose anhydrous, dextrose monohydrate, lactitol monohydrate, trehalose, sorbitol, erythritol, maltose monohydrate, mannitol, lactose anhydrous, lactose monohydrate, maltitol, xylitol, sucrose, sucrose 97%+maltodextrin 3%, ⁇ -cyclodextrin, D-raffinose pentahydrate, D-melezitose monohydrate and microcrystalline cellulose.
  • the pharmaceutical compositions according to the present invention show good tabletting characteristics, fast dissolution and a pharmaceutically acceptable stability.
  • the above saccharides constitute preferred embodiments of the present invention and any combination thereof may be used.
  • the ratio between the active ingredient and the above saccharides is in the range of 1:1-5, preferably 1:2-5 and more preferably a ratio selected from 1:5 and 1:2.
  • a further preferred embodiment of the invention is a pharmaceutical composition in a solid dosage form for oral administration, the composition comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient and at least one pharmaceutically acceptable excipient selected from dextrose anhydrous, dextrose monohydrate, lactitol monohydrate, trehalose, sorbitol, erythritol, maltose monohydrate, mannitol, lactose anhydrous, lactose monohydrate, maltitol, xylitol, sucrose, sucrose 97%+maltodextrin 3%, ⁇ -cyclodextrin, D-raffinose pentahydrate, D-melezitose monohydrate and microcrystalline cellulose and which composition shows a dissolution of the bendamustine of at least 60% in 10 minutes, 70% in 20 minutes and 80% in 30 minutes.
  • saccharides are mannitol, maltitol, erythritol, xylitol, lactose, sucrose, glucose, sorbitol, maltose, trehalose, lactitol and dextrose (anhydrous or monohydrate) and the weight ratio of the active ingredient to said saccharide is preferably in the range of 1:2-5. Combinations of two or more saccharides within the scope of the above saccharides are also included within the present invention.
  • a person skilled in the art is well in a position to select suitable combinations within the saccharide excipients mentioned above and obtain a composition which shows a dissolution of bendamustine of at least 60% in 20 minutes, 70% in 40 minutes and 80% in 60 minutes as measured with a paddle apparatus at 50 rpm according to the European Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5.
  • composition in the form of a tablet, a granulate, or a pill.
  • a preferred dosage form is a tablet.
  • the term tablet also comprises fast-disintegrating tablets, amongst which are dispersible tablets and effervescent tablets.
  • Direct compression involves compressing a mixture containing the active ingredient(s) and the excipient(s) on a tablet press (L. Lachman et al., in: The Theory and Practice of Industrial Pharmacy, 3rd ed., 1986).
  • the mixture to be compressed must possess both good flow and compression properties in order to produce tablets having a uniform content of the active ingredient(s).
  • Good flow properties cannot always be achieved by adding appropriate excipients, such as lubricants, anti-adhesive agents and flow-promoters to the mixture. Hence frequently the mixture is granulated prior to compression.
  • Granulation is a process by which sphere-like or regularly shaped aggregates called granules are formed out of the powder mixture. This can be achieved by dry granulation methods and wet granulation methods. Granulation is also used for converting a mixture of powders with poor cohesion into aggregates, which when compressed result in tablets that have good cohesion properties.
  • the active ingredient(s), optionally in admixture with one or more excipients is (are) advantageously provided with a coating in order to mask the taste of such ingredient(s) and/or to protect the same against possible harmful effects by light and/or moisture and in the case of bendamustine to protect the mucosa in the mouth against the harmful effects exerted by the active compound.
  • a granulate preferably is prepared and processed as further outlined below.
  • granulate refers to aggregates of particles, sometimes called granules.
  • a granulate in general is prepared by compaction and/or compression techniques (dry granulation) or by wet granulation techniques, using a liquid in which optionally a wet granulation binding agent is dissolved (Remington's Pharmaceutical Sciences 18th ed. 1990, page 1641).
  • Wet granulation techniques also include extrusion techniques.
  • the term granulate also comprises pellets, spherules, and extrudates, of which pellets preferably are used as examples of a granulate.
  • a pellet may be described as a small particle of approximately 1.0-1.6 mm in diameter and having a certain density, which particle is prepared by application of the pharmaceutical processes of extrusion and spheronisation to powder mixtures.
  • the active ingredient(s), optionally in admixture with one or more excipients, may be advantageously provided with a coating in order to mask the taste of such ingredient and/or to protect the same against possible harmful effects by light and/or moisture and/or to protect the mucosa in the mouth against the harmful effects exerted by the active compound.
  • Pills are small, round solid dosage forms, prepared by adding the active ingredient to a doughy mixture of triglycerides. The mixture is rolled into a long string, which is then cut into pieces and rolled (J. T. Carstensen: Pharmaceutical principles of solid dosage forms, 1993, Technomic Publishing Company, Inc. page 63).
  • the dosage forms according to the invention are prepared by dry compaction techniques. Suitable techniques are for example described in Remington's Pharmaceutical Science 18th. ed. 1990, page 1644. They comprise dry granulation, roller compaction and direct compression. When tablets are prepared by these techniques, it is even more advantageous to use direct compression.
  • the dosage forms according to the present invention are preferably provided with a coating.
  • the coating has different purposes: it may serve for masking the taste of the active ingredient(s) used in the composition, whilst at the same time it is protecting the active ingredient against possible harmful effects by light and/or moisture such as oxidation, degradation, etc. Furthermore, the coating layer may prevent the subject from damage of the oral mucosa by the active ingredient.
  • the coating layer can be applied to the dosage forms by techniques well-known in the art such as spray-coating and microencapsulation.
  • tablets it can be in the form of a film-coating, a saccharide-coating or a compression coating.
  • a film-coating process is used (Remington's Pharmaceutical Sciences 18th ed. 1990, page 1666).
  • an active ingredient requires the application of a coating for fast-disintegrating tablets the individual granules can suitably be provided with a coating prior to compression into tablets.
  • esters with alkyl alcohols and saccharide alcohols examples include C1-6-alkyl alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol.
  • alkyl alcohols C1-6-alkyl alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol.
  • saccharide alcohols are mannitol, maltitol, sorbitol, erythritol, glycol, glycerol, arabitol, xylitol and lactitol.
  • Preferred examples of the bendamustine esters are the ethyl ester, the isopropyl ester, the mannitol ester and the sorbitol ester, most preferred is the ethylester thereof.
  • pharmaceutically acceptable salt thereof describes any pharmaceutically acceptable salt of bendamustine that administered to a patient (directly or indirectly) provides bendamustine. This term further comprises the pharmaceutically acceptable salt of a bendamustine ester. Nevertheless, it will be considered that the pharmaceutically non-acceptable salts also are included within the limits of this invention since these compounds can be useful in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts of bendamustine are synthesized from the corresponding compound that contains an acid or basic group, by conventional chemical methods.
  • these salts are, for example, prepared by means of the reaction of free acidic or basic forms of these compounds in a stoichiometric amount with a corresponding base or acid in water or an organic solvent or a mixture of both.
  • Nonaqueous media like ether, ethyl acetate, isopropanol or acetonitrile are generally preferred.
  • acids which may be used for the salt formation of pharmaceutically acceptable salts of bendamustine include inorganic acids such as hydrochloride, hydrobromide, hydriodide, sulphuric, nitric, and phosphoric acids, and organic acids such as acetic, maleic, fumaric, citric, oxalic, succinic, tartaric, malic, lactic, methylsulphonic and p-toluenesulphonic acids.
  • inorganic acids such as hydrochloride, hydrobromide, hydriodide, sulphuric, nitric, and phosphoric acids
  • organic acids such as acetic, maleic, fumaric, citric, oxalic, succinic, tartaric, malic, lactic, methylsulphonic and p-toluenesulphonic acids.
  • Pharmaceutically acceptable salts of bendamustine may be derived from either inorganic or organic bases to yield ammonium salts; alkali metal salts (lithium, sodium, potassium, etc.), alkaline earth salts like calcium or magnesium, aluminium salts, lower alkylamine salts like methylamine or ethylamine salts, lower alkyldiamine salts like ethylenediamine salts, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, and glucamine salts, as well as basic salts of amino acids.
  • acid salts prepared from the hydrochloride, the hydrobromide, and the hydroiodide whereas the hydrochloride salt is the most preferred pharmaceutically acceptable salt of bendamustine.
  • the pharmaceutically acceptable salts are produced by conventional techniques well-known in the art.
  • the expression “pharmaceutically acceptable solvate thereof' describes any pharmaceutically acceptable solvate that, administered to a patient (directly or indirectly) provides bendamustine.
  • This term further comprises the pharmaceutically acceptable solvate of a bendamustine ester.
  • the solvate is a hydrate, a solvate with an alcohol such as methanol, ethanol, propanol, or isopropanol, a solvate with an ester such as ethyl acetate, a solvate with an ether such as methyl ether, ethyl ether or THF (tetrahydrofuran) or a solvate with DMF (dimethylformamide), of which a hydrate or a solvate with an alcohol such as ethanol is more preferred.
  • a solvent for constituting the solvate is preferably a pharmaceutically acceptable solvent.
  • the active ingredient in the invention's compositions is bendamustine or a pharmaceutically acceptable salt thereof. It is most preferred that the active ingredient is bendamustine hydrochloride.
  • the dose of the active ingredient in the pharmaceutical composition may readily be determined by the skilled artisan depending on the patient's condition, sex, body weight, body surface area, or age, especially depending on the patient's body weight and body surface area and ranges from 10 to 1000 mg. It is preferred that the daily dosage ranges from about 50 to about 1000 mg, preferably from about 100 to about 500 mg of the active ingredient.
  • the daily dosage may be taken as a single dose or as a multiple dose such as twice or three-times daily, most preferably as a single daily dose.
  • the daily dose may be taken once a week or several times a week.
  • the dosage form may contain the amount of a single daily dose or parts thereof. It is preferred that the dosage form of the present invention comprises about 10 to about 1000 mg, preferably about 25 to about 600 mg, more preferably about 50 to about 200 mg and most preferably about 100 mg of the active ingredient.
  • the saccharides are present in the compositions according to the invention in a substantial amount, preferably in an amount ranging from 2 to 5 times the weight of the active substance.
  • the saccharides when incorporated into the compositions of the present invention have shown to have a positive effect on the stability of the active compound. In addition to that it was surprisingly found that these excipients result in an increased bio-availability of the active compound, in particular bendamustine hydrochloride, when compared to the reference capsule.
  • saccharides include mannitol, maltitol, erythritol, xylitol, lactose, sucrose, glucose, sorbitol, maltose, trehalose, lactitol and dextrose (anhydrous or monohydrate).
  • composition according to the present invention may comprise further excipients as described in more detail below for lubricants, glidants, fillers (or diluents), binders and disintegrants.
  • Lubricants are substances which may have one or more of the following functions in pharmaceutical compositions and especially in tablet manufacture: preventing adhesion of the tablet material to the surface of parts of the tabletting machine (hopper, dies and punches), reducing interparticle friction, facilitating ejection of the tablets from the dies and improving the flow rate of the mixture (to be tabletted).
  • Said lubricant is typically selected from a group consisting of stearic acid, salts or esters of stearic acid, hydrogenated vegetable oils, magnesium oxide, polyethylene glycol, sodium lauryl sulphate and talc, and mixtures thereof.
  • said lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate and sodium stearyl fumarate, and mixtures thereof.
  • Stearic acid is the most preferred alternative.
  • glidant in this application is to be understood as a substance which improves the flow characteristics of the mixture to be tabletted.
  • any suitable glidant such as talc, silicon dioxide and silicagel (Cab-O-Sil®, Syloid®, Aerosil®), starch and calcium silicate may be used.
  • silicon dioxide is used.
  • filler represent excipients which are used to increase the bulk of the materials to be tabletted. This increase in size improves the handling of the solid compositions. Fillers are usually necessary if the dose of drug per solid composition is low and the solid composition would otherwise be too small. Examples of suitable fillers are lactose, sucrose, mannitol, sorbitol, saccharose, starch, pregelatinized starch, microcrystalline cellulose, powdered cellulose, calcium hydrogen phosphate, calcium carbonate and any combinations thereof. In a preferred embodiment the filler is selected from the group consisting of lactose, starch, microcrystalline cellulose, microfine cellulose and any combinations thereof, most preferably anhydrous lactose and microcrystalline cellulose.
  • binder is used for agents that impart cohesiveness to the pharmaceutical formulation, which cohesiveness ensures that the composition remains intact especially in case of tablets after compression.
  • suitable binders are lactose, sucrose, mannitol, sorbitol, saccharose, starch, pregelatinized starch, microcrystalline cellulose, powdered cellulose, calcium hydrogen phosphate, calcium carbonate and any combinations thereof.
  • the binder is selected from the group consisting of lactose, starch, microcrystalline cellulose, microfine cellulose and any combinations thereof, most preferably anhydrous lactose and microcrystalline cellulose.
  • binders can be used both as a solution and in a dry form.
  • suitable binders there may be mentioned, for example, polyvinylpyrrolidone, dispersible cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, starch, pregelatinized starch, partly pregelatinized starch, gum arabic, dextrin, pullulan and the like.
  • dispersible cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethyl cellulose are more preferred.
  • a disintegrant can be included in a pharmaceutical composition and especially a tablet composition to facilitate its breakup or disintegration after the tablet comes into contact with a physiological aqueous liquid.
  • the disintegrant When the tablet is swallowed, the disintegrant often is responsible for the quick disintegration of the tablet when it comes into contact with body fluids, such as saliva, gastric and intestinal fluids.
  • body fluids such as saliva, gastric and intestinal fluids.
  • Materials serving as disintegrants have been classified chemically as starches, celluloses, cross-linked polymers, etc.
  • starch a modified starch such as sodium starch glycolate (Primojel®), sodium carboxymethyl cellulose, crosslinked carboxymethylcellulose sodium (Ac-Di-Sol®), cross-linked polyvinylpyrrolidone, polacrilin potassium (Amberlite® IRP88) and low-substituted hydroxypropyl cellulose can produce a very good disintegrating effect.
  • a modified starch such as sodium starch glycolate (Primojel®), sodium carboxymethyl cellulose, crosslinked carboxymethylcellulose sodium (Ac-Di-Sol®), cross-linked polyvinylpyrrolidone, polacrilin potassium (Amberlite® IRP88) and low-substituted hydroxypropyl cellulose can produce a very good disintegrating effect.
  • the stability of an aqueous solution of bendamustine is strongly influenced by the pH. A significant hydrolytic decomposition of this compound is observed at pH values higher than about 5. At pH>5, the decomposition proceeds rapidly and the resulting content of by-products is high in this pH range.
  • the main hydrolysis products are 4-[5-[(2-Chloroethyl)-(2-hydroxy-ethyl)amino]-1-methyl-benzimidazo-2-yl]-butanoic acid (HP1), 4-[5-[Bis(2-hydroxyethyl)amino]-1-methyl-benzimidazo-2-yl]-butanoic acid (HP2) and 4-(5-Morpholino-1-methylbenzimidazol-2-yl)-butanoic acid (HP3):
  • compositions containing bendamustine show a fast dissolution, and in particular a dissolution of the bendamustine of at least 60% in 20, preferably 10 minutes, 70% in 40, preferably 20 minutes and 80% in 60, preferably 30 minutes, and most preferably of at least 75% in 10 minutes, 85% in 20 minutes and 90% in 30 minutes, as measured with a paddle apparatus at 50 rpm according to the European Pharmacopoeia in an artificial gastric fluid.
  • the artificial gastric fluid as used herein refers to a solution prepared by dissolving 2 g of sodium chloride in 1000 ml of water and then adjusting the pH to 1.5 ⁇ 0.05 with 5 N hydrochloric acid.
  • compositions according to this invention advantageously should reduce the degradation of bendamustine in the patient since the bendamustine is released and dissolved to a major extent while in the stomach, thus resulting in an improved bioavailability of the bendamustine containing compositions according to the invention.
  • the pharmaceutical compositions in a solid dosage form may be used for the treatment, induction, salvage therapy, conditioning prior to stem cell transplantation, maintenance therapy, treatment of residual disease of a medical condition in a human or animal, preferably a human, which medical condition is selected from chronic lymphocytic leukemia (CLL), acute lymphocytic leukaemia (ALL), chronic myelocytic leukaemia (CML), acute myelocytic leukaemia (AML), Hodgkin's disease, non-Hodgkin's lymphoma (NHL), multiple myeloma, breast cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer, and an autoimmune disease.
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphocytic leukaemia
  • CML chronic myelocytic leukaemia
  • AML acute myelocytic leukaemia
  • NHL non-Hodgkin's lymphoma
  • multiple myeloma breast cancer
  • the present invention also comprises a method of treatment of a medical condition selected from chronic lymphocytic leukemia, acute lymphocytic leukaemia, chronic myelocytic leukaemia acute myelocytic leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, breast cancer, ovaryian cancer, small cell lung cancer, non-small cell lung cancer, and an autoimmune disease, in a human or animal body comprising administering to the human or animal body in need thereof an effective amount of the pharmaceutical preparation of this invention.
  • the medical condition is non-Hodgkin's lymphoma.
  • the pharmaceutical composition may be administered in combination with at least one further active agent, wherein said further active agent is given prior, concurrently, or subsequently to the administration of the pharmaceutical composition.
  • This at least one further active agent is preferably an antibody specific for CD20 (such as rituximab or ofatumumab), an anthracyclin derivative (such as doxorubicin or daunorubicin), a vinca alkaloid (such as vincristine), a platin derivative (such as cisplatin or carboplatin), daporinad (FK866), YM155, thalidomide and analogues thereof (such as thalidomide or lenalidomide), or a proteasome inhibitor (such as bortezumib).
  • an antibody specific for CD20 such as rituximab or ofatumumab
  • an anthracyclin derivative such as doxorubicin or daunorubicin
  • a vinca alkaloid such
  • the pharmaceutical composition of this invention may also be administered in combination with at least one corticosteroid, wherein said corticosteroid is given prior, concurrently, or subsequently to the administration of the pharmaceutical composition.
  • corticosteroids are prednisone, prednisolone or dexamthasone.
  • mixtures containing bendamustine hydrochloride and an excipient at a ratio of 1:1 (m/m) were prepared.
  • the excipients were selected from Opadry®, Eudragit® E PO, sodium carboxymethylcellulose (Avicel® RC 591) and cross-linked polyvinylpyrrolidone (Crospovidone).
  • 253 g of a mixture comprising mannitol as the main excipient and microcrystalline cellulose, Ac-Di-Sol®, colloidal silicon dioxide, talc and stearic acid in the relative quantities mentioned in the following table 2a was prepared by mixing in a 1 liter cube blender (Erweka) for 15 minutes. Thereafter 10.612 g of the mixture and 3.0 g of bendamustine hydrochloride were sieved through a 0.425 mm sieve and then transferred into a Turbula mixer T2A, equipped with a glass vial of 50 ml and subsequently mixed for 10 minutes at 60 rpm.
  • a Turbula mixer T2A equipped with a glass vial of 50 ml and subsequently mixed for 10 minutes at 60 rpm.
  • Mean value diameter 9.1 mm; mean value mass: 247.7 mg; mean value hardness: 81N.
  • Tablets were stored at 40° C./75% RH (glass vial open) or 50° C. (glass vial closed).
  • the amount of bendamustine hydrochloride as well as of related substances, like degradation products, by-products of synthesis were measured with HPLC (column: Zorbax Bonus-RP, 5 ⁇ m; temperature of column oven: 30° C.; temperature of autosampler: 5° C.; detector: 254 nm). The results are shown in Table 2b.
  • NP1 4-[6-(2-Chloroethyl)-3,6,7,8-tetra-hydro-3-methyl-imidazo[4,5-h]-[1,4]benzothiazin-2-yl] butanoic acid
  • BM1Dimer 4- ⁇ 5-[N-(2-Chloroethyl)-N-(2- ⁇ 4-[5-bis(2-chloroethyl)amino-1-methylbenzimidazol-2-yl]butanoyloxy ⁇ ethyl)amino]-1-methylbenzimidazol-2-yl ⁇ butanoic acid
  • BM1EE 4-[5-[Bis(2-chloroethyl)amino]-1-methyl-benzimidazo-2-yl] butanoic ethyl ester * 2 n.d.: not detectable, i.e. beyond detection limit (area percentage less than 0.05%)
  • the capsule formulations were a lot less stable than the tablet formulations according to the invention although the capsule formulations were prepared from pure bendamustine hydrochloride without any further processing steps. Both at 40° C./75% RH (glass vial open) and 50° C. (closed vial) more degradation products are formed within one month of storage. In the case of open vial with 40° C. and 75% RH (relative humidity) the amount of hydrolysis product HP1 is increased by a factor of 4 after one month of storage. For the closed vials the HP1 content is even higher, which might be due to reaction with the capsules. Summarising, tablets provide a much more stable solid dosage form than the capsules.
  • Example 2 8.0 g of hydroxypropylmethyl cellulose and 1.5 g PEG 6000 are dissolved in 88.5 g purified water. Thereafter 2.0 g yellow ferric oxide and 0.5 g titanium oxide are dispersed therein yielding a coating liquid. Tablets as obtained in Example 2 are coated with 3% of this solution per tablet mass using a film coating device.
  • Mean value diameter 9.5 mm; mean value mass: 254.6 mg (begin)-257.2 mg (end); friability 0.1%; mean value hardness: 122N (begin)-128 (end).
  • the tablets were subsequently film-coated with the Opadry® dispersion until a mass increase of 5% had been achieved.
  • the mean mass of the film-coated tablets was 268.4 mg.
  • the mean mass of the film-coated tablets was 273.5 mg.
  • Mean value diameter 9.5 mm; mean value mass: 252.2 mg (begin)-250.7 mg (end); friability: 0.1% (begin)-0.2% (end); mean hardness value: 65N (begin)-73N (end).
  • the tablets were subsequently film-coated with the Eudragit® dispersion until a mass increase of 3% had been achieved.
  • the mean mass of the film-coated tablets was 253.6 mg.
  • composition coated tablets Composition PF1 PF2 PF3 component mg/tablet mg/tablet mg/tablet Bendamustine HCl 55.1 55.1 55.1 Anhydrous dextrose — — 205.8 Dextrose monohydrate 186.0 — — Trehalose — 66.0 — sorbitol — — 43.9 Lactose DCL 21 68.2 185.7 — Avicel ® PH 112 18.7 — 23.0 Crospovidone — 21.0 — Magnesium stearate 2.0 2.2 2.2 Opadry 8.0 8.0 8.0 Total 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 338.0 33
  • the tablet cores were subsequently coated in a coating pan (4M8 ForMate PanCoat) using a 9% Opadry® TM White aqueous suspension and dried.
  • the mean mass of the tablets was 342.42 mg. Thereafter the tablets were packed into amber glass bottles closed with screw plugs and stored at 40° C./75% RH.
  • the tablet cores were subsequently coated in a coating pan (4M8 ForMate PanCoat) using a 9% Opadry® TM White aqueous suspension and dried.
  • the mean mass of the tablets was 340.1 mg. Thereafter the tablets were packed into amber glass bottles closed with screw plugs and stored at 40° C.75% RH.
  • Sorbitol and anhydrous dextrose were weighed. 140.64 g of Sorbitol was dissolved in 105.48 g of purified water and the solution obtained was subsequently used to granulate 659.36 g of dextrose in a Fluid Bed Granulator (4M8ForMate FluidBed). Thereafter the granulate was dried at 60° C. and sieved through a 850 ⁇ m sieve.
  • the tablets were subsequently coated in a coating pan (4M8 ForMate PanCoat) using a 9% Opadry® TM White aqueous suspension. Mean mass of the tablets: 341.43 mg. Thereafter the tablets were packed into amber glass bottles closed with screw plugs and stored at 40° C.75% RH.
  • the dissolution samples are tested for assay by HPLC (column: Zorbax Bonus-RP, 5 ⁇ m; temperature of column oven: 30° C.; temperature of autosampler: 5° C.; detector: 254 nm).
  • Artificial gastric fluid pH 1.5 was prepared by dissolving 2 g of sodium chloride p.A. in 1000 ml of water and adjusting the pH to 1.5 ⁇ 0.05 with 5 N hydrochloric acid.
  • the dissolution test was conducted according to Chapter 2.9.3. of European Pharmacopoeia 6.0, using Apparatus 2 (Paddle-apparatus). The rotation speed of the paddle was 50 rpm, the temperature was 37° C. ⁇ 0.5° C., the amount of dissolution medium was 500 ml.
  • Example 2 tablette formulation 1
  • Example 3 tablette formulation 2
  • Tablet Tablet formulation formulation Tablet formulation example 9 (PF1) example 9 (PF2) example 9 (PF3) Mean value after Mean value after Mean value after 3 Dissolution 3 months at 3 months at months storage at after 40° C./75% RH 40° C./75% RH 40° C./75% RH 10 minutes 89.7 96.3 60.1 20 minutes 93.7 95.2 88.8 30 minutes 93.2 93.3 94.0
  • tablet formulations of the invention show a fast dissolution of bendamustine.
  • inventive formulations show a dissolution profile of the bendamustine as defined hereinbefore.
  • the objective was to determine the bioavailability of 1 dose (i.e. 50 mg) of bendamustine in 3 tablet formulations (T1-3) and 1 capsule formulation (C) with a total of 4 oral formulations: AUC and Cmax
  • the objective was to determine the bioavailability of 1 dose (i.e. 50 mg) of bendamustine in 1 tablet formulation T4, and 1 capsule formulation (C) with a total of 3 oral formulations: AUC and Cmax
  • Period 1 (single dose of capsule, day 1): Dose # Number of Animal Group Treatment Dose (mg) animals numbers 1 Bendamustine Capsule 50 4 Male + 4 Female 2 Bendamustine Capsule 50 4 Male + 4 Female
  • Example 9 The coated tablets of Example 9 (formulation 3, coated with Opadry® Tablets T4), containing 50 mg of bendamustine, were orally administered to male and female dogs in comparison with the capsules of the reference example.
  • the mean plasma profiles vs. time for both the capsule formulation and the coated tablet of Example 9 are shown in FIG. 1 .
  • coated tablets of Examples 6, 7, or 8 (Tablets T1 to T3), containing 50 mg of bendamustine, were orally administered to male and female dogs in comparison with the capsules of the reference example.
  • the mean plasma profiles vs. time of the capsule formulation and the coated tablets of Examples 6 to 8 are shown in FIG. 1 .
  • microcrystalline cellulose Avicel® PH 112
  • Cross-linked polyvinylpyrrolidone Crospovidone®
  • Table 14 and Table 15 summarize the composition of each Placebo formulation and the results of the analytical tests performed on both the final mixtures and the tablets. In Table 16, observations made during the manufacturing process of placebo batches and/or during their analytical characterization are reported.
  • Batch D001T/005 (filler: ⁇ -cyclodextrin) showed good behaviour in dry manufacturing process, high hardness, low friability but long disintegration time.
  • This formulation was further investigated by employing a super disintegrant (Crospovidone®) and adding the API (see following paragraph).
  • the placebo formulations evaluated as more suitable to manufacture tablets containing the active pharmaceutical ingredient (API) by dry granulation, were modified to include the API and two API/saccharide weight ratios were explored: 1:5 and 1:2.
  • microcrystalline cellulose Avicel® PH 112
  • Crosslinked polyvivylpyrrolidone Crosslinked polyvivylpyrrolidone
  • Magnesium stearate was used as lubricant for all the batches produced.
  • Table 17 summarizes the composition of each API-containing formulation manufactured and the results of the analytical tests performed on the API-containing final mixtures; table 18 summarizes the results of the analytical tests performed on the obtained products.
  • the obtained mixture was tabletted by using a 8 mm diameter punch.
  • microcrystalline cellulose Avicel® PH 112
  • Crosslinked polyvinylpyrrolidone Crosslinked polyvinylpyrrolidone®’
  • Table 19 and Table 20 summarize the composition of each API-containing formulation manufactured by dry granulation with an API/Saccharide weight ratio of 1:2 and the results of the analytical tests performed on both, the final mixtures and the tablets. All API-containing batches showed suitable uniformity of mass, homogeneity of API content and low impurities content. Friability and hardness values are, in the most of the cases, in compliance with the specifications. In the case of batches D001T/093, D001T/095 and D001T/096, the results of the dissolution test performed on 6 tablets showed out of specifications values with a high RSD and the test was extended to a sample of 12 tablets.
  • Cyclodextrin based tablets show good properties with both disintegrants (Avicel® PH 112 and Crospovidone®).
  • saccharides with suitable characteristics to be manufactured by dry granulation were also explored by using direct compression developing tablets with a 1:5 API/Saccharide ratio.
  • microcrystalline cellulose Avicel® PH 112
  • Crosslinked polyvinylpyrrolidone Crosslinked polyvinylpyrrolidone
  • This manufacturing process consisted of the following steps:
  • API-containing batches manufactured by Direct Compression D001T/026 D001T/027 D001T/028 D001T/029 D001T/030 (% w/w ) (% w/w ) (% w/w ) (% w/w ) (% w/w ) Bendamustine HCL 16.6 16.6 15.3 16.6 15.7 Lactose Monohydrate — — 78.4 — — (Supertab 14 SD) Sorbitol 77.1 — — — (Neosorb P60W) ⁇ -Cyclodextrin — — — 77.1 (Kleptose DC) Maltose (Food grade) 77.1 — — — — (Sunmalt S) Sucrose 97% + Maltodextrin — — — — 78.0 3% (EV Saccharide DC 3.75
  • the API-containing tablets manufactured by direct compression showed no critical differences from the ones produced by dry granulation except for batch D001T/030 (filler: Sucrose 97%+Maltodextrin 3%) that showed a non homogeneous API content and a slight increase in the value of friability.
  • Each saccharide was granulated according to the steps described in the flow-sheet of FIG. 2 . At the end of each step the wet granulated saccharide was dried and a compression trial was performed to evaluate if the granulate was suitable for tabletting. Placebo batches were manufactured only for the granulated saccharides with doubtful results of the compression test. The compositions and the relevant analytical results of the placebo trials are reported in Table 23.
  • Placebo batches were manufactured according to the following steps:
  • Manufacturing trials including a wet granulation process were carried out on all saccharides that turned out to be not suitable for tablet manufacturing by dry granulation or direct compression technologies.
  • Table 24 and Table 25 list the composition of each API-containing formulation manufactured by wet granulation and the results of the analytical tests performed on both, the final mixtures and the tablets.
  • the batches D001T/060, D001T/061, D001T/082, D001T/086 have low values in API assay and for the batches D001T/082 and D001T/086 the Uniformity of Content does not comply, though the granulate was sieved by using 850 micron and 710 micron nets. This result is probably due to poor powders mixing.
  • API-containing batches final mixture composition and analytical results.
  • API-containing Batches manufactured by Wet Granulation D001T/033 D001T/036 D001T/037 D001T/040 D001T/047 D001T/059 Components (% w/w ) (% w/w ) (% w/w ) (% w/w ) (% w/w ) (% w/w ) Bendamustine HCl 15.7 15.7 15.7 15.7 14.9 15.7 Dextrose Anhydrous 78 — — — — (Anhydrous Dextrose ST 0.5) Dextrose Monohydrate G — 78 — — — — Mannitol — — 78 — — (Pearlitol 200 SD) Lactitol Monohydrate — — — — 78 — — (Lacty M)(Food grade) D-Melezi
  • the fructose was not evaluated at a ratio of 1:2 because the obtained granulate is not suitable for tabletting.
  • step 3 (Dry granulation of the mixture) see above.
  • Table 26 and table 27 report the compositions and the analytical results of the API-containing batches manufactured by using wet granulated saccharides with a API/Saccharide weight ratio of 1:2. Friability is, in the most of the cases, out of specifications. The API/Saccharide weight change does not compromise the technological properties of the D001T/084 batch (Filler: granulated mannitol).
  • Mannitol based tablets were manufactured investigating the following API/mannitol ratios: (1:0.01, 1:0.1, 1:0.5, 1:1.7, 1:4, 1:5, 1:6 and 1:10). The formulation with a 1:5 API/mannitol weight ratio (standard formulation) was reported above.
  • the final mixture was tabletted using the tabletting machine equipped with a suitable punch (8 mm diameter punch for 1:1, 1:1.7 and 1:2 ratios, 10 mm in the case of 1:4 and 1:6 ratios, 12 mm for 1:7 ratio and 14 mm for 1:10 ratio).
  • Table 30 and Table 31 report the results concerning the saccharide combination study. The following combinations were investigated:
  • the manufacturing process consisted in direct compression of the unprocessed or granulated saccharide.
  • Saccharide Combination Study API-containing batches final mixture composition and analytical results.
  • Saccharide Combination Study API-containing Batches D001T/049 D001T/074 D001T/100 D001T/101 D001T/102 D001T/103 Components (% w/w ) (% w/w ) (% w/w ) (% w/w ) (% w/w ) (% w/w ) Bendamustine HCl 14.89 15.74 15.74 15.74 15.74 15.74 Saccharide combination Oligosaccharide/Monosaccharide 1:1 D-Melezitose monohydrate/ 78.81 — — — — — Dextrose anhydrous ST 0.5 Raffinose Pentahydrate/Mannitol — — — — 77.96 — (Pearlitol 200 SD) Saccharide combination Oligosaccharide/Disaccharide 1:1 Raffinose Pentahydrate/Lactose
  • the tablets manufactured for the saccharides combination studies show good properties.
  • the batch D001T/102 (Raffinose Pentahydrate/Mannitol (Pearlitol 200 SD))
  • Tablets containing bendamustine hydrochloride/mannitol in a weight ratio of 1: 1.2 were prepared by using either freeze dried material obtained from the commercially available product for intravenous application (Ribomustin®) or using wet granulated mannitol and Bendamustine HCl.
  • the manufacturing processes were performed according to the following experimental operations: the freeze dried powder was removed from the Ribomustin® vials and was sieved using a 850 micron net.
  • the obtained powder and the lubricant (magnesium stearate) were accurately weighed and mixed in a polyethylene bag for 5 minutes.
  • the mixture was slowly transferred in the pressing chamber of the tabletting machine and was manually pressed by using an 8 mm diameter punch in order to obtain small slugs.
  • the slugs were sieved using a 850 micron net and the obtained granulate was manually pressed using a 8 mm diameter punch.
  • composition of the formulations is reported in table 32.
  • Table 33 reports the data concerning the comparison between the tablets obtained using the freeze dried bendamustine hydrochloride/mannitol mixture and the non freeze-dried bendamustine hydrochloride/mannitol mixture.
  • batch D001T/125 showed an out of specification value for HP1 impurity.
  • the results of the dissolution test highlight that, although after 10 minutes the dissolution profile of the tablets, containing the freeze-dried bendamustine hydrochloride/mannitol mixture is faster, for both formulations, after 30 minutes the dissolution is in compliance with the current specifications.
  • the friability is out of specification for batch D001T/126, whereas the test was not performed for batch D001T/125 due to lack of sufficient amounts of material.
  • compositions according to the present invention show many advantages. They can be easily used by the patient without assistance of supervisory medical staff. Hence the time-consuming trips to the hospital may become obsolete, thereby increasing the patient compliance.
  • the dosage forms are solid, they can be swallowed as such, which means that the patient does not need to wait until dissolution of the active ingredient has been achieved. Further due to the good stability of the dosage forms they can be easily stored at room temperature and without the need of any special storage conditions.
  • the dosage forms according to the present invention By using the dosage forms according to the present invention, a considerable reduction of the volume of the dosage form may be achieved.
  • the reduced size is desirable both from a manufacturing and handling standpoint and patient compliance.
  • compositions show a high dissolution in vitro reducing the degradation of bendamustine in vivo, thus resulting in an improved bioavailability of the bendamustine in vivo.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Physiology (AREA)
  • Nutrition Science (AREA)
  • Hematology (AREA)
  • Transplantation (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US13/132,343 2008-12-03 2009-12-03 Solid Dosage Forms Of Bendamustine Abandoned US20120003309A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP08020996.8 2008-12-03
EP08020996 2008-12-03
PCT/EP2009/008639 WO2010063476A2 (en) 2008-12-03 2009-12-03 Solid dosage forms of bendamustine

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/008639 A-371-Of-International WO2010063476A2 (en) 2008-12-03 2009-12-03 Solid dosage forms of bendamustine

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/917,144 Continuation US20140004190A1 (en) 2008-12-03 2013-06-13 Solid Dosage Forms of Bendamustine

Publications (1)

Publication Number Publication Date
US20120003309A1 true US20120003309A1 (en) 2012-01-05

Family

ID=40588072

Family Applications (4)

Application Number Title Priority Date Filing Date
US13/132,343 Abandoned US20120003309A1 (en) 2008-12-03 2009-12-03 Solid Dosage Forms Of Bendamustine
US13/917,144 Abandoned US20140004190A1 (en) 2008-12-03 2013-06-13 Solid Dosage Forms of Bendamustine
US14/717,743 Abandoned US20160106716A1 (en) 2008-12-03 2015-05-20 Solid Dosage Forms of Bendamustine
US15/291,713 Active US11160793B2 (en) 2008-12-03 2016-10-12 Solid dosage forms of bendamustine

Family Applications After (3)

Application Number Title Priority Date Filing Date
US13/917,144 Abandoned US20140004190A1 (en) 2008-12-03 2013-06-13 Solid Dosage Forms of Bendamustine
US14/717,743 Abandoned US20160106716A1 (en) 2008-12-03 2015-05-20 Solid Dosage Forms of Bendamustine
US15/291,713 Active US11160793B2 (en) 2008-12-03 2016-10-12 Solid dosage forms of bendamustine

Country Status (26)

Country Link
US (4) US20120003309A1 (zh)
EP (1) EP2367538B1 (zh)
JP (3) JP5658679B2 (zh)
KR (1) KR101710935B1 (zh)
CN (2) CN102292073B (zh)
AU (1) AU2009321728B2 (zh)
BR (1) BRPI0922804B8 (zh)
CA (1) CA2745509A1 (zh)
CO (1) CO6400185A2 (zh)
CY (1) CY1119839T1 (zh)
DK (1) DK2367538T3 (zh)
EA (1) EA028179B1 (zh)
ES (1) ES2645008T3 (zh)
HR (1) HRP20171421T1 (zh)
HU (1) HUE036481T2 (zh)
IL (1) IL213269A (zh)
LT (1) LT2367538T (zh)
MX (1) MX2011005633A (zh)
NZ (1) NZ592971A (zh)
PL (1) PL2367538T3 (zh)
PT (1) PT2367538T (zh)
RS (1) RS56408B1 (zh)
SI (1) SI2367538T1 (zh)
UA (2) UA107186C2 (zh)
WO (1) WO2010063476A2 (zh)
ZA (1) ZA201103790B (zh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130209558A1 (en) * 2010-06-02 2013-08-15 Astellas Deutschland Gmbh Oral Dosage Forms of Bendamustine and Therapeutic Use Thereof
EP2641592A1 (en) 2012-03-23 2013-09-25 Salmon Pharma GmbH Pharmaceutical formulation comprising bendamustine
WO2015031198A3 (en) * 2013-08-27 2015-04-23 Voudouris Vasilios Bendamustine pharmaceutical compositions
US10632074B2 (en) 2015-10-05 2020-04-28 Daido Chemical Corporation Composite granulated product including sugar or sugar alcohol, swelling binder, disintegrating agent and highly absorbent excipient, and method for manufacturing composite granulated product
CN117257913A (zh) * 2023-11-23 2023-12-22 江西中医药大学附属医院 一种温肺化纤颗粒剂及其制备方法

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA107186C2 (xx) * 2008-12-03 2014-12-10 Тверді форми дозування бендамустину
DK2575784T3 (en) 2010-06-02 2018-10-15 Astellas Deutschland Gmbh ORAL DOSAGE FORMS OF BENDAMUSTIN
CN102375044B (zh) * 2010-08-18 2015-04-08 重庆华邦胜凯制药有限公司 一种盐酸苯达莫司汀中间体z6有关物质的分析方法
JP2016153374A (ja) * 2013-06-25 2016-08-25 シンバイオ製薬株式会社 炎症性疾患を治療又は予防するための医薬組成物
CN105566226B (zh) * 2014-05-06 2019-06-21 南京先声东元制药有限公司 盐酸苯达莫司汀二聚体的制备方法与应用
JP6608193B2 (ja) * 2014-06-27 2019-11-20 花王株式会社 固形状組成物
WO2016005995A2 (en) * 2014-07-10 2016-01-14 Leiutis Pharmaceuticals Pvt. Ltd. Glycol free stable liquid compositions of bendamustine
CN111201019A (zh) * 2017-10-05 2020-05-26 图贝药物有限公司 口服苯达莫司汀制剂
CN110437261A (zh) * 2018-05-02 2019-11-12 南京诺瑞特医药科技有限公司 苯达莫司汀杂质g的合成方法
CN113768038A (zh) * 2021-09-14 2021-12-10 江苏省协同医药生物工程有限责任公司 一种精准定量实验动物功能性饲料及制备方法与设备

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060128777A1 (en) * 2004-11-05 2006-06-15 Bendall Heather H Cancer treatments
US20090264488A1 (en) * 2008-03-26 2009-10-22 Cephalon, Inc. Novel solid forms of bendamustine hydrochloride

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY191349A (en) * 2004-08-27 2022-06-17 Bayer Pharmaceuticals Corp New pharmaceutical compositions for the treatment of hyper-proliferative disorders
US8436190B2 (en) 2005-01-14 2013-05-07 Cephalon, Inc. Bendamustine pharmaceutical compositions
UA107186C2 (xx) * 2008-12-03 2014-12-10 Тверді форми дозування бендамустину

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060128777A1 (en) * 2004-11-05 2006-06-15 Bendall Heather H Cancer treatments
US20090264488A1 (en) * 2008-03-26 2009-10-22 Cephalon, Inc. Novel solid forms of bendamustine hydrochloride

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130209558A1 (en) * 2010-06-02 2013-08-15 Astellas Deutschland Gmbh Oral Dosage Forms of Bendamustine and Therapeutic Use Thereof
US10485787B2 (en) 2010-06-02 2019-11-26 Astellas Deutschland Gmbh Oral dosage forms of bendamustine and therapeutic use thereof
EP2641592A1 (en) 2012-03-23 2013-09-25 Salmon Pharma GmbH Pharmaceutical formulation comprising bendamustine
AU2014311570B2 (en) * 2013-08-27 2018-04-19 Vasilios VOUDOURIS Bendamustine pharmaceutical compositions
US9849115B2 (en) 2013-08-27 2017-12-26 Vasilios Voudouris Bendamustine pharmaceutical compositions
US20180071263A1 (en) * 2013-08-27 2018-03-15 Vasilios Voudouris Bendamustine pharmaceutical compositions
CN105491886A (zh) * 2013-08-27 2016-04-13 V·沃道里斯 苯达莫司汀医药组合物
AU2014311570C1 (en) * 2013-08-27 2018-08-02 Vasilios VOUDOURIS Bendamustine pharmaceutical compositions
WO2015031198A3 (en) * 2013-08-27 2015-04-23 Voudouris Vasilios Bendamustine pharmaceutical compositions
US10786486B2 (en) 2013-08-27 2020-09-29 Vasilios Voudouris Bendamustine pharmaceutical compositions
US11701344B2 (en) 2013-08-27 2023-07-18 Vasilios Voudouris Bendamustine pharmaceutical compositions
US10632074B2 (en) 2015-10-05 2020-04-28 Daido Chemical Corporation Composite granulated product including sugar or sugar alcohol, swelling binder, disintegrating agent and highly absorbent excipient, and method for manufacturing composite granulated product
CN117257913A (zh) * 2023-11-23 2023-12-22 江西中医药大学附属医院 一种温肺化纤颗粒剂及其制备方法

Also Published As

Publication number Publication date
JP2012510483A (ja) 2012-05-10
BRPI0922804A2 (pt) 2015-12-22
EA028179B1 (ru) 2017-10-31
US11160793B2 (en) 2021-11-02
HRP20171421T1 (hr) 2017-11-03
MX2011005633A (es) 2011-09-27
JP5658679B2 (ja) 2015-01-28
LT2367538T (lt) 2017-12-27
WO2010063476A2 (en) 2010-06-10
BRPI0922804A8 (pt) 2017-12-26
PT2367538T (pt) 2017-11-14
WO2010063476A3 (en) 2010-08-05
KR101710935B1 (ko) 2017-02-28
ZA201103790B (en) 2012-08-29
UA116334C2 (uk) 2018-03-12
IL213269A0 (en) 2011-07-31
IL213269A (en) 2017-04-30
JP2017057225A (ja) 2017-03-23
UA107186C2 (xx) 2014-12-10
JP6396980B2 (ja) 2018-09-26
HUE036481T2 (hu) 2018-07-30
EA201190012A1 (ru) 2012-02-28
EP2367538A2 (en) 2011-09-28
BRPI0922804B1 (pt) 2020-11-17
US20160106716A1 (en) 2016-04-21
SI2367538T1 (sl) 2017-11-30
KR20110102392A (ko) 2011-09-16
CN107080742A (zh) 2017-08-22
PL2367538T3 (pl) 2017-12-29
RS56408B1 (sr) 2018-01-31
DK2367538T3 (en) 2017-10-02
CO6400185A2 (es) 2012-03-15
BRPI0922804B8 (pt) 2021-05-25
CY1119839T1 (el) 2018-06-27
US20170100376A1 (en) 2017-04-13
JP2015061864A (ja) 2015-04-02
CN102292073A (zh) 2011-12-21
CN107080742B (zh) 2020-08-18
EP2367538B1 (en) 2017-08-02
NZ592971A (en) 2013-08-30
AU2009321728B2 (en) 2016-07-07
CA2745509A1 (en) 2010-06-10
US20140004190A1 (en) 2014-01-02
AU2009321728A1 (en) 2011-06-30
CN102292073B (zh) 2018-07-10
ES2645008T3 (es) 2017-12-01

Similar Documents

Publication Publication Date Title
US11160793B2 (en) Solid dosage forms of bendamustine
JP6259490B2 (ja) ベンダムスチンの経口投与形及びその治療的使用
AU2009321745A1 (en) Oral dosage forms of bendamustine
US20090298944A1 (en) Pharmaceutical composition
SK50132006A3 (sk) Flukonazolové kapsuly so zlepšeným uvoľňovaním
US20180344648A1 (en) Clobazam tablet formulation and process for its preparation
US20170056323A1 (en) Formulations of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione

Legal Events

Date Code Title Description
AS Assignment

Owner name: ASTELLAS DEUTSCHLAND GMBH, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:COLLEDGE, JEFFREY;PROFITLICH, THOMAS ALFRED;PATZAK, ULRICH;AND OTHERS;SIGNING DATES FROM 20110817 TO 20110905;REEL/FRAME:026935/0561

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION