Pharmaceutical preparation

Abstract

The present invention relates to a solid pharmaceutical preparation of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile, its method of manufacture and its medical use.

Description

Technical Field

[0001] The present invention relates to a solid pharmaceutical preparation of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile, as well as a method for producing the same and its medical use.

Background Art

[0002] 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile is disclosed in Example 40 of WO 2009 / 006959 as one member of a family of pyridazone derivatives that have been found to have useful pharmacological properties. WO 2009 / 007074 discloses certain salts of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile. It is a potent c-Met inhibitor that inhibits the enzymatic activity of c-Met tyrosine kinase. c-Met is a proto-oncogene encoding a protein known as a hepatocyte growth factor receptor (HGFR) inhibitor. Inhibition of c-Met has proven to be a promising approach for the treatment of cancer, alone and in combination with other treatments including chemotherapy, radiotherapy, and / or immunotherapy. 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile has very low solubility in water and biologically relevant media. Specifically, 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile has a solubility of 43 μg / mL in fasting simulated intestinal fluid (FaSSIF) and 319 μg / mL in fed simulated intestinal fluid (FeSSIF). Despite such low solubility, its use in therapy requires fairly high doses well above 100 mg. Since the estimated effective human dose is about 500 mg, 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile has a dose / solubility ratio of >10,000 and can be classified as BCS IV (Amidon et al., 1995). Therefore, pharmaceutical preparations for oral administration must have high bioavailability in order to provide the high doses necessary to achieve the desired therapeutic effect. Otherwise, the pharmaceutical preparation would need to be increased in size to such an extent that it could not be used for oral administration due to problems with swallowability.

[0003] Micronization of 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile improves bioavailability but causes other effects such as adverse compression properties that are detrimental to the development of a robust formulation that can be produced on an industrial scale (e.g., 50,000 - 100,000 tablets / batch) to enable supply for Phase III clinical studies and commercial supply. In addition, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile exhibits high elasticity, which is known to be associated with poor compression properties. In fact, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile has an elasticity equivalent to that of corn starch, which is known to have poor compressibility (Lean M. et al., Pharm Dev Technol, 2015; 20(1):12-21). This cited reference proposes a classification of the properties of various pharmaceutically used excipients and their use for various manufacturing processes. In the case of corn starch, the risk is higher with dry granulation techniques due to its high elastic recovery properties, and thus this excipient is described as not being suitable for this manufacturing method.

[0004] Furthermore, it is known in the art that direct compression is usually only feasible with active drugs where the drug content is less than 30% of the formulation (Jivraj M. et al., PSTT 3(2), February 2000). The formulation has to deliver a high dose of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in the range of about 500 mg, and since the size of the formulation is limited to be swallowable, a drug load above 30% is required. Alternative approaches to overcome the poor compression properties of micronized 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile by using wet granulation techniques that can be used on an industrial scale have failed. For example, when micronized 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile is used in fluid bed granulation, as soon as the fluid bed is installed in place, it is blown into the filter, and thus pharmaceutical formulations containing such an active ingredient cannot be obtained. Manufacture by high shear granulation has proven unsuccessful because prototypes developed using this manufacturing technique did not show sufficient in-vitro dissolution results.

[0005] Accordingly, an object of the present invention is to provide a pharmaceutical dosage form of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile that provides sufficient bioavailability and has a high drug loading, and a method suitable for its manufacture. Attempts to provide suitable pharmaceutical preparations for its use in therapies such as oral solutions, self-micro-emulsifying drug delivery systems (SEDDS), or SMEDDS have failed. SEDDS / SMEDDS or emulsions cannot be prepared because the solubility of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in the tested oils is low (for example, the solubility in neutral oil is <5 mg / mL). Since the dose required for the therapeutic effect is relatively high (approximately 500 mg) and the maximum dose in self-emulsifying capsule formulations (SEDDS or SMEDDS) is 5 mg or less, patients would have to take 100 capsules to achieve the target dose. Therefore, this formulation route has proven to be infeasible.

Summary of the Invention

[0006] The present invention relates to a solid preparation comprising micronized 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof and a filler, wherein 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof is present in an amount of 20 to 80% by mass. 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile is illustrated as follows.

Chemical Formula

[0007] As used herein, the term "about", whether explicitly stated or not, refers to a numerical value that includes, for example, integers, fractions, and percentages. The term "about" generally refers to a range of numerical values (e.g., + / - 1-3% of the recited value) that would be considered equivalent to the recited value by one of ordinary skill in the art (e.g., having the same function or result). In some cases, the term "about" can include numerical values that are rounded to the nearest significant digit. As used herein, "a" or "an" shall mean one or more. As used herein, when used in conjunction with the word "comprising", the words "a" or "an" shall mean one or more than one. As used herein, "another" shall mean at least a second or more. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular.

[0008] As used herein, "% " or "percent" shall mean weight percent (% (weight / weight)) unless otherwise specified herein. The present invention relates to a pharmaceutical preparation comprising the above solid preparation, a method for preparing a solid preparation, a method for preparing a pharmaceutical preparation, and the use of the solid preparation and the corresponding pharmaceutical preparation in the treatment of cancer either alone or in any combination with radiotherapy, chemotherapy, and / or immunotherapy. The term "solid preparation" as used herein refers to a three-dimensional solid pharmaceutical preparation comprising a pharmaceutical active ingredient (API) and at least one pharmaceutically acceptable excipient. Preferably, the solid preparation is a compression mixture of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile, and one or more pharmaceutically acceptable excipients selected, for example, from fillers and optionally one or more pharmaceutically acceptable excipients. The compression mixture can be obtained by dry granulation and preferably exists in the form of particles which may have an irregular or regular shape. The solid preparation may be processed into other pharmaceutical preparations such as tablets, for example, but can also be administered directly to a patient without any modification. In addition to fillers, one or more further excipients such as binders, glidants, disintegrants, and lubricants may be present in the solid preparation.

[0009] The term "micronized" as used herein refers to particles that have been reduced to micron size. According to a suitable embodiment, the micronized 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile present in the solid preparation has an average particle size characterized by a d50 value in the range of 5 μm to 80 μm, preferably 5 μm to 50 μm, more preferably 5 μm to 25 μm. Accordingly, the present invention also relates to a solid preparation in which 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile has an average particle size characterized by a d50 value in the range of 5 μm to 80 μm, preferably 5 μm to 50 μm, more preferably 5 μm to 25 μm.

[0010] d of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile 50 The value is measured by laser diffraction with a Malvern Mastersizer 2000 (wet method using Hydro2000S; micro volume tray; sample amount 100 mg; stirrer speed 2200 rpm; sonication for 1 minute; measurement time 7.5 seconds; obscuration 10 - 15%). The d 50 value refers to a size in micrometers where the distribution is divided into upper and lower halves by its diameter. d50 is the median of the volume distribution and is often also referred to as Dv50 (or Dv0.5).

[0011] The particle size of the solid preparation is measured by dynamic image analysis (Retsch CamSizer X2) using a brush and pins, with a sample volume of at least 20 mL, a slit width of 4.0 mm, a dispersion pressure of 30.0 kPa, and no speed adjustment. The size is defined by corresponding spheres and the sample form is defined as angular particles.

[0012] The term "filler", as used herein, is an agent that increases the bulk of a pharmaceutical preparation by providing an amount of material necessary for the formation of a solid preparation. Also, fillers such as tablet fillers and capsule fillers play a role in creating the desired flow characteristics and compression features in the preparation of solid preparations and in the preparation of solid pharmaceutical preparations. Fillers that can be used in the present invention may be sugar alcohols such as sorbitol or mannitol, dulcitol, xylitol or ribitol, preferably sorbitol or mannitol, particularly preferably mannitol; sugars such as glucose, fructose, mannose, lactose, sucrose, or maltose, preferably lactose, sucrose, or maltose, particularly preferably lactose; starches such as potato starch, rice starch, corn starch, or pregelatinized starch. The filler may be present in the solid preparation according to the present invention in a proportion of 20 to 80% (mass / mass), preferably 30 to 70% (mass / mass), particularly preferably 40 to 65% (mass / mass) based on the total mass of the solid formulation.

[0013] In addition to the filler, one or more further excipients such as binders, glidants, disintegrants, and lubricants may be present in the solid preparation.

[0014] The solid preparation of the present invention contains 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in an amount of 20 to 80% by mass based on the total mass of the solid preparation. According to a preferred embodiment, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile is present in the solid preparation in an amount of 25 to 70% by mass, more preferably in an amount of 30 to 60% by mass, and most preferably in an amount of 35 to 55% by mass, based on the total mass of the solid preparation. Accordingly, the present invention also relates to a solid preparation in which 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile is present in an amount of 20 to 80% by mass, preferably 25 to 70% by mass, more preferably 30 to 60% by mass, and most preferably 35 to 55% by mass, based on the total mass of the solid preparation.

[0015] Any reference to the amount or mass or mass percentage of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof shall be understood to refer to the anhydrous free form of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile, unless otherwise specified herein.

[0016] The solid preparation may contain 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile not only in the form of its free base but also in the form of its pharmaceutically acceptable ones. The term "pharmaceutically acceptable" as used herein generally refers to being useful in the preparation of pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes being acceptable for veterinary as well as human pharmaceutical use. The term "pharmaceutically acceptable salts" as used herein refers to salts of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile that are pharmaceutically acceptable as defined herein and retain the desired pharmacological activity of the parent 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile. The term "pharmaceutically acceptable salts" includes all hydrates of the respective salts. Suitable salts may be acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, and trimethylacetic acid. Particularly preferred pharmaceutically acceptable salts of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile that may be present in the solid preparation are sulfate, phosphate, mesylate, besylate, tosylate, fumarate, monohydrochloride monohydrate, or maleate, preferably monohydrochloride monohydrate.Accordingly, the present invention also relates to a solid pharmaceutical preparation in which 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile is present in the form of its sulfate, phosphate, mesylate, besylate, tosylate, fumarate, monohydrochloride monohydrate, or maleate, preferably monohydrochloride monohydrate.

[0017] According to a preferred embodiment of the present invention, the solid preparation contains, as a filler, sugar, sugar alcohol, or dicalcium phosphate. According to a particularly preferred embodiment, the filler present in the solid preparation is a sugar alcohol, and the sugar alcohol is sorbitol and / or mannitol, preferably mannitol. According to a further preferred embodiment of the present invention, the solid preparation contains a binder. Accordingly, the present invention also relates to a solid preparation further containing a binder. The term "binder", as used herein, refers to an agent that provides aggregation and strength to the solid preparation. Binders that can be used in the present invention include, for example, polyvinylpyrrolidone, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, starch paste such as corn starch paste, cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, or microcrystalline cellulose, preferably microcrystalline cellulose. Accordingly, the present invention also relates to a solid pharmaceutical preparation in which the binder is polyvinylpyrrolidone, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, starch paste such as corn starch paste, cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, or microcrystalline cellulose, preferably microcrystalline cellulose. The binder may be present in the solid preparation according to the present invention in a proportion of 0 to 20% (mass / mass), preferably 0 to 10% (mass / mass), particularly preferably 0 to 5% (mass / mass), based on the total mass of the solid preparation.

[0018] The solid preparation may further contain a lubricant. As used herein, the term "lubricant" refers to an inert ingredient used to prevent components from sticking to each other when dry granulated, filled into capsules, or compressed into tablets. Lubricants reduce the sliding friction between the powder sticking to the roll surface of a roller compactor and the tablet material and the die punch during the tableting operation, and prevent sticking to the tablet punch. Suitable lubricants are alkaline earth metal salts of fatty acids such as magnesium stearate or calcium stearate, fatty acids such as stearic acid, higher fatty alcohols such as cetyl alcohol or stearyl alcohol, fats such as glyceryl dipalmitostearate, glyceryl distearate, stearin, or glyceryl dibehenate, alkaline earth metal salts of C16-C18 alkyl-substituted dicarboxylic acids such as sodium stearyl fumarate, hydrated vegetable oils such as hydrated castor oil or hydrated cottonseed oil, or minerals such as talc. Preferred lubricants are sodium stearyl fumarate, esters of glycerol and fatty acids, stearic acid, or pharmaceutically acceptable salts of stearic acid and divalent cations, preferably magnesium stearate. The lubricant may be present in the solid preparation according to the invention in a proportion of 0 to 5% (mass / mass), preferably 0.1 to 2% (mass / mass), particularly preferably 0.3 to 1% (mass / mass), and most preferably about 0.5% (mass / mass) based on the total mass of the solid preparation.

[0019] The solid preparation may further contain a disintegrant. As used herein, the term "disintegrant" refers to a compound that swells and dissolves when wet, causing the tablet or granule to disintegrate and break apart, releasing the active pharmaceutical agent. Also, the disintegrant functions to ensure that 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile comes into contact with a solvent such as water. The disintegrant serves to disintegrate tablets or granules, etc., and thus promotes the dissolution of the solid dosage form upon contact with a liquid dissolution medium. Suitable disintegrants include crospovidone (crosslinked polyvinyl N-pyrrolidone), carboxymethyl cellulose, and derivatives such as their salts and crosslinked derivatives, for example, croscarmellose sodium (crosslinked polymer of carboxymethyl cellulose sodium), sodium carboxymethyl glycolate, sodium starch glycolate, carrageenan, agar, and pectin. Crospovidone and croscarmellose sodium are particularly preferred. The disintegrant is present in the pharmaceutical preparation according to the invention in a proportion of 0 to 10% (mass / mass), preferably 0.25 to 5% (mass / mass), particularly preferably 0.5 to 3% (mass / mass), based on the total mass of the solid preparation.

[0020] The solid preparation may further contain a glidant. As used herein, the term "glidant" refers to an inert ingredient used as a flow aid to improve the flow characteristics of particles such as powders or granules. In the present invention, it refers to the flow characteristics of the solid preparation or a mixture containing the solid preparation during further processing such as encapsulation or tableting. Non-limiting examples of glidants for use in the present invention include colloidal silicon dioxide (Aerosil 200, Cab-O-Sil), talc, magnesium carbonate, and combinations thereof. The glidant is present in the pharmaceutical preparation according to the invention in a proportion of 0 to 7.5% (mass / mass), preferably 0 to 5% (mass / mass), particularly preferably 0 to 3% (mass / mass), based on the total mass of the solid preparation.

[0021] According to a suitable embodiment of the present invention, the solid preparation is in the form of particles having an average particle size characterized by a d50 value in the range of 50 μm to 1 mm, preferably 60 μm to 800 μm, more preferably 70 to 600 μm. Accordingly, the present invention also relates to a solid preparation having an average particle size characterized by a d50 value in the range of 50 μm to 1 mm, preferably 60 μm to 800 μm, more preferably 70 to 600 μm. For forming the solid preparation, dry granulation can be used. The term "dry granulation" or "dry granulating" as used herein specifically refers to a granulation technique including at least a compression step. In the pharmaceutical industry, two dry granulation methods, namely slug compression and roller compression, are mainly used, and both can be used for the preparation of solid preparations. Dry granulation by slug typically includes a compression step in which a compression machine including two steel punches in a steel die cavity is used. The granules are formed by applying pressure to the material particles by the punches in the die cavity, and typically have a diameter of about 25 mm and a thickness of about 10 to 15 mm, but the specific size of the slug is not a limiting factor of the present invention. Dry granulation by the use of roller compression includes a roller compression step in which the material particles are compressed between rotating press rolls, and a subsequent grinding step of grinding the compressed material into granules. In "dry granulation", the methods available for preparing the solid preparation typically do not use liquids and / or do not require a drying step. The term "granule" itself does not necessarily imply a specific shape. This is because the final shape of the granule will be controlled by the specific preparation method.

[0022] The present invention also provides a pharmaceutical preparation comprising the solid preparation according to the present invention. Accordingly, the present invention also relates to a pharmaceutical preparation comprising the solid preparation. The solid preparation can be used as a pharmaceutical preparation without any modification, but can also be processed into other pharmaceutical preparations such as tablets, or filled into sachets or capsules. Preferably, the pharmaceutical preparation is for oral administration. Accordingly, the present invention also relates to a pharmaceutical preparation which is a pharmaceutical preparation for oral administration. Even more preferably, the pharmaceutical preparation is an immediate-release preparation. Accordingly, the present invention further relates to a pharmaceutical preparation that is an immediate-release preparation. In an exemplary embodiment, the pharmaceutical preparation, preferably a tablet, is characterized by a disintegration time of 30 minutes or less, such as 20 minutes or less, preferably 15 minutes or less, more preferably 10 minutes or less. The disintegration time referred to above is measured in 0.01 N HCl at 37 °C using a disintegration apparatus conforming to USP-NF <701> (USP39-NF34, page 537; Pharmacopeial Forum: Volume 34(1), page 155). The apparatus consists of a basket-rack assembly, a low-form beaker for 1000 mL of immersion fluid, a thermostatic device for heating, and a device for moving the basket up and down within the immersion fluid. The basket-rack assembly moves vertically along its axis and is composed of six transparent tubes with open ends. The tubes are held in a vertical position by two plates. A stainless-steel woven wire cloth is attached to the lower surface of the lower plate. If specified in the individual monograph, each tube is provided with a cylindrical disk. The disk is made of a suitable transparent plastic material. Place one dosage unit in each of the six tubes of the basket and add the disks. Use the specified medium as the immersion fluid and operate the apparatus while maintaining it at 37 ± 2 °. Lift the basket out of the fluid at the end of the time limit or at preset intervals and observe whether the tablets have completely disintegrated.

[0023] In a preferred embodiment, the pharmaceutical preparation according to the present invention is a solid preparation and a capsule containing one or more pharmaceutically acceptable excipients optionally. The capsule itself may be any pharmaceutically acceptable capsule, such as a hard gelatin capsule, but preferably should be easily soluble. In an exemplary embodiment, the pharmaceutical preparation is based on the total mass of all the materials contained in the capsule, i.e., the total mass of the capsule minus the mass of the capsule shell, 40 to 100% (mass / mass), for example at least 50% (mass / mass), more preferably at least 70, 80, 90, 95, or 99% (mass / mass) of the solid preparation according to the present invention, and 0 to 60% (mass / mass), i.e., the remaining mass of the mixture (the difference from 100% (mass / mass)), preferably a mixture composed of at least one pharmaceutically acceptable excipient selected from a filler, a lubricant, a glidant, a disintegrant, and an inorganic alkali metal salt, in a capsule.

[0024] Inorganic alkali metal salts, i.e., salts composed of alkali metal ions and inorganic acid anions, have been relatively recently found to be useful for promoting dissolution, and include sodium chloride, sodium sulfate, sodium carbonate, sodium bicarbonate, sodium phosphate, sodium dihydrogen phosphate, potassium chloride, potassium carbonate, and sodium bicarbonate. Sodium chloride is particularly preferred. A preferred embodiment of the present invention relates to a pharmaceutical preparation which is a capsule containing 40 to 100% (mass / mass) of a solid preparation based on the total mass of all the materials contained in the capsule, and 0 to 60% (mass / mass), preferably at least one pharmaceutically acceptable excipient selected from a filler, a glidant, a disintegrant, and a lubricant. As will be shown by way of example, the capsule formulation may contain a solid formulation in any range enclosed by, for example, 100, 99.5, 99, 90, 80, 75, 70, 60, or 50% (mass / mass), or any combination of such values, based on the total mass of all the materials contained in the capsule. The filler of the remainder (the difference from 100% (mass / mass)) is composed of at least one pharmaceutically acceptable excipient as shown above.

[0025] In an exemplary embodiment, the pharmaceutical preparation is based on the total mass of the capsule, 50 to 100% (mass / mass) of the solid preparation according to the present invention, 0 to 20% (mass / mass) of a disintegrant, 0 to 50% (mass / mass) of a filler, 0 to 5% (mass / mass) of a lubricant, 0 to 5% (mass / mass) of a flow promoter, 0 to 20% (mass / mass) of an inorganic alkali metal salt, and a total of 0 to 20% (mass / mass) of one or more additional pharmaceutically acceptable excipients is a capsule containing a filler containing the same. In the above exemplary embodiments, the filler may be present, for example, in the range of 5 to 50% (mass / mass), or in the range of 7.5 to 50% (mass / mass), or in the range of 10 to 40% (mass / mass). In the above exemplary embodiments, preferably, an inorganic alkali metal salt is present and may be included, for example, in an amount of 2.5 to 20% (mass / mass), or 5 to 17.5% (mass / mass), or at least 7.5% (mass / mass), such as about 10 or 15% (mass / mass). In a more preferred embodiment, the pharmaceutical preparation is a tablet and thus typically contains at least one further pharmaceutically acceptable excipient in addition to the pharmaceutically acceptable excipients present in the solid preparation. The at least one additional pharmaceutically acceptable excipient is preferably selected from a filler, a flow promoter, a disintegrant, a lubricant, an inorganic alkali metal salt, or a combination thereof. Accordingly, the present invention also relates to a pharmaceutical preparation which is a tablet and contains, in addition to the pharmaceutically acceptable excipients present in the solid preparation, optionally one or more pharmaceutically acceptable excipients selected from a filler, a disintegrant, a flow promoter, and a lubricant.

[0026] In an exemplary embodiment, the pharmaceutical preparation is a tablet containing a solid preparation and optionally a further excipient, and the tablet, based on its total mass, i) 20 to 80% (mass / mass) of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof, ii) 10 to 70% (mass / mass) of a filler, iii) 0 to 20% (mass / mass) of a binder, iv) 0 to 20% (mass / mass) of a disintegrant, v) 0 to 5% (mass / mass) of a lubricant, vi) 0 to 7.5% (mass / mass) of a glidant, and vii) a total of 0 to 20% (mass / mass) of one or more additional pharmaceutically acceptable excipients are included. Examples of one or more additional pharmaceutically acceptable excipients include one or more selected from preservatives, antioxidants, sweeteners, flavorants, colorants, surfactants, and wicking agents. Many excipients can perform more than one function depending on the other components of the pharmaceutical dosage form. For clarity, especially when calculating mass percentages, each pharmaceutically acceptable excipient used in the pharmaceutical preparation according to the present invention is preferably associated with only one functionality, i.e., either a disintegrant or a lubricant.

[0027] In another exemplary embodiment, the pharmaceutical preparation is a tablet comprising a solid preparation and optionally further excipients, and the tablet, based on its total mass, i) 30 to 70% (mass / mass) of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof, ii) 20 to 60% (mass / mass) of a filler, iii) 0 to 10% (mass / mass) of a binder, iv) 0.25 to 10% (mass / mass) of a disintegrant, v) 0 to 4% (mass / mass) of a lubricant, vi) 0 to 5% (mass / mass) of a glidant, and vii) a total of 0 to 10% (mass / mass) of one or more additional pharmaceutically acceptable excipients are included.

[0028] In a further exemplary embodiment, the pharmaceutical preparation is a tablet comprising a solid preparation and optionally a further excipient, and the tablet, based on its total mass, i) 35 to 60% (mass / mass) of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof, ii) 40 to 60% (mass / mass) of a filler, iii) 0 to 5% (mass / mass) of a binder, iv) 0.5 to 5% (mass / mass) of a disintegrant, v) 0.25 to 3% (mass / mass) of a lubricant, vi) 0 to 2% (mass / mass) of a glidant, and vii) a total of 0 to 10% (mass / mass) of one or more additional pharmaceutically acceptable excipients is included.

[0029] Preferably, in such embodiments, the filler is mannitol or lactose, the binder is microcrystalline cellulose, the disintegrant is selected from crospovidone, carboxymethyl cellulose, and salts and derivatives thereof, in particular croscarmellose sodium, the lubricant is selected from magnesium stearate, calcium stearate, and sodium stearyl fumarate, and / or the glidant is selected from colloidal silicon dioxide and derivatives thereof. In a particularly preferred embodiment, the filler is mannitol, the binder is microcrystalline cellulose, the disintegrant is crospovidone, the lubricant is magnesium stearate, and the glidant is colloidal silicon dioxide.

[0030] Preferably, the total of the one or more additional pharmaceutically acceptable excipients is 0 to 10% (mass / mass), 0 to 7.5% (mass / mass), 0 to 5% (mass / mass), 0 to 2.5% (mass / mass), or 0 to 1% (mass / mass), for example 0% (mass / mass). The tablets may be coated in order to improve the taste, and / or appearance and / or to protect the tablets from external influences such as moisture. Any coating shall not be included in the total 100% (mass / mass) of the pharmaceutically active ingredients and drug substances constituting the tablets as listed above. In the case of film coating, for example, macromolecular substances such as modified cellulose including hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polymethacrylate, polyethylene glycol, and zein can be used. The thickness of the coating is preferably less than 200 μm. The present invention also provides a method for preparing a solid preparation, which includes performing dry granulation such as slug compression and roller compression, preferably roller compression. Therefore, the present invention also relates to a method for preparing a solid preparation, and a method for performing dry granulation, preferably roller compression.

[0031] The term "roller compression" or "roller compressing" refers to a process in which powder or particles are pushed between two oppositely rotating rolls and pressed into a solid compress or ribbon. Roller compression can be carried out using any suitable roller compressing machine known to those skilled in the art. Suitable roller compressing machines include, for example, the Fitzpatrick® Chilsonator IR220 roller compressing machine of Fitzpatrick Company, USA. Process parameters, particularly the rolling force, can be easily achieved by routine experimental work based on the common general knowledge of those skilled in the art. Suitable rolling forces may be, for example, in the range of 2 to 16 kN / cm, more preferably in the range of 4 to 12 kN / cm, and most preferably in the range of 4 to 8 kN / cm.

[0032] In an exemplary embodiment, the method (a) 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof, and a filler, and optionally mixing one or more further pharmaceutically acceptable excipients, (b) dry granulating the mixture prepared by step (a) to form a solid preparation, and (c) optionally performing milling comprising. The preferred pharmaceutically acceptable excipients used in step (a) are selected from binders, disintegrants, lubricants, and glidants. According to a preferred embodiment, the dry granulation used in this method is roller compaction.

[0033] The prepared solid preparation can be used for the preparation of pharmaceutical preparations such as tablets or capsules. An exemplary method for preparing a pharmaceutical preparation that is a tablet comprising the solid preparation is (a) performing the method described above to form a solid preparation, (b) mixing the solid preparation and one or more pharmaceutically acceptable excipients, (c) tableting the mixture prepared in step (b), and (d) optionally film coating the tablet prepared by step (c) comprising.

[0034] Tableting, the corresponding compression into tablets can be carried out using a generally used eccentric press or rotary press. An exemplary method for preparing a pharmaceutical preparation that is a capsule comprising the solid preparation is (a) performing the above method to form a solid preparation, (b) optionally mixing the solid preparation and one or more pharmaceutically acceptable excipients, and optionally granulating the mixture obtained preferably by roller compaction (c) Filling the mixture or granules prepared in step (b), or the solid preparation prepared in step (a), into capsules comprises. As shown in the foregoing introductory section, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile has been found to exhibit useful properties as a c-Met tyrosine kinase inhibitor for the treatment of cancer. This substance is currently under investigation in clinical trials.

[0035] Accordingly, the present invention provides a solid preparation as described above for use in the treatment of cancer, and a corresponding pharmaceutical preparation. Optionally, the treatment of cancer further includes radiotherapy. Accordingly, the present invention also relates to a pharmaceutical preparation of the present invention for use in the treatment of cancer, optionally together with radiotherapy. Suitable radiotherapy treatments are described in WO 2012 / 028233 pamphlet, which is incorporated herein by reference. Optionally, instead of or in addition to radiotherapy, the treatment of cancer may include chemotherapy. Accordingly, the present invention also relates to a pharmaceutical preparation for use in the treatment of cancer, wherein the treatment further includes chemotherapy. Suitable pharmaceutically active ingredients that can be used in chemotherapy in combination with 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile include, for example, cisplatin and etoposide or combinations thereof.

[0036] Optionally, instead of or in addition to radiotherapy and / or chemotherapy, the treatment of cancer may include immunotherapy. Accordingly, the present invention also relates to a pharmaceutical preparation for use in the treatment of cancer, wherein the treatment further includes immunotherapy. Accordingly, the present invention also provides a method for treating cancer in a patient in need thereof, which comprises administering to the patient a pharmaceutical preparation according to the present invention, optionally in combination with radiotherapy, chemotherapy, or immunotherapy, or any combination thereof. In an exemplary embodiment, the present invention provides a method for treating cancer in a patient in need thereof, selected from the colon, lung, head and neck, pancreas, and their histological subtypes, which comprises a solid preparation or a pharmaceutical preparation according to the present invention. 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof is administered to the patient in combination with at least one additional therapeutic agent selected from etoposide and platinum. In the following, the present invention will be described by referring to its exemplary embodiments, which are not considered to limit the present invention.

Brief Description of the Drawings

[0037]

Figure 1

Figure 2

Figure 3

Figure 4

Examples

[0038] Pre-formulation examples Examples for evaluating wet granulation techniques Example A) Example A (white triangles in Figure 1) containing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (30.99%), lactose (32.39%), microcrystalline cellulose type 101 (23.00%), povidone 25 (3.76%), and crospovidone (3.76%) was manufactured by high-shear granulation method. Subsequently, the obtained granules were sieved through a 1.0 mm sieve, and then mixed with crospovidone (2.35%), povidone 25 (1.41%), magnesium stearate (0.94%), talcum (0.94%), and silicon dioxide (0.47%), and processed into tablets with a crushing resistance of approximately 125 N, a disintegration time of <10 minutes, and a total mass of approximately 645 mg using a single-punch press.

[0039] Example B) Example B (black circles in Figure 1) containing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (77.29%) and starch 1500 (19.32%) was manufactured by the high-shear granulation method. Subsequently, the obtained granules were sieved through a 1.0 mm sieve, and then mixed with sodium carboxymethyl starch (1.93%), magnesium stearate (0.97%), and silicon dioxide (0.48%), and processed into tablets with a single-punch press. The tablets had a crushing resistance of approximately 144 N, a disintegration time of <8 minutes, and a total mass of approximately 259 mg.

[0040] Example C) Example C (black triangles in Figure 1) containing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (26.50%), lactose (4.41%), hypromellose (1.11%), and calcium phosphate dihydrate (53.01%) was manufactured by the fluid bed granulation method which would be selected by those skilled in the art. Subsequently, the obtained granules were sieved through a 0.8 mm sieve, and then mixed with pregelatinized starch (9.89%), magnesium stearate (0.99%), sodium carboxymethyl starch (2.47%), and silicon dioxide (0.49%), and processed into tablets with a single-punch press. Then, the tablets were coated using a commercially available premixed film coating mixture based on polyvinyl alcohol, and the coating was present at 1.13% of the total formulation. The obtained tablets had a crushing resistance of approximately 159 N, a disintegration time of <6 minutes, and a total mass of approximately 755 mg.

[0041] Example D) Example D (white circles in Figure 1), containing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (26.66%), lactose (4.44%), hypromellose (1.11%), and calcium phosphate anhydrous (53.31%), was manufactured by the fluidized bed granulation method, which would be selected by those skilled in the art. Subsequently, the obtained granules were sieved through a 0.8 mm sieve, and then mixed with starch 1500 (9.89%), magnesium stearate (0.99%), sodium carboxymethyl starch (1.98%), and silicon dioxide (0.49%), and processed into tablets with a single punch press to obtain tablet cores of approximately 741.8 mg. Subsequently, the tablets were coated using a commercially available pre-formulated film coating mixture based on polyvinyl alcohol, and the coating was present at 1.13% of the total formulation. The obtained tablets had a crushing resistance of approximately 159 N, a disintegration time of <6 minutes, and a total mass of approximately 750 mg. As can be understood from Figure 1, tablets manufactured from granules prepared by high-shear granulation (Examples A and B) do not show good in vitro release characteristics. Furthermore, tablets manufactured from granules prepared by fluidized bed granulation (Examples C and D) show better in vitro release characteristics than the high-shear granulation prototypes (Examples A and B), but there are limitations to the maximum achievable drug load.

[0042] Example of evaluating the Young's modulus of material properties The Young's modulus was evaluated as an index of material stiffness (the higher the Young's modulus, the harder the substance), and its measurement was carried out depending on the solid fraction, which has a complementary relationship with porosity (i.e., solid fraction = 1 - porosity). This indicates that when the solid fraction is 1, there is no porosity, that is, no air is trapped in the solid phase. The pharmaceutically relevant solid fraction is usually in the range of 0.75 to 0.85. The porosity was determined by the nitrogen pycnometer method. Measurements for determining the Young's modulus were carried out on a commercially available instrumented single punch press (Romaco Kilian StylOne system) with an ultrasonic-assisted measuring punch. For this purpose, the neat material was compressed between the upper and lower punches to densify the material. The ultrasonic velocity of the sample, which depends on the degree of densification, was recorded and used to calculate the Young's modulus of the specific substance. In this investigation, the following neat materials were selected.

Table 1

[0043] As can be understood from Figure 3, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (black dots) exhibits similar properties to corn starch (white dots), a substance known to be highly elastic and having unfavorable compression characteristics. Furthermore, Figure 4 shows that 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile has a significantly lower Young's modulus compared to widely used pharmaceutical fillers (dicalcium phosphate, mannitol, and lactose).

[0044] Formulation Examples Example E Exemplary Solid Preparation Formulations D 50 Values were recorded as described above. D 50 The values are in the range of 70 - 530 μm. The bulk density was determined in accordance with DIN53468 using a 100 mL beaker.

[0045] Example 1 The ingredients were weighed (batch size 103.2 kg) and sieved through a 1.0 mm sieve. A commercially available bin blender (e.g., Servolift) was used to produce the formulation by mixing all ingredients except magnesium stearate for 15 minutes at 12 rpm. Thereafter, magnesium stearate was added and the entire mixture was mixed again for 5 minutes at 12 rpm. Thereafter, the mixture was transferred to a roller compactor to produce a solid preparation. The roller compactor (Gerteis Macropactor) was operated at the following settings: compression force 12 kN / cm, gap width 2.5 mm, roll speed 3.0 rpm. The obtained granules were sieved through a 0.8 mm sieve. Example 2 The ingredients were weighed (batch size 2.4 kg) and sieved through a 1.0 mm sieve except for magnesium stearate. A commercially available Turbula T50A blender was used to produce the formulation by mixing all ingredients except magnesium stearate for 15 minutes. Magnesium stearate was sieved through a 0.5 mm sieve and then added to the mixture, which was then mixed again for 5 minutes. Thereafter, the mixture was transferred to a roller compactor to produce a solid preparation. The roller compactor (Alexanderwerk WP120P) was operated at the following settings: compression force 4.0 kN / cm, gap width 1.0 mm, roll speed 4.0 rpm. The obtained granules were sieved through a 1.0 mm sieve. Examples 3 - 8 The ingredients were weighed (batch size 1.0 kg) and sieved through a 1.0 mm sieve. A commercially available Servolift bin blender was used to produce the formulation by mixing all ingredients for 15 minutes at 12 rpm. Thereafter, the mixture was transferred to a roller compactor to produce a solid preparation. The roller compactor (Gerteis Macropactor) was operated at the following settings: compression force 3.0 kN / cm, gap width 3.0 mm, roll speed 3.0 rpm. The obtained granules were sieved through a 1.0 mm sieve.

[0046] Example 9 The ingredients were weighed (batch size 33.2 kg) and sieved through a 1.0 mm sieve. The formulation was produced by mixing all the ingredients in a commercially available Servolift bin blender for 15 minutes at 12 rpm. The mixture was then transferred to a roller compactor to produce a solid preparation. The roller compactor (Gerteis Macropactor) was operated at the following settings: compression force 4.5 kN / cm, gap width 3.0 mm, roll speed 3.0 rpm. The resulting granules were sieved through a 0.8 mm sieve.

Table 2

[0047] Exemplary tablet formulation The disintegration and friability tests are described in the European Pharmacopoeia, 9th Edition, section 2.9.1 (Disintegration) and section 2.9.7 (Friability of uncoated tablets). Example 10 The solid preparation of Example 1 was mixed with crospovidone for 15 minutes. Magnesium stearate was then added and the whole mixture was mixed again for 5 minutes at 12 rpm. The whole mixture was tableted using a rotary tablet press at a main compression force of 17.1 kN, with a punch size of 18.8×9.2 mm, a pre-compression force of 1.6 kN, and a tableting speed of 20000 units / hour. Example 11 The solid preparation of Example 2 was mixed with the ingredients for 10 minutes. The whole mixture was tableted using a single punch press at a compression force of 12 kN, with a punch size of 18×8 mm, and a tableting speed of 1860 units / hour. The disintegration time and friability values are for resistance to crushing at 100 N. Example 12 The solid preparation of Example 3 was mixed with all the components at 12 rpm for 15 minutes. The whole mixture was tabletted using a single punch press with a 19×9 mm punch and a compression force of 15 kN at a tabletting speed of 1500 units / hour. The values of the disintegration time and friability are for resistance to crushing at 150 N.

[0048] Example 13 The solid preparation of Example 4 was mixed with all the components at 12 rpm for 15 minutes. The whole mixture was tabletted using a single punch press with a 19×9 mm punch and a compression force of 21 kN at a tabletting speed of 2460 units / hour. The values of the disintegration time and friability are for resistance to crushing at 110 N. Example 14 The solid preparation of Example 5 was mixed with all the components at 12 rpm for 15 minutes. The whole mixture was tabletted using a single punch press with a 19×9 mm punch and a compression force of 17 kN at a tabletting speed of 2520 units / hour. The values of the disintegration time and friability are for resistance to crushing at 160 N. Example 15 The solid preparation of Example 6 was mixed with all the components at 12 rpm for 15 minutes. The whole mixture was tabletted using a single punch press with a 19×9 mm punch and a compression force of 17 kN at a tabletting speed of 2460 units / hour. The values of the disintegration time and friability are for resistance to crushing at 150 N.

[0049] Example 16 The solid preparation of Example 7 was mixed with all the components at 12 rpm for 15 minutes. The whole mixture was tabletted using a single punch press with a 19×9 mm punch and a compression force of 17 kN at a tabletting speed of 2460 units / hour. The values of the disintegration time and friability are for resistance to crushing at 110 N. Example 17 The solid preparation of Example 8 was mixed with all the components at 12 rpm for 15 minutes. The entire mixture was tabletted using a single-punch press with a 19×9 mm punch and a compression force of 17 kN at a tabletting speed of 2,460 units / hour. The values for disintegration time and friability are for resistance to crushing at 150 N. Example 18 The solid preparation of Example 6 was mixed with all the components at 12 rpm for 15 minutes. The entire mixture was tabletted using a single-punch press with a 19×9 mm punch and a compression force of 15 kN at a tabletting speed of 2,460 units / hour. The values for disintegration time and friability are for resistance to crushing at 165 N. Example 19 The solid preparation of Example 8 was mixed with all the components at 12 rpm for 15 minutes. The entire mixture was tabletted using a single-punch press with a 19×9 mm punch and a compression force of 15 kN at a tabletting speed of 2,460 units / hour. The values for disintegration time and friability are for resistance to crushing at 170 N. Example 20 The solid preparation of Example 7 was mixed with all the components at 12 rpm for 15 minutes. The entire mixture was tabletted using a single-punch press with a 19×9 mm punch and a compression force of 17 kN at a tabletting speed of 2,460 units / hour. The values for disintegration time and friability are for resistance to crushing at 150 N.

[0050] Example 21 The solid preparation of Example 9 was mixed with all the components at 12 rpm for 15 minutes. The entire mixture was tabletted using a rotary tablet press with an 18×9 mm punch, a pre-compression force of 5.0 kN, and a main compression force of 13.0 kN at a tabletting speed of 30,000 units / hour.

Table 3

[0051] Exemplary capsule formulation The disintegration test is described in the European Pharmacopoeia, 9th Edition, Section 2.9.1 (Disintegration). Example 22: Exemplary capsule formulation HPMC capsules containing the different solid preparations of Examples 1 - 9 were prepared by mixing such preparations with further excipients as shown below and filling such mixtures into capsule shells. The disintegration of the capsule formulation is less than 9 minutes. [Table 4]

Claims

1. A solid preparation comprising micronized 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof and a filler, wherein 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof is present at 20 to 80% (mass / mass) based on the total mass of the solid preparation, and the solid preparation is a compressed mixture obtained by dry granulation.

2. The solid preparation according to claim 1, wherein 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile is present in the form of its sulfate, phosphate, mesylate, besylate, tosylate, fumarate, monohydrochloride monohydrate, or maleate.

3. The solid preparation according to claim 1 or 2, wherein 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile has an average particle size characterized by a d50 value in the range of 5 μm to 80 μm.

4. The solid preparation according to any one of claims 1 to 3, wherein the filler is sugar, sugar alcohol, or dicalcium phosphate.

5. The solid preparation according to claim 4, wherein the filler is sugar alcohol, and the sugar alcohol is sorbitol and / or mannitol.

6. The solid preparation according to any one of claims 1 to 5, further comprising a binder.

7. The solid preparation according to claim 6, wherein the binder is polyvinylpyrrolidone, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, starch paste such as corn starch paste, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, or microcrystalline cellulose.

8. The solid preparation according to any one of claims 1 to 7, further comprising a lubricant.

9. The solid preparation according to claim 8, wherein the lubricant is sodium stearyl fumarate, an ester of glycerol and a fatty acid, stearic acid, or a pharmaceutically acceptable salt of stearic acid and a divalent cation.

10. The solid preparation according to any one of claims 1 to 9, having an average particle size characterized by a d50 value in the range of 50 μm to 1 mm.

11. A pharmaceutical preparation comprising the solid preparation according to any one of claims 1 to 10.

12. The pharmaceutical preparation according to claim 11, which is a pharmaceutical preparation for oral administration.

13. The pharmaceutical preparation according to claim 11 or 12, which is an immediate release preparation.

14. The pharmaceutical preparation according to any one of claims 11 to 13, which is a capsule containing the solid preparation and one or more pharmaceutically acceptable excipients.

15. Based on the total mass of all materials contained in the capsule, 40 to 100% (mass / mass) of the solid preparation according to any one of claims 1 to 10, and 60% (mass / mass) or less of at least one pharmaceutically acceptable excipient selected from a filler, a glidant, a disintegrant, and a lubricant. The pharmaceutical preparation according to claim 14.

16. The pharmaceutical preparation according to any one of claims 11 to 13, which is a tablet, and contains one or more pharmaceutically acceptable excipients selected from a filler, a disintegrant, a glidant, and a lubricant in addition to the filler, the binder, and / or the lubricant present in the solid preparation.

17. The tablet is based on its total mass, i) 20 to 80% (mass / mass) of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof, ii) 10 to 70% (mass / mass) of a filler, iii) If present, 20% (mass / mass) or less of a binder, iv) If present, 20% (mass / mass) or less of a disintegrant, v) If present, 5% (mass / mass) or less of a lubricant, vi) If present, 7.5% (mass / mass) or less of a glidant, and vii) If present, a total of 20% (mass / mass) or less of one or more additional pharmaceutically acceptable excipients The pharmaceutical preparation according to claim 16.

18. The tablet is based on its total mass, i) 30 to 70% (mass / mass) of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof, ii) 20 to 60% (mass / mass) of a filler, iii) when present, 10% (mass / mass) or less of a binder, iv) 0.25 to 10% (mass / mass) of a disintegrant, v) when present, 4% (mass / mass) or less of a lubricant, vi) when present, 5% (mass / mass) or less of a glidant, and vii) when present, one or more additional pharmaceutically acceptable excipients in a total of 10% (mass / mass) or less The pharmaceutical preparation according to claim 16 or 17, comprising the same.

19. i) 35 to 60% (mass / mass) of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof, ii) 40 to 60% (mass / mass) of a filler, iii) when present, 5% (mass / mass) or less of a binder, iv) 0.5 to 5% (mass / mass) of a disintegrant, v) 0.25 to 3% (mass / mass) of a lubricant, vi) when present, 2% (mass / mass) or less of a glidant, and vii) when present, one or more additional pharmaceutically acceptable excipients in a total of 10% (mass / mass) or less The pharmaceutical preparation according to claim 16, 17, or 18, which is a tablet comprising the same.

20. The filler is mannitol, the binder is microcrystalline cellulose, the disintegrant is selected from crospovidone, carboxymethyl starch glycolate, carboxymethyl cellulose, and salts thereof, the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, glycerol fatty acid ester, and sodium stearyl fumarate, and / or the glidant is colloidal silicon dioxide. The pharmaceutical preparation according to any one of claims 16 to 19.

21. A method for preparing a solid preparation according to any one of claims 1 to 10, the method comprising dry granulation.

22. (a) 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof, and a filler, and optionally a binder and / or a lubricant are mixed; (b) the mixture prepared in step (a) is dry granulated to form the solid preparation; and (c) comminution is carried out A method for preparing the solid preparation according to claim 21, comprising the steps.

23. The method for preparing the solid preparation according to claim 21 or 22, wherein the dry granulation is roller compression.

24. A method for preparing a pharmaceutical preparation which is a tablet and contains the solid preparation according to any one of claims 1 to 10, comprising: (a) implementing the method according to claim 21, 22, or 23 to form the solid preparation; (b) mixing the solid preparation and one or more pharmaceutically acceptable excipients; (c) tableting the mixture prepared in step (b); and (d) film coating the tablet prepared in step (c) A method comprising the steps.

25. A method for preparing a pharmaceutical preparation which is a capsule and contains the solid preparation according to any one of claims 1 to 10, comprising: (a) implementing the method according to claim 21, 22, or 23 to form the solid preparation; (b) mixing the solid preparation and one or more pharmaceutically acceptable excipients; and (c) filling the solid preparation prepared in step (a) or the mixture prepared in step (b) into a capsule A method comprising the steps.

26. A pharmaceutical preparation according to any one of claims 11 to 20 for use in the treatment of cancer.

27. The pharmaceutical preparation according to claim 26, wherein the treatment further comprises chemotherapy.

28. The pharmaceutical preparation according to claim 26 or 27, wherein the treatment further comprises immunotherapy.

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