US20130202693A1 - Oral Dosage Forms of Bendamustine - Google Patents

Oral Dosage Forms of Bendamustine Download PDF

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US20130202693A1
US20130202693A1 US13/701,269 US201113701269A US2013202693A1 US 20130202693 A1 US20130202693 A1 US 20130202693A1 US 201113701269 A US201113701269 A US 201113701269A US 2013202693 A1 US2013202693 A1 US 2013202693A1
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bendamustine
pharmaceutical composition
minutes
viscosity
dissolution
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Jeffrey Colledge
Margaretha Olthoff
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Astellas Deutschland GmbH
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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
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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
    • A61K9/485—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present invention relates to oral dosage forms comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof.
  • 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 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.
  • Bendamustine hydrochloride is only sparingly soluble in water at a pH of 2.0 and is slightly or very slightly soluble in a range of organic solvents. A good solubility has been observed however in ethanol and methanol. Therefore it is not surprising that the oral bendamustine compositions, as investigated by Preiss et al. and Weber gave rise to relatively poor bioavailability results and a large inter-individual variability.
  • 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 apart from having a good stability also have an appropriate dissolution profile.
  • FIG. 1 shows the mean plasma concentration vs. time curve obtained after administering bendamustine hydrochloride in the form of the prior art capsule (reference example 1) and the liquid filled hard capsule formulation of Example 2 to dogs. It is apparent from FIG. 1 that the liquid filled hard capsule formulation provides for a higher maximum concentration of bendamustine, as compared with the prior art reference capsule formulation.
  • the present invention relates to a pharmaceutical composition for oral administration, the composition comprising bendamustine or a pharmaceutically acceptable, ester, salt or solvate thereof as an active ingredient, and a pharmaceutically acceptable excipient, which is a non-ionic hydrophilic surfactant.
  • An embodiment is a pharmaceutical composition, comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof and a pharmaceutically acceptable excipient, which is a non-ionic hydrophilic surfactant, wherein the composition is suitable for oral administration by including it into a hard gelatine capsule.
  • a further embodiment is a pharmaceutical composition for oral administration in a solid dosage-form, which is a hard gelatine capsule, the composition comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof and a pharmaceutically acceptable excipient, which is a non-ionic hydrophilic surfactant, wherein the use of the specific non-ionic hydrophilic surfactant leads to a dissolution of bendamustine from the composition of at least 80% after 60 minutes, as measured with a paddle apparatus at 50 rpm during 30 minutes and at 200 rpm during a further 30 minutes according to the European Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5.
  • the use of the specific non-ionic surfactant results in a dissolution profile of at least 60% bendamustine dissolved after 20 minutes, 70% dissolved after 40 minutes and 80% dissolved after 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 use of the specific non-ionic hydrophilic surfactant results in a dissolution of bendamustine from the composition of at least 80% after 30 minutes and most preferably results in a dissolution profile of at least 60% bendamustine dissolved after 10 minutes, 70% after 20 minutes and 80% after 30 minutes, both when 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 preferred embodiment is a pharmaceutical composition for oral administration in a solid dosage-form, which is a hard gelatine capsule, the composition comprising bendamustine hydrochloride and a pharmaceutically acceptable excipient, which is a non-ionic hydrophilic surfactant, wherein the use of the specific non-ionic surfactant results in a dissolution of at least 60% bendamustine dissolved after 10 minutes, 70% after 20 minutes and 80% after 30 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 present invention is based on the surprising finding that stable compositions of bendamustine having a specific and desirable dissolution profile can be obtained by incorporating into the pharmaceutical composition certain non-ionic surfactants. It has been found that, if a pharmaceutically acceptable non-ionic hydrophilic surfactant is used as an excipient in a pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable ester, a salt or a solvate thereof as an active ingredient, a particularly favourable profile of the composition with respect to stability and degradation products, dissolution, bioavailability and a reduced variability in bioavailability is achieved.
  • non-ionic hydrophilic surfactants which are a polyethoxylated castor oil or a derivative thereof (in particular macrogol glycerol hydroxystearate or polyoxyl-35-castor oil), a block copolymer of ethylene oxide and propylene oxide (in particular Pluronic® L44 NF or Poloxamer® 124; Pluronic® L35 or Poloxamer® 105; Pluronic® L64 or Poloxamer 184), a macrogol glycerol cocoate (Glycerox® HE), a macrogol 15 hydroxy stearate (Solutol® HS15), Polysorbate 20 and 40, but are not limited hereto, in bendamustine-containing compositions results in a dissolution profile of at least 60% bendamustine dissolved after 20 minutes, 70% dissolved after 40 minutes and 80% dissolved after 60 minutes, as measured with a paddle apparatus at 50 rpm according to the European Pharmacopoeia in 500 ml of a
  • esters with alkyl alcohols and sugar alcohols examples include C 1-6 -alkyl alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol.
  • alkyl alcohols C 1-6 -alkyl alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol.
  • sugar 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. 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 multiple doses 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.
  • non-ionic hydrophilic surfactant refers to an amphiphilic compound having a polar, hydrophilic group and a non-polar, lipophilic group or chain and wherein the hydrophilic and lipophylic properties of the compound are characterised by the so-called Hydrophilic-Lipophilic Balance (HLB) value.
  • the non-ionic surfactant to be used for preparing the compositions of the present invention has an HLB-value between 10 and 20.
  • the non-ionic surfactant further has a melting point, pour point or melting range between 5° C. and body temperature (37° C.).
  • the non-ionic surfactant can be in a liquid or a semi-solid state at room temperature.
  • the non-ionic hydrophilic surfactant is a carrier for the bendamustine active ingredient, which can be present in a dissolved form, a suspended form or partly in a dissolved and partly in a suspended form.
  • the non-ionic hydrophilic surfactants that are advantageously used for the preparation of the compositions according to the present invention preferably have an HLB-value of between 10 and 19, more preferably between 12 and 18, and are liquid at room temperature or have a melting point, pour point or melting range of between just below room temperature (20° C.) and body temperature, preferably at approximately 30° C. Examples thereof can be found in the group of a polyethoxylated castor oil or derivatives thereof, in the group of block copolymers of ethylene oxide and propylene oxide and in the group of Polysorbates.
  • the non-ionic surfactant is a polyethoxylated castor oil.
  • a polyethoxylated castor oil is sold under the tradename Cremophor®. Cremophor® products of various purities and viscosities are produced and may be used in the present invention. In particular macrogol glycerol hydroxystearate (Cremophor® RH 40) and polyoxyl-35-castor oil (Cremophor® EL or Cremophor® ELP) can be used. Cremophor® ELP and Cremophor® EL are known as nonionic solubilizers and emulsifiers, produced by reacting castor oil with ethylene oxide in a molar ratio of 1 to 35.
  • Macrogol glycerol hydroxystearate (commercially available as Cremophor® RH 40) is a semi-solid material at 25° C., having a viscosity range at the same temperature of 20-40 cps (as a 30% aqueous solution). It is known as a nonionic solubiliser and emulsifier. It is produced by reacting castor oil with ethylene oxide in a molar ratio of 1 to 45. Its HLB-value ranges from 14-16 and the melting range is from 20-28° C. In experiments it was shown that macrogol glycerol hydroxystearate can advantageously be used on its own for the preparation of compositions according to the present invention.
  • Pluronic® block copolymers consist of ethylene oxide and propylene oxide blocks and are characterised by the following formula: HO(C2H4O)a(C3H6O)b(C2H4O)aH.
  • the ethylene oxide units have a hydrophilic character whereas the propylene oxide units have a lipophilic character Variations in the number of hydrophilic ethylene oxide units and lipophilic propylene oxide units results in copolymers with a different molecular mass and different hydrophilic-lipophilic-balance (HLB).
  • Pluronic® L35, Pluronic L64 and Pluronic® L43 All are liquids at room temperature.
  • Polysorbates are oily liquids derived from PEG-ylated sorbitan (a derivative of sorbitol) esterified with fatty acids. Examples are:
  • non-ionic hydrophilic surfactants that can be used as carriers for bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof can be found in in the examples.
  • non-ionic surfactants are all liquids having a viscosity value which may be too low to avoid sedimentation of the bendamustine hydrochloride.
  • the additional problem to be solved was to find an excipient or a combination of excipients that would allow for a total value for the viscosity of the mixture that would be high enough to avoid segregation of the bendamustine chloride when added to the mixture.
  • compositions according to the present invention that contain a liquid non-ionic surfactant, advantageously further contain a viscosity improving agent.
  • Suitable viscosity-improving agents include a powder such as colloidal silicon dioxide (commercially available under the trademark Aerosil®) or a semi-solidwaxy material, such as lauroyl macrogol glycerides (commercially available under the trademark Gelucire® 44/14).
  • the amount of the powder or the semi-solid material to be added to the liquid non-ionic surfactant depends on the viscosity of the liquid non-ionic surfactant. Different concentrations have been tested in order to find the minimum suitable amount of viscosity improving agent to be added to visually avoid sedimentation of the active ingredient.
  • Typical relative concentrations of colloidal silicon dioxide to be added range from about 1% to about 8%, but are preferably as low as 1.7% or 2.0% in order not to have a negative impact on the dissolution characteristics of the active ingredient.
  • Typical relative concentrations of lauroyl macrogol glycerides range from 5 to 50%, and are preferably about 10% and about 45%.
  • compositions according to the present invention are disclosed in example 4 and comprise bendamustine hydrochloride in combination with:
  • compositions of the present invention can include additional excipients, in particular protective agents, such as anti-oxidants and antimicrobial preservatives, e.g. methyl-, ethyl- and propylparaben, as illustrated in examples 1-3.
  • protective agents such as anti-oxidants and antimicrobial preservatives, e.g. methyl-, ethyl- and propylparaben, as illustrated in examples 1-3.
  • the antioxidant may be d-alpha tocopherol acetate, dl-alpha tocopherol, ascorbyl palmitate, butylated hydroxyanidole, ascorbic acid, butylated hydroxyanisole, butylatedhydroxyquinone, butylhydroxyanisol, hydroxycoumarin, butylated hydroxytoluene, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, or mixtures thereof.
  • the anti-oxidant is preferably added to compositions containing macrogol glycerol hydroxystearate or polyoxyl-35-castor oil.
  • compositions according to the present invention are advantageously filled into a capsule, as described in the examples, which capsule can then easily be taken by the patient.
  • capsules Two types of capsule are commonly used and are classified according to the nature and flexibility of the capsule shell: soft and hard capsules.
  • Soft capsules are single unit solid dosage forms comprising a liquid or semi-solid fill. They are formed, filled and sealed in one operation using a rotary die process. They have been used as unit dose containers for liquids for many years, whereas hard capsules have conventionally been used for the delivery of solids in the form of powders, granulates and pellets.
  • Hard capsules are single unit dosage forms, consisting of a cap and a body, which are manufactured separately and which are supplied empty for filling.
  • Soft capsules are most commonly manufactured from gelatine, to which a plasticiser, usually glycerine or sorbitol, is added in addition to water. Also for hard capsules the most commonly used polymer is gelatine. An additional component is water, which acts as a plasticiser. This component however may be responsible for degradation of active ingredients, such as bendamustine hydrochloride. Therefore as an alternative hard capsules may be manufactured from hydroxypropylmethyl cellulose.
  • Both soft and hard capsules in addition can include colouring agents and opacifiers.
  • the preferred type of capsule for the compositions according to the present invention is the hard capsule and more in particular the hard gelatine capsule.
  • the materials to be filled into the capsule are fluid at room temperature, which would avoid heating during the filling operation. Generally, heating could result in an easy degradation of the active component.
  • fill formulations for hard capsules may be Newtonian liquids, such as oils, thixotropic or shear thinning gels or semi-solid matrix products that are filled at elevated temperatures and in which the active ingredient is either dissolved or suspended as a fine dispersion.
  • any excipient or mixture of excipients can be used provided that the viscosity of the fill material confirms to the requirements of the filling process.
  • the uniformity of capsule fill weights is important. Further fill formulations should not show stringing and should allow for a clean break from the dosing nozzle.
  • compositions according to the present invention can be advantageously administered in hard gelatine capsules.
  • the particular non-ionic hydrophilic surfactants selected from the group consisting of a polyethoxylated castor oil or derivative thereof and a block copolymer of ethylene oxide/propylene oxide, and in particular from the group consisting of macrogol glycerol hydroxystearate, polyoxyl-35-castor oil and Pluronic® L44 or Poloxamer® 124, if incorporating bendamustine or a pharmaceutically acceptable ester, salt, or solvate thereof, and after incorporation into hard gelatine capsules result in achieving a good stability, a good dissolution profile and a good bioavailability.
  • Cremophor® A 25 ceteareth-25 or macrogol (25) cetostearyl ether
  • Cremophor® A 6 ceteareth-6 and stearylalcohol or macrogol (6) cetostearyl ether
  • 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):
  • Absorption of an orally administered drug usually happens from the stomach, the small intestine and/or the large intestine.
  • the pH in the stomach is about 1 to 3.5, in the small intestine about 6.5 to 7.6, and in the large intestine about 7.5 to 8.0.
  • compositions comprising bendamustine hydrochloride in a pharmaceutically acceptable excipient, which is a non-ionic hydrophilic surfactant, selected from the group consisting of a polyethoxylated castor oil or derivative thereof and a block copolymer of ethylene oxide and propylene oxide, surprisingly show a fast dissolution, and in particular a dissolution of the bendamustine of at least 60% in 20 minutes, 70% in 40 minutes and 80% in 60 minutes, and preferably of at least 60% in 10 minutes, 70% in 20 minutes and 80% 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 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.
  • the total time of a drug to pass the stomach to the small intestine is between about 20 minutes to 5 hours, usually between about 30 minutes to 3 hours.
  • pharmaceutical 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.
  • bioavailability of the bendamustine containing compositions according to the invention may be expected.
  • the oral pharmaceutical compositions may be used for the treatment or prevention of relapse of a medical condition in a human or animal, preferably a human, which medical condition is selected from chronic lymphocytic leukemia (abbreviated as CLL), acute lymphocytic leukaemia (abbreviated as ALL), chronic myelocytic leukaemia (abbreviated as CML), acute myelocytic leukaemiam (abbreviated as AML), Hodgkin's disease, non-Hodgkin's lymphoma (abbreviated as 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 leukaemiam
  • NHL non-Hodgkin's lymphoma
  • MM multiple my
  • the present invention also comprises a method of treatment or prevention of relapse 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, ovarian 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.
  • 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, ovarian cancer, small cell lung cancer, non-small cell lung cancer, and an autoimmune
  • 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 (an examples is rituximab or ofatumumab), an anthracyclin derivative (an example is doxorubicin or daunorubicin), a vinca alkaloid (an example is vincristine), a platin derivative (an example is cisplatin or carboplatin), daporinad (FK866), YM155, thalidomide and analogues thereof (an example is lenalidomide), or a proteasome inhibitor (an example is bortezumib).
  • an antibody specific for CD20 an examples is rituximab or ofatumumab
  • an anthracyclin derivative an example is doxorubicin or daunorubicin
  • 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 and dexamethasone.
  • compositions according to the present invention further is, that the active ingredient(s), optionally in admixture with one or more excipients, do not need to be provided with a coating in order to further mask the taste of such ingredient and/or to protect the same against possible harmful effects by light and/or moisture such as oxidation, degradation, or to prevent that the subject may experience damage of the oral mucosa, due to the interaction with the active ingredient.
  • 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 blend was transferred to a capsule filling machine (Zanassi AZ 5) and filled into hard gelatine capsules (size 2) (mean mass: 259.5 mg (begin)-255.3 mg (end)) and hypromellose capsules (size 2) (mean mass: 255.8 (begin)-253.4 mg (end)) respectively.
  • Capsules were stored at 40° C./75% RH in a closed glass vial.
  • 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).
  • Table 2b filled in hypromellose capsules
  • 2c filled in gelatine capsules.
  • the blend was transferred to a capsule filling machine (Zanassi AZ 5) and filled into hard gelatine capsules (size 2) (mean mass: 257.9 mg (begin)-255.2 mg (end)) and hypromellose capsules (size 2) (mean mass: 261.1 (begin)-257.8 mg (end)) respectively.
  • Capsules were stored at 40° C./75% RH in a closed glass vial.
  • the amount of bendamustine hydrochloride and of related substances was measured with HPLC, as described above. The results are shown in Table 3b (filled in hypromellose capsules) and 3c (filled in gelatine capsules).
  • the blend was transferred to a capsule filling machine (Zanassi AZ 5) and filled into hard gelatine capsules (size 2) (mean mass: 241.3 mg (begin)-244. mg (end)) and hypromellose capsules (size 2) (mean mass: 243.5 (begin)-243. mg (end)) respectively.
  • Capsules were stored at 40° C./75% RH in a closed glass vial.
  • the amount of bendamustine hydrochloride and of related substances was measured with HPLC, as described above. The results are shown in Table 4b (filled into hypromellose capsules) and 4c (filled in gelatine capsules).
  • Cremophor® RH 40 0.68 g of methylparaben, 0.068 g of propylparaben and 0.068 g of butylhydroxytoluene were weighed and dissolved in 6.14 g of ethanol. Cremophor® RH 40 was melted at 40° C. in a sufficient amount. 5.56 g of the ethanolic solution obtained, 36.83 g of the melted Cremophor® RH 40 and 202.82 g of Pluronic® L44 NF were weighed and mixed at 800 rpm using a mechanical stirrer until the mixture became transparent. The mixture was allowed to solidify by placing it at 10° C.
  • Cremophor® RH 40 0.68 g of methylparaben, 0.068 g of propylparaben and 0.068 g of butylhydroxytoluene were weighed and dissolved in 6.14 g of ethanol. Cremophor® RH 40 was melted at 40° C. in a sufficient amount. 5.56 g of the ethanolic solution obtained and 239.65 g of the melted Cremophor® RH 40 were weighed and mixed at 800 rpm using a mechanical stirrer until the mixture became transparent. The mixture was allowed to solidify and cool to room temperature.
  • the liquid filled capsules so obtained were stored in closed amber glass bottles with screw plugs at 40° C./75% RH, at 30° C./65% RH, at 25° C./60% RH and at 5° C.
  • the amount of bendamustine hydrochloride as well as of related substances, like degradation products, by-products of synthesis was measured with HPLC, as described above.
  • LFHC-formulations were prepared based on an oily suspension suitable to obtain a physico-chemically stable formulation. Below the formulation development of liquid filled hard capsules (LFHC) together with the analytical evaluation of these products during formulation development and stability program is represented.
  • LFHC liquid filled hard capsules
  • Tested features of the final LFHC included appearance, dissolution rate and physical and chemical stability, under different conditions, for at least 3 months.
  • the carriers used were initially selected and characterised according to their physico-chemical compatibility with both, bendamustine hydrochloride and LiCaps and according to their ability to allow both a stable formulation and a fast dissolution.
  • a carrier with a low purity grade such as a physically aged carrier, could affect the stability of the formulation: this aspect was investigated by using aged carriers in batch manufacturing.
  • the moisture content of the carrier could affect the physic-chemical stability of the formulation.
  • a high water content could degrade bendamustine hydrochloride, due to its sensitivity, while a hygroscopic carrier could damage the capsule shell and increase its brittleness.
  • Water sorption/desorption analysis was performed on the selected carriers in order to increase their moisture content and predict their behavior during the storage. Furthermore, the moisture content of two different carriers was artificially modified and these were used in batch manufacturing.
  • low viscosity carriers were used in batch manufacturing, in combination with the minimum suitable amount of a viscosity increaser to avoid, visually, sedimentation phenomena.
  • Two different kinds of viscosity increaser were used: a silicon powder (Aerosil®) and a semisolid matrix with a melting point higher than 40° C. (Gelucire® 44/14). The same carriers were also tested without the viscosity increaser and the resulting formulations compared with the above mentioned ones.
  • Two different carriers were submitted to an artificial treatment to accelerate a possible “aging” phenomenon and were used in batch manufacturing, in order to evaluate the effect on the stability of the formulation of a carrier with a low purity level.
  • the bendamustine hydrochloride dissolved in the vehicle may be exposed to chemical degradation more than the suspended one.
  • an analytical method to quantify the actual amount of bendamustine hydrochloride and related impurities solubilised by the oil was developed.
  • a fast dissolution is one of the most important features of LFHC. Due to the poor miscibility with water of some of the oils used in capsule manufacturing, a visual appearance of the behavior of the suspension during the in vitro dissolution was found to be helpful to clarify different physical aspects of the manufactured suspensions and also to predict the correspondent in vivo behavior.
  • the amount of viscosity increaser added to the suspension was estimated as the minimum suitable amount to obtain a liquid formulation viscous enough to keep the bendamustine hydrochloride in suspension and to avoid its sedimentation.
  • the amount of viscosity increaser to be added was found to be strongly related to the initial viscosity of the carrier.
  • the bendamustine hydrochloride:Carrier ratio in all the developed formulations was the same (about 1:10).
  • the bendamustine hydrochloride:Carrier ratio in all the developed formulations was the same (about 1:10).
  • the suspensions were manufactured according to the following standard formulation for evaluation:
  • the bendamustine hydrochloride:Carrier ratio in all the developed formulations was the same (about 1:10).
  • the selection of the carriers was performed among both categories of carriers, low and high viscosity, in order to obtain representative data about two kind of suspensions.
  • the formulations with low viscosity carrier included a viscosity modifier, to ensure the physical stability of the suspension.
  • the suspensions were manufactured according to the following standard formulation for evaluation:
  • the carriers were used in batch manufacturing according to the following formulation:
  • the bendamustine hydrochloride:Carrier ratio in all the developed formulations was the same (about 1:10).
  • the carriers were chosen among the more hygroscopic ones. Two carriers were dispensed in open glass beakers and placed in the following conditions:
  • the bendamustine hydrochloride:Carrier ratio in all the developed formulations was the same (about 1:10).
  • the batches were intended to be made by adding the viscosity increaser (Aerosil®) to the carrier, and subsequently homogenising the mixture thus obtained. Thereafter the bendamustine hydrochloride was added, followed by homogenisation. The mixture obtained was filled into LiCaps® capsules. Only for one batch (D001L/035) this manufacturing method was used: the second homogenisation step, after adding the bendamustine, resulted in a massive increase in the viscosity of the suspension, and therefore caused problems during the subsequent filling step. The suspension was for this reason hand-filled in gelatin capsules, sealed by Capsule Filling and Sealing machine CFS 1200.
  • the manufacturing method for the batches was therefore optimised, which resulted in the following manufacturing method:
  • the batches were made by adding the viscosity increaser (Aerosil®) to the carrier. Thereafter the bendamustine hydrochloride was added, followed by homogenisation. The mixture obtained was filled into LiCaps® capsules.
  • the manufacturing process was further optimized as follows: bendamustine was added to the carrier and the mixture thus obtained was homogenized. Thereafter the viscosity increaser (Aerosil®) was added, under stirring, in the minimum amount suitable to obtain a viscous liquid suspension. In this way batches D001L/037 to D001L/049 and batch D0011/052 were prepared. Except for batch D001L/038 and D001L/052 (suspensions with low viscosity), all other suspensions were liquids having a high viscosity which were hand-filled in gelatin LiCaps. The minimum amount of Aerosil® added depended on the initial viscosity of the carrier.
  • the proposed manufacturing method for batches in which Gelucire® 44/14 was used as a viscosity increaser comprised the steps of adding the viscosity increasing agent to the carrier and homogenizing the mixture thus obtained. Thereafter bendamustine was added and the so obtained mixture was again homogenized prior to filling it in the LiCaps® capsules.
  • No. D001L/049, 050, 053, 085 and 086 were prepared. All suspensions were semisolid matrices at room temperature which upon increase of the temperature showed a decrease of their viscosity. All manufactured suspensions were hand-filled in gelatin Licaps, except for batches D001L/085 and D001L/086, dosed by CFS1200.
  • the amount of Gelucire® 44/14 employed in the manufacturing was determined in order to obtain a semisolid vehicle at room temperature but liquid at about 35° C., depending on the initial viscosity of the carrier.
  • carriers having a low viscosity were used in the preparation of bendamustine containing suspensions according to the following manufacturing method: bendamustine was added to the carrier, without any viscosity increasing agent, the mixture was homogenized and thereafter filled in LiCaps.
  • Several LFHC formulations were manufactured by using this type of carrier. Thanks to their low viscosity all suspensions could be filled into the LiCaps with the Capsule Filling and Sealing machine CFS 1200.
  • the composition of all batches made with the corresponding analytical results at time zero are reported in tables 13a, b and c.
  • Complies Complies Complies CV 6.07 6.07 Assay (HPLC) 95.0%-105.0% 90.3 86.9 93.0 90.3 91.6 Related substances (HPLC) HP1 ⁇ 0.50% 0.07 0.47 0.17 0.07 0.1 BM1 Dimer ⁇ 0.20% 0.28 0.06 0.17 0.28 0.16 BM1EE ⁇ 0.50% 0.11 0.10 0.09 0.11 0.10 NP1 ⁇ 0.20% 0.01 0.01 0.01 0.01 0.01 0.01 Major Unknon impurity (RRT) ⁇ 0.10% 0.04 (0.70) 0.17 (0.70) 0.49 0.04 (0.70) 0.25 (0.22) Total impurities ⁇ 1.50% 0.51 1.00 1.14 0.51 1.04 Dissolution Test 80% in 30 mins fail fail fail fail fail fail (% 10 min) Average (%) 16.6 9.0 31.1 16.6 39.8 min (%)-max (%) 2.70-31.7 4.70-15.7 16.4-66.2 2.70-31.7 28.2-54.3 RSD 65.9 44.6 58.8 65.9 25.2 (% 20
  • Carriers that are semisolid or solid at room temperature and have a high viscosity were selected for use in the preparation of formulations containing bendamustine hydrochloride in order to evaluate the effect of temperature from the early stages of preparation up till and including the shelf life.
  • High viscosity carriers are listed in table 14.
  • the proposed manufacturing method for the LFHC formulations containing bendamustine hydrochloride was adding bendamustine hydrochloride to the melted carrier, homogenizing the mixture and filling the mixture at a temperature above 25° in the LiCaps® capsules.
  • the suspensions are semisolid or solid at room temperature; thus it was found to be necessary to fill these into the LiCaps® capsules with the Capsule Filling and Sealing Machine CFS 1200 within a certain temperature range depending on their melting point (see table 14). Due to the high viscosity of the carriers at room temperature, sedimentation in these suspensions was not observed.
  • Miglyol® 812 and Softisan® 649 having a low and high viscosity respectively were selected as suitable for this study.
  • the formulation with Miglyol® 812 included Aerosil® as a viscosity modifier, to ensure the physical stability of the suspension.
  • the API/Carrier ratio was established first, regardless of the final amount of the suspension.
  • the viscosity increaser was only useful to suspend the amount of API added.
  • Batches No. D001L/071 and 072 were manufactured by adding the bendamustine hydrochloride to the melted carrier, homogenizing the mixture and filling it into the LiCaps® capsules with the Capsule Filling and Sealing machine CFS 1200.
  • the bendamustine hydrochloride/Carrier ratio was established first, regardless of the final amount of the suspension.
  • Labrafil® M1944 CS and Pluronic® L44 NF INH were placed in open transparent glass bottles and exposed for about 5 days to:
  • the aged Labrafil® M1944 CS and Pluronic® L44 NF INH were used in the preparation of formulations containing bendamustine hydrochloride (batches D001L/074 and D001L/079 in table 17a).
  • the batches were manufactured by adding the bendamustine hydrochloride to the aged carrier, followed by homogenization. Thanks to their suitable viscosity, all suspensions could be filled into LiCaps® capsules with the Capsule Filling and Sealing machine CFS 1200.
  • the selection of carriers was performed according to their water sorption/desorption profiles.
  • the carriers were selected amongst the ones that showed more hygroscopicity.
  • the apparatus consists of a Calm microbalance housed inside a temperature controlled cabinet. Experimental conditions were:
  • the first condition was achieved in a climatic chamber; the second one in a vacuum desiccator with the space under the platform filled with distilled water.
  • the samples were stored in static conditions, without stirring.
  • Cremophor® A6 and Pluronic® L44 NF INH with the moisture content modified as described above were used in the preparation of batches containing bendamustine hydrochloride (D001L/075 and D001L/076 for Cremophor® and D001L/080 and D001L/081 for Pluronic®). All suspensions could be filled into LiCaps® capsules with the Capsule Filling and Sealing machine CFS 1200. However, because of its semisolid physical status at 25° C., Cremophor® A6 had to be heated to 50° C. prior to using it in the suspensions preparation. The batches containing Cremophor® A6 were manufactured by adding bendamustine hydrochloride to the melted carrier, followed by homogenization and filling of the batch at an elevated temperature (about 55° C.) into the LiCaps® capsules.
  • the batches containing Pluronic® L44 INH NF were manufactured by adding bendamustine hydrochloride to the carrier, followed by homogenization and filling into LiCaps® capsules.
  • the composition of all batches and the corresponding analytical results at time zero are reported in table 20a and b.
  • samples for the solubility evaluation were prepared by adding, under stirring, a quantity of active ingredient (API) suitable to generate a phase segregation to a determined amount of each carrier.
  • API active ingredient
  • the samples were prepared at a temperature slightly above the melting point of each carrier (except for liquid vehicles) and kept at this temperature for about 5 hrs (estimated manufacturing process time). Where applicable, each sample was centrifuged to accelerate phase segregation; an amount of the supernatant, corresponding to the filling weight of a capsule (about 600 mg), was withdrawn and evaluated for assay to determine the amount of API actually dissolved.
  • table 22a and 22b are listed brief visual descriptions of the appearance of the solution in the vessel at the end of the dissolution test for the LFHC batches selected for this purpose.
  • Impurity profiles showed a general increase of unknown impurity compared to time zero. Furthermore, batches D001L/097, 099, 100 showed high levels for HP1 probably due to an increase of the humidity during stability time. Possible chemical incompatibilities could have generated in several batches (e.g. D001L/093, 094, 095, 097, 098, 099, 100, 101, 103, 104, 106, 109, 110, 111 and 113) a high level for BM1EE dimer and major unknown impurity.
  • the analytical methodologies applied for determination of assay, content uniformity and impurity profile of the manufactured batches were previously developed and optimized for capsule formulations containing Cremophor® RH40 as the carrier.
  • the capsules filled with only Bendamustine hydrochloride do not show a change in impurity profile and dissolution behavior compared to time zero.
  • 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.
  • liquid filled hard capsule formulation of example 2 according to the invention shows the preferred fast dissolution profile of bendamustine, which is at least 60% in 10 minutes, 70% in 20 minutes and 80% in 30 minutes, as measured with a paddle apparatus at 50 rpm according to the European Pharmacopoeia in 500 ml of an artificial gastric fluid.
  • the liquid filled hard capsules of example 2 containing 50 mg of bendamustine, were orally administered to male and female beagle dogs in comparison with the capsules of reference example 1 in order to determine the bioavailability of 1 dose (i.e. 50 mg) of bendamustine (AUC and Cmax) and to determine the level of variability in bioavailability of these capsule formulations: (i.e. % CV on AUC and Cmax).
  • a further formulation (formulation X) was also included in the test but since this formulation was outside the scope of the present invention no details are provided. The total number of animals required was 16.
  • the basic study design was a cross-over design with 8 animals per arm.
  • Period 1 Single Dose of Capsule, Day 1:
  • Period 2 (1 Week after Period 1, Single Dose of Either of the Following Formulations, Day 8):
  • the mean plasma profiles vs. time for both the capsule formulation (reference example 1) and the liquid filled capsule formulation of Example 2 are shown in FIG. 1 .
  • Bendamustine was provided a) orally as capsules, a LFHC formulation (liquid-filled, hard-shell capsule) and b) intravenously as a solution after reconstituting a powder for the preparation of a solution for injection.
  • the LFHC formulation (per capsule) was prepared from 55.1 mg bendamustine hydrochloride, 1.2 mg methylparaben, 0.12 mg polyparaben, 0.12 mg butylated hydroxytoluene, 10.9 mg ethanol and 532.56 mg Cremophor® RH40.
  • the vial with powder for concentrate for solution was the marketed product in Germany (Ribomustine®) which contains per vial 100 mg of bendamustine hydrochloride and mannitol as an excipient. This product was reconstituted with water for injection to a final concentration of 2.5 mg/ml of bendamustine HCl and was further diluted with 0.9% NaCl until about 500 ml before administration to the patient, in accordance with the instructions of the
  • Bendamustine is metabolized via hydrolysis to the inactive metabolites monohydroxybendamustine (HP 1) and dihydroxybendamustine (HP2) and via cytochrome P450 (CYP 1A2) to the active metabolites ⁇ -hydroxybendamustine (M3) and N-desmethylbendamustine (M4).
  • HP 1 monohydroxybendamustine
  • HP2 dihydroxybendamustine
  • CYP 1A2 cytochrome P450
  • M3 ⁇ -hydroxybendamustine
  • M4 N-desmethylbendamustine
  • bendamustine After oral and intravenous administration of bendamustine the concentration of bendamustine, as well as that of the active metabolites of bendamustine (M3 and M4), were determined in plasma and urine samples on day 1 and day 8. Patients returned to the study site for an end-of-study visit 7 to 14 days after completion of the second treatment period, or after early discharge/withdrawal. Subsequently the pharmacokinetic parameters of bendamustine and its metabolites were calculated.
  • M3 and M4 exposure in plasma was considerably lower than for bendamustine.
  • Mean AUC inf of bendamustine was 10.6 and 88 times higher than for M3 and M4, respectively, after oral administration.
  • M3 and M4 AUC inf values were similar for oral and intravenous administration. Based on statistical analysis, after oral administration AUC inf of M3 was 86% of AUC inf after intravenous administration (90% CI: 76%, 98%). For M4 this was 88% (90% CI: 77%, 102%).
  • 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. Further there is the advantage that hospital staff is less exposed to the contact with the cytotoxic material, thereby decreasing occupational hazards. Also there is less environmental hazard, as no vials containing the cytotoxic compound need to be discarded.
  • the dosage forms can be swallowed as such, which means that the patient does not need to wait until dissolution of the active ingredient has been achieved. On top of that swallowing the medication is a preferred way of taking it, in order to avoid any contact of the active ingredient with the oral mucosa. 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 which should reduce the degradation of bendamustine in vivo.
  • inventive compositions may show an improved bioavailability profile of the bendamustine in vivo, as compared to prior art oral formulations.

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