RU2822063C2 - Pharmaceutical preparation - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical industry. Invention proposes a solid preparation for treating cancer in the form for oral administration, containing 20–80 wt./wt.% micronised 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 an excipient selected from sugar, sugar alcohol and dicalcium phosphate; pharmaceutical preparation containing said solid preparation; method of producing said solid preparation by mixing an active agent and an excipient, followed by dry granulation of the obtained mixture; methods of producing a pharmaceutical preparation, which is a tablet or capsule; use of the pharmaceutical preparation in treating cancer.

EFFECT: group of inventions provides high content of the active agent in the preparation and improved bioavailability.

25 cl, 4 dwg, 2 tbl, 26 ex

Description

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 the method of its manufacture and its use in medicine.

3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)- Benzonitrile is described in Example 40 in WO 2009/006959 A1 as one member of a family of pyridazone derivatives which have been found to have valuable pharmacological properties. Specific salts 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl )-benzonitrile are described in WO 2009/007074 A1. It is a potent c-Met inhibitor that inhibits the enzymatic activity of c-Met tyrosine kinase. c-Met is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR) inhibitors. Inhibition of c-Met has been shown to be a promising approach for cancer treatment alone and in combination with other treatments, including chemotherapy, radiation therapy and/or immunotherapy.

3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)- Benzonitrile has very low solubility in water and biological media.

Details 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl) -benzonitrile has a solubility in fasting artificial intestinal fluid (FaSSIF) of 43 μg/ml and in postprandial artificial intestinal fluid (FeSSIF) of 319 μg/ml. Despite this low solubility, fairly high doses, well in excess of 100 mg, are required for its use in therapy. At an estimated effective human dose of approximately 500 mg, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6 -Dihydro-pyride azin-3-yl)-benzonitrile has a dose/solubility ratio of >10,000 and can be classified as BCS IV (Amidon et al., 1995). Accordingly, a pharmaceutical preparation for oral administration must have high bioavailability to provide the high doses required to achieve the desired therapeutic effect. Otherwise, the pharmaceutical product must be oversized, unsuitable for oral administration due to problems with swallowing.

Micronization of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl) -benzonitrile improves bioavailability, but causes other effects such as stickiness and very poor flow, as well as unfavorable compaction properties, which negatively affect the development of a durable formulation that can be produced on an industrial scale (e.g. 50,000 to 100,000 tablets per batch) , as necessary to enable Phase III clinical trials to be conducted as well as to be offered to the market.

In addition, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-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-dihydropyride azin-3 -yl)-benzonitrile silt has elasticity comparable to corn starch, which is known to have a low likelihood of compaction due to its elasticity (Lean M. et al., Pharm Dev Technol, 2015; 20(1): 12-21 ). The cited reference proposes a classification of the properties of various excipients used in pharmaceuticals and their use in various manufacturing processes. Corn starch has been described as having a higher risk for dry granulation methods due to its high elastic recovery properties, making this filler unsuitable for this production process.

In addition, it is known in the art that direct compression is usually only possible for potent drugs where the drug content is less than 30% of the formulation (Jivraj M. et al., PSTT Vol. 3, No. 2 February 2000). Since the drug should deliver 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazine-3 -yl)-benzonitrile in high doses in the range of approximately 500 mg, the size of the drug is limited to ensure ease of ingestion, so drug content above 30% is required.

Alternative approaches to overcome the unfavorable compaction 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 using wet granulation methods that can be used on an industrial scale have been unsuccessful. For example, if micronized 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3 -yl)-benzonitrile is used in fluidized bed granulation, it is blown into the filter once the fluidized bed is in place, so that a pharmaceutical composition containing such an active substance cannot be obtained. Fabrication by high shear granulation was unsuccessful as prototypes developed using this production technology did not show sufficient in vitro dissolution results.

Therefore, the object of the present invention was to provide a pharmaceutical dosage form of 3-(1-{3-[5-(1-setyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo- 1,6-dihydropyridazin-3-yl)-benzonitrile, which provides sufficient bioavailability and which has a high drug content, and a suitable method for its preparation.

Various attempts have been made to provide a suitable pharmaceutical formulation that provides bioavailability of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6 -dihydropyridazin-3-yl)-benzonitrile in quantities necessary for its use in therapy, such as oral solutions, self-emulsifying drug delivery system SEDDS or SMEDDS have not been successful. SEDDS/SMEDDS or emulsions cannot be prepared due to the low solubility of 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo -1,6-dihydropyridazin-3-yl)-benzonitrile in the tested oils (e.g. solubility in neutral oil < 5 mg/ml). Due to the relatively high doses required for therapeutic effect (approximately 500 mg) and the maximum dose in self-emulsifying capsules (SEDDS or SMEDDS) of no more than 5 mg, the patient must take 100 capsules to achieve the target dose. Accordingly, this method of preparing the composition turned out to be unfeasible.

The essence of the invention

The present invention relates to a solid preparation containing micronized 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6- dihydropyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof and an excipient in which 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]- benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof is present in an amount of from 20 to 80% by weight.

3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)- Benzonitrile is shown below:

The term "about" as used herein refers to a numerical value, including, for example, whole numbers, fractions and percentages, whether or not explicitly stated. The term “about” generally refers to a range of numerical values (eg, +/- 1-3% of a stated value) that would be considered by one of ordinary skill in the art to be equivalent to the stated value (eg, having the same function or result). In some cases, the term “approximately” may include numerical values rounded to the nearest significant number.

As used herein, the term “other” means at least a second or more. In addition, unless the context otherwise requires, terms in the singular include the plural and terms in the plural include the singular.

As used herein, "%" or "percentage" means percentage by weight (% (w/w)), unless otherwise specified herein.

The present invention also relates to a pharmaceutical preparation containing said solid preparation, methods for preparing the solid preparation and methods for preparing the pharmaceutical preparation, as well as the use of the solid preparation or pharmaceutical preparation in the treatment of cancer, either alone or in combination with radiation therapy, chemotherapy and/or or immunotherapy.

As used herein, the term “solid preparation” refers to a three-dimensional solid pharmaceutical preparation containing an active pharmaceutical ingredient (API) and at least one pharmaceutically acceptable excipient. Preferably, the solid preparation is a compressed mixture of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazine -3-yl)-benzonitrile and one or more pharmaceutically acceptable excipients, for example selected from an excipient and optionally one or more pharmaceutically acceptable excipients. The compressed mixture may be produced by dry granulation and preferably exists in the form of particles, which may be irregular or regular in shape. The solid drug can be processed into other pharmaceutical products, such as tablets, but can also be administered directly to the patient without any modification.

In addition to the excipient, one or more other excipients may be present in the solid preparation, such as a binder, a glidant, a disintegrant and a lubricant.

As used herein, the term “micronized” refers to particles that have been reduced in size to micron size. In a corresponding embodiment, micronized 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin- The 3-yl)-benzonitrile present in the solid preparation has an average particle size which is characterized by a d50 value in the range of 5 µm to 80 µm, preferably 5 µm to 50 µm and more preferably 5 µm to 25 µm. Therefore, the 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-dihydropyridazin-3-yl)-benzonitrile has an average particle size which is characterized by a d50 value in the range of 5 µm to 80 µm, preferably 5 µm to 50 µm and more preferably 5 µm to 25 µm.

d^o values for 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin- 3-yl)-benzonitrile measured by laser diffraction on a Malvern Mastersizer 2000 (wet method using Hydro 2000S; microvolume tray; sample quantity 100 mg; stirrer speed 2200 rpm, sonication for 1 min, measurement time 7.5 s; darkening 10-15%). The dso value given here is the size in micrometers that divides the distribution into half above and half below that diameter. d50 is the median for the volume distribution and is often also referred to as Dv50 (or Dv0.5).

Particle sizes of solid preparations are measured using dynamic image analysis (Retsch CamSizer X2) using a brush and pin, sample volume is at least 20 ml, slit width is 4.0 mm, dispersion pressure is 30.0 kPa, without speed adaptation. The dimensions are determined for the corresponding spheres, the shape of the sample is determined as particles with curved corners.

As used herein, the term “excipient” means a means that increases the volume of a pharmaceutical preparation by providing the amount of material necessary to form a solid preparation. The filler also serves to create the desired flow properties and compression characteristics in the preparation of a solid drug, as well as solid pharmaceuticals such as tablets and capsule fillers. The excipients used in the present invention may be a sugar alcohol such as sorbitol or mannitol, dulcitol, xylitol or ribitol, preferably sorbitol or mannitol, especially preferably mannitol, a sugar such as glucose, fructose, mannose, lactose, sucrose or maltose, preferably lactose, sucrose or maltose, particularly preferably lactose, starch such as potato starch, rice starch, corn starch or pregelatinized starch. The filler may be present in the solid preparation according to the invention in an amount of from 20 to 80% (w/w), preferably from 30 to 70% (w/w), especially preferably from 40 to 65% (w/w) , in terms of the total mass of the solid composition.

In addition to the filler, the solid preparation may contain one or more additional auxiliary substances, such as a binder, a glidant, a disintegrant and a lubricant.

The solid preparation in accordance with 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 from 20 to 80 wt.%, based on the total weight of the solid preparation. In preferred embodiments, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazine -3-yl)-benzonitrile is present in the solid preparation in an amount of from 25 to 70 wt.%, more preferably in an amount from 30 to 60 wt.% and most preferably in an amount from 35 to 55 wt.%, based on the total weight of the solid drug. Therefore, the 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-dihydropyridazin-3-yl)-benzonitrile is present in an amount of from 20 to 80 wt.%, preferably from 25 to 70 wt.%, more preferably in an amount from 30 to 60 wt.% and most preferably in an amount from 35 up to 55 wt.% based on the total weight of the solid preparation.

Any reference to amounts, weight or weight percentages of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6- Dihydropyridazin-3-yl)-benzonitrile or pharmaceutically acceptable salts thereof should be understood to refer to the anhydrous free form of 3-(1-{3-[5-(1-ethyl-piperidin-4-ylmethoxy)-pyrimidin-2- yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)-benzonitrile, unless otherwise indicated in this application.

The solid preparation may contain 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3 -yl)-benzonitrile in the form of its free base, as well as in the form of a pharmaceutically acceptable substance thereof. The term "pharmaceutically acceptable" as used herein refers to that which is suitable for the preparation of a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise objectionable and includes that which is acceptable both to veterinary medicine and for use in pharmaceuticals for humans. The term "pharmaceutically acceptable salt" as used herein refers to the salt a 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6 -oxo-1,6-dihydropyridazin-3-yl)-benzonitrile, which is pharmaceutically acceptable as defined herein, and which has the desired pharmacological activity of the parent 3-(1-{3-[5-(1 -methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)-benzonitrile. The term "pharmaceutically acceptable salt" includes all hydrates of the corresponding salt. Suitable salts may be acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with 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, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, trimethylacetic acid, etc. Particularly suitable pharmaceutically acceptable salts are 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin- 3-yl)-benzonitrile which may be present in the solid preparation are sulfate, phosphate, mesylate, besylate, tosylate, fumarate, monohydrochloride monohydrate or maleate, preferably monohydrochloride monohydrate. Thus, the 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-Dihydropyridazin-3-yl)-benzonitrile is present as its sulfate, phosphate, mesylate, besylate, tosylate, fumarate, monohydrochloride monohydrate or maleate, preferably monohydrochloride monohydrate.

According to a preferred embodiment of the invention, the solid preparation contains sugar, sugar alcohol or dicalcium phosphate as excipient. According to a particularly preferred embodiment, the excipient present in the solid preparation is a sugar alcohol, wherein the sugar alcohol is sorbitol and/or mannitol, preferably mannitol.

According to another preferred embodiment of the invention, the solid preparation contains a binder. Thus, the invention also relates to a solid preparation, where the solid preparation further contains a binder.

The term "binder" as used herein refers to an agent that provides cohesion and strength to a solid preparation. Binders that can be used in the present invention are, for example, polyvinylpyrrolidone, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, starch paste such as corn starch paste, a cellulose derivative such as hydroxypropyl methylcellulose, hydroxypropylcellulose or microcrystalline cellulose, preferably microcrystalline cellulose. Therefore, 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, a cellulose derivative such as hydroxypropyl methylcellulose, hydroxypropylcellulose or microcrystalline cellulose, preferably microcrystalline cellulose. The binder may be present in the solid preparation according to the invention in an amount of from 0 to 20% (w/w), preferably from 0 to 10% (w/w), especially preferably from 0 to 5% (w/w), in terms of the total mass of the solid composition.

The solid preparation may further contain a lubricant. The term "lubricant" as used herein refers to an inactive ingredient used to prevent ingredients from sticking together when dry granulated, filled into capsules, or compressed into tablets. The lubricant reduces the adhesion of the powder to the surface of the roller compactor rolls and the sliding friction of the tableting material and dies in the die during the tableting operation and prevents tablets from sticking to the punches. 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 C^-C^-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, glycerol fatty acid esters, stearic acid or pharmaceutically acceptable salts of stearic acid and divalent cations, preferably magnesium stearate. Lubricants may be present in the solid preparation according to the invention in an amount of 0 to 5% (w/w), preferably 0.1 to 2% (w/w), particularly preferably 0.3 to 1% ( w/w), most preferably about 0.5% (w/w), based on the total weight of the solid composition.

The solid preparation may additionally contain a disintegrant. The term "disintegrant" as used herein refers to a compound that expands and dissolves when wet, causing tablets or granules to disintegrate, break down, and release the active pharmaceutical agent. Disintegrant also acts 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 was in contact with a solvent such as water. Disintegrants serve to disintegrate tablets or granules, etc. and thus accelerate the dissolution of the solid dosage form upon contact with the liquid dissolution medium. Suitable disintegrants include crospovidone (crosslinked polyvinylpyrrolidone), carboxymethylcellulose and their salts and derivatives, such as crosslinked derivatives, for example croscarmellose sodium (crosslinked polymer of sodium carboxymethylcellulose), sodium carboxymethylglycolate, sodium starch glycolate, carrageenan, agar and pectin. Crospovidone and croscarmellose sodium are particularly preferred. Disintegrants are present in the pharmaceutical preparation according to the invention in an amount of 0 to 10% (w/w), preferably 0.25 to 5% (w/w), particularly preferably 0.5 to 3% (w/w). wt), in terms of the total mass of the solid composition.

The solid preparation may additionally contain a glidant. The term "glidant" as used herein refers to an inactive ingredient used as a flow aid that improves the flow characteristics of particles such as powders or granules. In the present invention, the flow characteristics of the solid drug or mixtures containing the solid drug can be improved during further processing such as encapsulation or tabletting. Non-limiting examples of glidants for use in the present invention include colloidal silica (Aerosil 200, Cab-O-Sil), talc, magnesium carbonate, and combinations thereof. Glidants are present in the pharmaceutical preparation according to the invention in an amount of 0 to 7.5% (MAE), preferably 0 to 5% (MAE), particularly preferably 0 to 3% (MAE), in terms of the total mass of the solid composition.

According to a corresponding embodiment of the invention, the solid preparation is in the form of particles having an average particle size, which is characterized by a d50 value in the range from 50 µm to 1 mm, preferably from 60 µm to 800 µm and more preferably from 70 to 600 µm. Thus, the invention also relates to a solid preparation, wherein the solid preparation has an average particle size which is characterized by a d50 value in the range of 50 µm to 1 mm, preferably 60 µm to 800 µm and more preferably 70 to 600 µm.

Dry granulation can be used to obtain a solid preparation. The term "dry granulation" or "dry granulation" as used herein particularly refers to granulation methods including at least a compaction step. The pharmaceutical industry mainly uses two dry granulation methods, namely impact compaction and roller compression, both of which can be used to prepare a solid drug. Dry compaction granulation involves a compaction step using compression equipment, which typically contains two steel punches in a steel die cavity. The granules are formed when dies in the cavity apply pressure to the particles of material, and are typically about 25 mm in diameter and about 10-15 mm in thickness, but the specific size of the workpiece is not a limiting factor to the present invention. Dry granulation using roller compaction involves a roller compaction step in which particles of material are compacted between rotating pressure rolls, and a subsequent grinding step to grind the compacted material into granules. "Dry granulation" processes, which can be used to prepare a solid drug, typically do not use liquids and/or do not require drying steps. The term "pellet" itself does not necessarily imply a specific shape, since the final shape of the granule(s) will be controlled by the particular production method.

The present invention also provides a pharmaceutical preparation containing a solid preparation in accordance with the invention. Accordingly, the present invention also relates to a pharmaceutical preparation containing a solid preparation. The solid preparation can be used as a pharmaceutical preparation without any modification, but it can also be processed into other pharmaceutical preparations, such as tablets, or placed in sachets or capsules.

Preferably the pharmaceutical preparation is for oral administration. Therefore, 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. Therefore, the present invention further relates to a pharmaceutical preparation that is an immediate release preparation.

In exemplary embodiments, the pharmaceutical preparation, preferably a tablet, has a disintegration time of 30 minutes or less, for example, 20 minutes or less, preferably 15 minutes or less, and more preferably 10 minutes or less. The above decay time is measured in 0.01 N. HC1 at 37 °C in a disintegration device in accordance with USP-NF <701> (USP39-NF34 p. 537; Pharmacopeial Forum: Vol. No. 34(1) p. 155) Disintegration. The device consists of a basket-stand assembly, a low 1000 ml beaker for immersion liquid, a thermostatic device for heating and a device for raising and lowering the basket in the immersion liquid. The basket-rack assembly moves vertically along its axis and consists of six transparent tubes with an open end; the tubes are held in a vertical position by two plates. A woven stainless steel wire mesh is attached to the bottom surface of the bottom plate. If specified in a separate monograph, each tube is equipped with a cylindrical disk. The disc is made of suitable transparent plastic. Place 1 dose into each of the six tubes in the basket and add the disc. Run the device using the specified medium as the immersion liquid, maintained at 37 ± 2°. After the set time or at set intervals, lift the basket of liquid and observe whether the tablets have completely disintegrated.

In a preferred embodiment, the pharmaceutical preparation in accordance with the present invention is a capsule containing a solid preparation and optionally one or more pharmaceutically acceptable excipients. The capsule itself may be any pharmaceutically acceptable capsule, such as a hard gelatin capsule, but should preferably be readily soluble.

In an exemplary embodiment, the pharmaceutical preparation is a capsule that contains a mixture consisting of from 40 to 100% (w/w), for example at least 50% (w/w), more preferably at least 70, 80 , 90, 95 or 99% (w/w) of a solid preparation in accordance with the present invention; and from 0 to 60% (w/w), i.e. remainder (up to 100% (w/w) difference) of a mixture of at least one pharmaceutically acceptable excipient, preferably selected from filler, lubricant, glidant, disintegrant and inorganic alkali metal salt, based on the total weight of all material contained in a capsule, i.e. the total mass of the capsule minus the mass of the capsule shell.

Inorganic alkali metal salts, that is, salts consisting of alkali metal ions and inorganic acid anions, have relatively recently been discovered useful for enhancing dissolution and include sodium chloride, sodium sulfate, sodium carbonate, sodium bicarbonate, sodium phosphate, sodium dihydrogen phosphate, chloride potassium, potassium carbonate and potassium bicarbonate. Sodium chloride is particularly preferred.

A preferred embodiment of the invention relates to a pharmaceutical preparation, which is a capsule containing from 40 to 100% (w/w) solid drug; and from 0 to 60% (w/w) of at least one pharmaceutically acceptable excipient, preferably selected from a filler, glidant, disintegrant and lubricant, based on the total weight of all material contained in the capsule.

As will be shown in the examples, capsule formulations may contain, for example, 100, 99.5, 99, 90, 80, 75, 70, 60 or 50% (w/w) solids, or any range covered by any combination of these values, based on the total mass of all material contained in the capsule. The remainder of the excipient (up to 100% (w/w) difference) consists of at least one pharmaceutically acceptable excipient as described above.

In an exemplary embodiment, the pharmaceutical preparation is a capsule containing an excipient including:

from 50 to 100% (w/w) of the solid preparation in accordance with the invention;

from 0 to 20% (w/w) baking powder;

from 0 to 50% (w/w) filler;

0 to 5% (w/w) lubricant;

0 to 5% (w/w) glidant;

from 0 to 20% (w/w) inorganic alkali metal salt; and a total of 0 to 20% (w/w) one or more additional pharmaceutically acceptable excipients, based on the total weight of the capsule.

The filler may be present in the above exemplary embodiment, for example, in the range of 5 to 50% (w/w), or in the range of 7.5 to 50% (w/w), or for example, in the range of 10 to 40 % (May/May).

The inorganic alkali metal salt is preferably present in the above exemplary embodiment and may be contained in an amount of 2.5 to 20% (w/w), or 5 to 17.5% (w/w), for example, or at least 7.5% (w/w), for example about 10 or 15% (w/w).

In a more preferred embodiment, the pharmaceutical preparation is a tablet and therefore typically contains, in addition to the pharmaceutically acceptable excipients present in the solid preparation, at least one other pharmaceutically acceptable excipient. The at least one additional pharmaceutically acceptable excipient is preferably selected from a filler, a glidant, 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 in the form of a tablet and which, in addition to the pharmaceutically acceptable excipients present in the solid preparation, optionally contains one or more amounts of a pharmaceutically acceptable excipient selected from a filler, a disintegrant, a glidant and a lubricant. substances.

In an exemplary embodiment, the pharmaceutical preparation is a tablet containing a solid preparation and optionally additional excipients, wherein the tablet, based on its total weight, contains:

i) from 20 to 80% (may/may) 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1 ,6-dihydropyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof;

ii) from 10 to 70% (w/w) filler;

iii) from 0 to 20% (w/w) binder;

iv) 0 to 20% (w/w) baking powder;

v) 0 to 5% (w/w) lubricant;

vi) from 0 to 7.5% (w/w) glidant; And

vii) a total of 0 to 20% (w/w) of one or more additional pharmaceutically acceptable excipients.

The one or more additional pharmaceutically acceptable excipients may include one or more selected from preservatives, antioxidants, sweeteners, flavorings, colors, surfactants and moisture absorbents.

Many excipients can perform more than one function depending on other components of the pharmaceutical dosage form. For clarity, particularly when calculating weight percentages, each pharmaceutically acceptable excipient used in the pharmaceutical preparation according to the present invention is preferably associated with one functionality, that is, considered as either a disintegrant or a lubricant.

In another exemplary embodiment, the pharmaceutical preparation is a tablet containing a solid preparation and optionally additional excipients, wherein the tablet, based on its total weight, contains:

i) from 30 to 70% (w/w) 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo- 1,6-dihydropyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof;

ii) from 20 to 60% (w/w) filler;

iii) from 0 to 10% (w/w) binder;

iv) 0.25 to 10% (w/w) baking powder;

v) 0 to 4% (w/w) lubricant;

vi) from 0 to 5% (w/w) glidant and

vii) a total of 0 to 10% (w/w) of one or more additional pharmaceutically acceptable excipients.

In another exemplary embodiment, the pharmaceutical preparation is a tablet containing a solid preparation and optionally additional excipients, wherein the tablet, based on its total weight, contains:

i) from 35 to 60% (w/w) 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo- 1,6-dihydropyridazin-3-yl)-

benzonitrile or a pharmaceutically acceptable salt thereof;

ii) 40 to 60% (w/w) filler;

iii) from 0 to 5% (w/w) binder;

iv) 0.5 to 5% (w/w) baking powder;

v) 0.25 to 3% (w/w) lubricant;

vi) 0 to 2% (w/w) glidant; And

vii) a total of 0 to 10% (w/w) of one or more additional pharmaceutically acceptable excipients.

Preferably in these embodiments, the filler is mannitol or lactose, the binder is microcrystalline cellulose, the disintegrant is selected from crospovidone, carboxymethylcellulose and their salts and derivatives, especially 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 its derivatives. 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 silica.

Preferably, the total amount of one or more additional pharmaceutically acceptable excipients is from 0 to 10% (w/w), from 0 to 7.5% (w/w), from 0 to 5% (w/w), from 0 to 2.5% (w/w) or from 0 to 1% (w/w), for example, 0% (w/w).

Of course, the tablet may be coated to improve taste and/or appearance and/or to protect the tablet from external influences such as moisture. Any coating shall not be counted towards the calculation of 100% (may/may) of the pharmaceutically active ingredients and drug substance composing the tablets as stated above. For film coating, for example, macromolecular substances such as modified celluloses including hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polymethacrylates, polyethylene glycols and zein can be used. The coating thickness is preferably less than 200 µm.

The present invention also provides a method for preparing a solid preparation which includes dry granulation such as roll compaction, preferably roll compaction. Accordingly, the present invention also relates to a method for preparing a solid preparation, a dry granulation method, preferably roller compaction.

The term "roller compaction" or "roller compaction" refers to a process in which powders or particles are forced between two counter-rotating rollers and compressed into a solid compact or strip. Roller compaction can be accomplished using any suitable roller press known to one skilled in the art. Suitable roller presses include, for example, the Fitzpatrick® Chilsonator IR220 roller press from the Fitzpatrick Company, USA. The process parameters, especially the roll force, can be easily obtained by routine experiments based on the general knowledge of one skilled in the art. A suitable roll force 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.

In an exemplary embodiment, the method includes:

(a) mixing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3 -yl)-benzonitrile or a pharmaceutically acceptable salt thereof, and excipient and optionally one or more other pharmaceutically acceptable excipients;

(b) dry granulating the mixture obtained in step (a) to form a solid preparation; And

(c) optional grinding.

Preferred pharmaceutically acceptable excipients used in step (a) are selected from a binder, a disintegrant, a lubricant and a glidant. According to a preferred embodiment, the dry granulation used in the method is roller compaction.

The resulting solid preparation can be used to prepare pharmaceuticals such as tablets or capsules. An exemplary method for preparing a pharmaceutical preparation that is a tablet containing a solid drug includes:

(a) carrying out 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 obtained in step (b); And

(d) optionally film coating the tablets obtained in step (c).

Tableting or compression into tablets can be done using commonly used eccentric presses or rotary presses.

An exemplary method for preparing a pharmaceutical preparation that is a capsule containing a solid preparation includes:

(a) carrying out a method for forming a solid preparation;

(b) optionally mixing the solid preparation and one or more pharmaceutically acceptable excipients and optionally granulating the resulting mixture, preferably by roll compaction;

(c) filling the mixture or granulate obtained in step (b) or the solid preparation obtained in step (a) into capsules.

As stated above in the introductory section, it was found that 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1, 6-Dihydropyridazin-3-yl)-benzonitrile exhibits valuable properties as a c-Met tyrosine kinase inhibitor, which is used in the treatment of cancer. It is currently undergoing clinical trials.

Accordingly, the present invention provides a solid preparation or pharmaceutical preparation, as described above, for use in the treatment of cancer.

Optionally, cancer treatment additionally includes radiation therapy. Accordingly, the present invention also relates to a pharmaceutical preparation according to the invention for use in the treatment of cancer electively in conjunction with radiation therapy. Suitable radiotherapy treatment methods are described in WO 2012/028233 A1 and are incorporated herein by reference.

Optionally, as an alternative to or in addition to radiation therapy, cancer treatment may include chemotherapy. Accordingly, the present invention also relates to a pharmaceutical preparation for use in the treatment of cancer, where 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-dihydropyridazin-3-yl)-benzonitrile include cisplatin and etoposide or a combination thereof, to name just one example.

Optionally, as an alternative to or in addition to radiation therapy and/or chemotherapy, cancer treatment may include immunotherapy. Accordingly, the present invention also relates to a pharmaceutical preparation for use in the treatment of cancer, where the treatment further includes immunotherapy.

Accordingly, the present invention also provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical preparation in accordance with the present invention, optionally in combination with radiation therapy, chemotherapy or immunotherapy, or any combination thereof. In an exemplary embodiment, the present invention provides a method of treating a cancer selected from colon, lung, head and neck, pancreatic, and histological subtypes thereof in a patient in need thereof, comprising administering to said patient 3-(1-{3-[ 5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof in a solid preparation or a pharmaceutical preparation according to the present invention, in combination with at least one additional therapeutic agent selected from etoposide and platinum.

The present invention will now be described with reference to exemplary embodiments thereof, which should not be construed as limiting the invention.

Detailed Description of the Invention

Brief description of the figures

In FIG. 1 shows the dissolution curves for prototype formulations (open triangles: Example A; filled circles: Example B; filled triangles: Example C; open circles: Example D), which all contain 3-(1-{3-[5-(1- methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)-benzonitrile. The dissolution conditions are as follows: 900 ml acetate buffer pH 4.5 with 5 mmol/L sodium chloride and 0.1% Tween 80 using a paddle stirrer at 75 rpm at 37°C.

In FIG. Figure 2 shows the dissolution curves of examples 12-19 in a dissolution medium of acetate buffer pH 4.5 + 3 mmol / NaCl + 0.1% Tween, showing satisfactory dissolution. Example 12: filled circles; Example 13: light circles; Example 14: filled triangles; Example 15: light triangles; Example 16: filled squares; Example 17: light squares; filled diamonds: Example 18; light diamonds: Example 19.

In FIG. Figure 3 shows a comparison of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3- yl)-benzonitrile (black dots) with corn starch (light dots) regarding its elastic properties.

In FIG. 4. shows a comparison of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3 -yl)-benzonitrile with various pharmaceutically used excipients. Black triangles: dicalcium phosphate, open circles: mannitol, open triangles: lactose, black dots: 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl }-6-oxo-1,6-dihydropyridazin-3-yl)-benzonitrile.

Examples of pre-composition

Examples of evaluation of wet granulation methods

EXAMPLE A)

Example A (open triangles in Figure 1), containing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1, 6-dihydropyridazin-3-yl)-benzonitrile (30.99%), lactose (32.39%),

microcrystalline cellulose type 101 (23.00%), povidone 25 (3.76%), crospovidone (3.76%) are manufactured using high shear granulation method. After this, the resulting granules are sifted through a 1.0 mm sieve and then mixed with crospovidone (2.35%), povidone 25 (1.41%), magnesium stearate (0.94%), talc (0.94%) and dioxide silicon (0.47%) and processed into tablets using a single punch press with a crush strength of approx. 125 N, disintegration time <10 minutes and total mass approx. 645 mg.

EXAMPLE B)

Example B (solid circles in Figure 1) containing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1, 6-Dihydropyridazin-3-yl)-benzonitrile (77.29%) and starch 1500 (19.32%) were prepared using a high shear granulation method. The resulting granules were then sifted through a 1.0 mm sieve and then mixed with sodium carboxymethyl starch (1.93%), magnesium stearate (0.97%) and silica (0.48%) and processed into tablets using a single press. punch with crushing strength of approx. 144 N, decay time <8 minutes and total mass approx. 259 mg.

EXAMPLE C)

Example C (filled triangles in Figure 1) containing 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1, 6-dihydropyridazin-3-yl)-benzonitrile (26.50%), lactose (4.41%), hypromellose (1.11%) and calcium phosphate dihydrate (53.01%) were prepared by fluidized granulation method layer, which could be selected by one skilled in the art. The resulting granules were then sifted through a 0.8 mm sieve and then mixed with pregelatinized starch (9.89%), magnesium stearate (0.99%), sodium carboxymethyl starch (2.47%) and silica (0.49%) and processed into tablets using a single punch press. The tablets were then coated using a commercially available polyvinyl alcohol based film coating premix, with coating present at up to 1.13% of the entire formulation. The resulting tablets showed a crushing strength of approx. 159 N, disintegration time <6 minutes and total mass approx. 755 mg.

EXAMPLE D)

Example D (open circles in Figure 1) containing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1, 6-dihydropyridazin-3-yl)-benzonitrile (26.66%), lactose (4.44%), hypromellose (1.11%) and anhydrous calcium phosphate (53.31%) were prepared by granulation in fluidized bed, which could be selected by one skilled in the art.

The resulting granules were then sifted 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 on a single punch press to obtain tablet cores measuring approx. 741.8 mg.

The tablets were then coated using a commercially available polyvinyl alcohol based film coating premix, with coating present at up to 1.13% of the entire formulation. The resulting tablets showed a crushing strength of approx. 159 N, disintegration time <6 minutes and total mass approx. 750 mg.

As can be seen from FIG. 1, tablets prepared from granulates obtained by high shear granulation (Examples A and B) do not show satisfactory in vitro release properties. In addition, tablets that are made from granulates produced by fluidized bed granulation (Examples C and D) exhibit better in vitro release properties, high shear granulation prototypes (Examples A and B), but they are limited in their maximum achievable content of the drug.

Examples of assessing material properties using Young's modulus

Young's modulus is regarded as an indicator of the stiffness of a material (the higher the Young's modulus, the stiffer the substance), and its measurement is carried out depending on the solid fraction that complements the porosity (i.e. solid fraction = 1 porosity fraction). In this case, solid fraction 1 indicates the absence of porosity, i.e. for the absence of air absorption by the solid phase. Solid fractions of pharmaceutical interest typically range from 0.75 to 0.85. Porosity was determined by nitrogen pycnometry.

Measurements to determine Young's modulus are carried out on a commercially available single-punch tool press (Romaco Kilian StylOne system) with punches for ultrasonic measurement. To do this, pure substances are compacted between the upper and lower punch, resulting in compaction of the material. The speed of ultrasound in the sample, depending on the degree of compaction, is recorded and used to calculate the Young's modulus of a particular substance.

The following pure materials were selected for this study:

As can be seen in 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 properties similar to those of corn starch (light dots), a substance that is known for its high elasticity and therefore unfavorable compression characteristics. Additionally, Figure 4 shows that 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6- Dihydropyridazin-3-yl)-benzonitrile has lower Young's moduli compared to commonly used pharmaceutical excipients (dicalcium phosphate, mannitol and lactose)/

Cooking examples

EXAMPLE E

Approximate compositions of solid preparation

D ₅₀ values are recorded as described above and are in the range of 70 - 530 µm.

Bulk density is determined using a 100 ml beaker in accordance with DIN 53468.

EXAMPLE 1

The ingredients are weighed (batch size 103.2 kg) and sifted through a 1.0 mm sieve. The mixture is prepared by mixing all ingredients except magnesium stearate in a commercially available hopper mixer (eg Servolift) for 15 minutes at 12 rpm. Magnesium stearate is then added and the entire mixture is mixed again for 5 minutes at 12 rpm. The mixture is then transferred to a roller press to produce a solid preparation. The roller press (Gerteis Macropactor) operates with the following settings: compaction force 12 kN/cm, gap width 2.5 mm, roll speed 3.0 rpm. The resulting granules are sifted through a 0.8 mm sieve.

EXAMPLE 2

The ingredients are weighed (batch size 2.4 kg) and sifted through a 1.0 mm sieve, except magnesium stearate. The mixture is prepared by mixing all ingredients except magnesium stearate in a commercially available Turbula T50A mixer for 15 minutes. Magnesium stearate is sifted through a 0.5 mm sieve and then added to the mixture, which is then mixed again for 5 minutes. The mixture is then transferred to a roller press to produce a solid preparation. The roller press (Alexanderwerk WP120P) operates with the following settings: compaction force 4.0 kN/cm, gap width 1.0 mm, roll speed 4.0 rpm. The resulting granules are sifted through a 1.0 mm sieve.

EXAMPLES 3-8

The ingredients are weighed (batch size 1.0 kg) and sifted through a 1.0 mm sieve. The mixture is prepared by mixing all ingredients in a commercially available Servolift hopper mixer for 15 min at 12 rpm. The mixture is then transferred to a roller press to produce a solid preparation. The roller press (Gerteis Minipactor) operates with the following settings: compaction force 3.0 kN/cm, gap width 3.0 mm, roll speed 3.0 rpm. The resulting granules are sifted through a 1.0 mm sieve.

EXAMPLE 9

The ingredients are weighed (batch size 33.2 kg) and sifted through a 1.0 mm sieve. The mixture is prepared by mixing all ingredients in a commercially available Servolift hopper mixer for 15 min at 12 rpm.

The mixture is then transferred to a roller press to produce a solid preparation. The roller press (Gerteis Macropactor) operates with the following settings: compaction force 4.5 kN/cm, gap width 3.0 mm, roll speed 3.0 rpm. The resulting granules are sifted through a 0.8 mm sieve.

Approximate compositions of tablets

The disintegration and abrasion strength test is described in the European Pharmacopoeia, version 9.8, sections 2.9.1 (Disintegration) and section 2.9.7 (abrasion strength of uncoated tablets).

EXAMPLE 10

The solid preparation from Example 1 is mixed with crospovidone for 15 minutes. Then magnesium stearate is added and the whole mixture is stirred again for 5 minutes at 12 rpm. The entire mixture was tableted using a rotary tablet press using 18.8 x 9.2 mm punches, a pre-compression force of 1.6 kN and a main compression force of 17.1 kN at a tableting speed of 20,000 units/hour.

EXAMPLE 11

The solid preparation from Example 2 is mixed with the ingredients for 10 minutes. The entire mixture is tableted using a single punch press using 18 x 8 mm punches and a compaction force of 12 kN with a tableting speed of 1860 units/hour. Breakdown time and abrasion strength values are based on a crushing strength of 100 N.

EXAMPLE 12

The solid preparation from Example 3 is mixed for 15 minutes at 12 rpm. with all the ingredients. The entire mixture is tableted using a single punch press using 19 × 9 mm punches and a compaction force of 15 kN at a tableting rate of 1500 units/hour. Decay time and abrasion strength values are based on a crushing strength of 150 N.

EXAMPLE 13

The solid preparation from Example 4 is mixed for 15 minutes at 12 rpm with all ingredients. The entire mixture was tableted using a single punch press using 19 × 9 mm punches and a compaction force of 21 kN at a tableting rate of 2460 units/hour. Breakdown time and abrasion strength values are based on a crushing strength of 110 N.

EXAMPLE 14

The solid preparation from Example 5 is mixed for 15 minutes at 12 rpm with all ingredients. The entire mixture was tableted using a single punch press using 19 × 9 mm punches and a compaction force of 17 kN at a tableting rate of 2520 units/hour. Decay time and abrasion strength values are based on a crushing strength of 160 N.

EXAMPLE 15

The solid preparation from Example 6 is mixed for 15 minutes at 12 rpm with all ingredients. The entire mixture was tableted using a single punch press using 19 × 9 mm punches and a compaction force of 17 kN at a tableting rate of 2460 units/hour. Decay time and abrasion strength values are based on a crushing strength of 150 N.

EXAMPLE 16

The solid preparation from Example 7 is mixed for 15 minutes at 12 rpm with all ingredients. The entire mixture was tableted using a single punch press using 19 × 9 mm punches and a compaction force of 17 kN at a tableting rate of 2460 units/hour. Breakdown time and abrasion strength values are based on a crushing strength of 110 N.

EXAMPLE 17

The solid preparation from Example 8 is mixed for 15 minutes at 12 rpm with all ingredients. The entire mixture was tableted using a single punch press using 19 × 9 mm punches and a compaction force of 17 kN at a tableting rate of 2460 units/hour. Decay time and abrasion strength values are based on a crushing strength of 150 N.

EXAMPLE 18

The solid preparation from Example 6 is mixed for 15 minutes at 12 rpm with all ingredients. The entire mixture was tableted using a single punch press using 19 × 9 mm punches and a compaction force of 15 kN with a tableting rate of 2460 units/hour. Decay time and abrasion strength values are based on a crushing strength of 165 N.

EXAMPLE 19

The solid preparation from Example 8 is mixed for 15 minutes at 12 rpm. with all the ingredients. The entire mixture was tableted using a single punch press using 19 × 9 mm punches and a compaction force of 15 kN with a tableting rate of 2460 units/hour. Decay time and abrasion strength values are based on a crushing strength of 170 N.

EXAMPLE 20

The solid preparation from Example 7 is mixed for 15 minutes at 12 rpm with all ingredients. The entire mixture was tableted using a single punch press using 19 × 9 mm punches and a compaction force of 17 kN at a tableting rate of 2460 units/hour. Decay time and abrasion strength values are based on a crushing strength of 150 N.

EXAMPLE 21

The solid preparation from Example 9 is mixed for 15 minutes at 12 rpm with all ingredients. The entire mixture is tableted using a rotary tablet press using 18 × 9 mm punches, a pre-compression force of 5.0 kN and a main compaction force of 13.0 kN at a tableting rate of 30,000 units/hour.

Approximate capsule compositions

The degradation test is described in the European Pharmacopoeia, version 9.8, sections 2.9.1 (Degradation).

EXAMPLE 22

Approximate capsule compositions

HPMC capsules containing various solid preparations from Examples 1-9 are prepared by mixing such preparations with additional excipients as shown below and filling such mixtures into capsule shells. The disintegration of capsule formulations is less than 9 minutes.

Claims (55)

1. A solid preparation for the treatment of cancer in an oral form containing micronized 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6- oxo-1,6-dihydropyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof and an excipient which is sugar, sugar alcohol or dicalcium phosphate, wherein 3-(1-{3-[5-(1 -methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof is present in an amount of from 20 to 80 % w/w, based on the total weight of the solid preparation. 2. Solid preparation according to claim 1, in which 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1, 6-dihydropyridazin-3-yl)-benzonitrile is present as its sulfate, phosphate, mesylate, besylate, tosylate, fumarate, monohydrochloride monohydrate or maleate, preferably monohydrochloride monohydrate. 3. Solid preparation according to claim 1 or 2, in which 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo- 1,6-Dihydropyridazin-3-yl)-benzonitrile has an average particle size which is characterized by a d50 value in the range of 5 µm to 80 µm, preferably 5 µm to 50 µm and more preferably 5 µm to 25 µm. 4. A solid preparation according to claim 1, wherein the excipient is a sugar alcohol, wherein the sugar alcohol is sorbitol and/or mannitol, preferably mannitol. 5. Solid preparation according to one or more claims. 1-4, in which the solid preparation additionally contains a binder. 6. A solid preparation according to claim 5, wherein the binder is polyvinylpyrrolidone, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, starch paste such as corn starch paste, or a cellulose derivative such as hydroxypropyl methylcellulose, hydroxypropylcellulose or microcrystalline cellulose, preferably microcrystalline cellulose. 7. Solid preparation according to one or more claims. 1-6, in which the solid composition further contains a lubricant. 8. The solid preparation of claim 7, wherein the lubricant is sodium stearyl fumarate, glycerol fatty acid esters, stearic acid or pharmaceutically acceptable salts of stearic acid and divalent cations, preferably magnesium stearate. 9. Solid preparation according to one or more claims. 1-8, wherein the solid preparation has an average particle size, which is characterized by a d50 value in the range from 50 µm to 1 mm, preferably from 60 µm to 800 µm and more preferably from 70 to 600 µm. 10. A pharmaceutical preparation for the treatment of cancer in a form for oral administration, containing a solid preparation according to one or more claims. 1-9. 11. The pharmaceutical preparation according to claim 10, which is an immediate release preparation. 12. The pharmaceutical preparation according to claim 10 or 11, which is a capsule that contains a solid preparation and optionally one or more pharmaceutically acceptable excipients. 13. The pharmaceutical preparation according to claim 12, which is a capsule that contains from 40 to 100% wt./wt. solid preparation according to one of paragraphs. 1-9; and from 0 to 60% w/w. at least one pharmaceutically acceptable excipient, preferably selected from a filler, a glidant, a disintegrant and a lubricant, based on the total weight of all materials contained in the capsule. 14. The pharmaceutical preparation according to claim 10 or 11, which is a tablet and which, in addition to the pharmaceutically acceptable excipients present in the solid preparation, optionally contains one or more pharmaceutically acceptable excipients selected from a filler, disintegrant, glidant and lubricant . 15. The pharmaceutical preparation according to claim 14, which is a tablet containing a solid preparation according to one of paragraphs. 1-9 and optionally additional excipients, wherein the tablet, based on the total weight, contains: i) from 20 to 80% w/w. 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)- benzonitrile or a pharmaceutically acceptable salt thereof; ii) from 10 to 70% w/w. filler; iii) from 0 to 20% w/w. binder; iv) from 0 to 20% w/w. baking powder; v) from 0 to 5% w/w. lubricant; vi) from 0 to 7.5% w/w. sliding substance; And vii) from 0 to 20% w/w in total. one or more additional pharmaceutically acceptable excipients. 16. Pharmaceutical preparation according to claim 14 or 15, which is a tablet containing a solid preparation according to one of claims. 1-9 and optionally additional excipients, wherein the tablet, based on the total weight, contains: i) from 30 to 70% w/w. 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)- benzonitrile or a pharmaceutically acceptable salt thereof; ii) from 20 to 60% w/w. filler; iii) 0 to 10% w/w. binder; iv) 0.25 to 10% w/w. baking powder; v) from 0 to 4% w/w. lubricant; vi) 0 to 5% w/w. sliding substance; And vii) only 0 to 10% w/w. one or more additional pharmaceutically acceptable excipients. 17. Pharmaceutical drug according to claims. 14, 15 or 16, which is a tablet containing: i) from 35 to 60% w/w. 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)- benzonitrile or a pharmaceutically acceptable salt thereof; ii) 40 to 60% w/w. filler; iii) 0 to 5% w/w. binder; iv) 0.5 to 5% w/w. baking powder; v) from 0.25 to 3% w/w. lubricant; vi) 0 to 2% w/w. sliding substance; And vii) only 0 to 10% w/w. one or more additional pharmaceutically acceptable excipients. 18. Pharmaceutical preparation according to one or more claims. 14-17, in which the filler is mannitol, the binder is microcrystalline cellulose, the disintegrant is selected from crospovidone, carboxystarch glycolate, carboxymethylcellulose and their salts and derivatives, especially croscarmellose sodium, the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, complex esters of glycerol and fatty acids and sodium stearyl fumarate and/or a glidant selected from colloidal silicon dioxide and its derivatives. 19. Method for obtaining a solid preparation according to one of paragraphs. 1-9, including: (a) mixing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3 -yl)-benzonitrile or a pharmaceutically acceptable salt and excipient thereof; (b) dry granulation of the mixture obtained in step (a) to form a solid preparation. 20. The method according to claim 19, characterized in that in step (a) one or more other pharmaceutically acceptable excipients is added to the mixture. 21. The method according to claim 19 or 20, characterized in that it additionally includes stage (c) of grinding. 22. Method according to one of paragraphs. 19-21, where dry granulation is roller compaction. 23. A method for producing a pharmaceutical preparation, which is a tablet containing a solid preparation according to one of paragraphs. 1-9, including: (a) implementation of the method according to paragraphs. 19, 20, 21 or 22 to form a solid preparation; (b) mixing the solid preparation and one or more pharmaceutically acceptable excipients; (c) tableting the mixture obtained in step (b); And (d) optionally film coating the tablets obtained in step (c). 24. A method for producing a pharmaceutical preparation, which is a capsule containing a solid preparation according to one or more claims. 1-9, including: (a) implementation of the method according to paragraphs. 19, 20, 21 or 22 to form a solid preparation; (b) optionally, mixing the solid preparation and one or more pharmaceutically acceptable excipients; And (c) filling the solid preparation obtained in step (a) or the mixture obtained in step (b) into capsules. 25. Use of a pharmaceutical preparation according to one or more claims. 10-18 in the treatment of cancer, optionally in conjunction with radiation therapy, chemotherapy or immunotherapy or any combination thereof.