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, a method of making same, and medical uses thereof.

Claims

1) 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 pharmaceutical 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 its pharmaceutical acceptable salt is present from 20 to 80% (w/w) based upon the total weight of the solid preparation.

2) A 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 sulphate, phosphate, mesylate, besylate, tosylate, fumarate, monohydrochloride monohydrate or maleate, preferably monohydrochloride monohydrate.

3) A 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 has a mean particle size that is characterized by a d50 value in the range from 5 μm to 80 μm, preferably from 5 μm to 50 μm and more preferably from 5 μm to 25 μm.

4) A solid preparation according to claim 1, wherein the filler is a sugar, a sugar alcohol or dicalcium phosphate.

5) A solid preparation according to claim 4, wherein the filler is a sugar alcohol, whereby the sugar alcohol is sorbitol and/or mannitol, preferably mannitol.

6) A solid preparation according to claim 1, wherein the solid preparation further comprises a binder.

7) A solid preparation according to claim 6, wherein the binder is polyvinylpyrrolidone, polyvinyl acetate, a vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, a starch paste such as maize starch paste, or a cellulose derivative such as hydroxypropyl methylcellulose, hydroxypropyl cellulose or microcrystalline cellulose, preferably microcrystalline cellulose.

8) A solid preparation according to claim 1, wherein the solid formulation further comprises a lubricant.

9) A solid preparation according to claim 8, wherein the lubricant is sodium stearyl fumarate, esters of glycerol with fatty acids, stearic acid, or pharmaceutically acceptable salts of stearic acid and divalent cations, preferably magnesium stearate.

10) A solid preparation according to claim 1, wherein the solid preparation has a mean particle size that 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.

11) A pharmaceutical preparation comprising the solid preparation according to claim 1.

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

13) A pharmaceutical preparation according to claim 11, which is an immediate release preparation.

14) A pharmaceutical preparation according to claim 11, which is a capsule comprising the solid preparation and optionally one or more pharmaceutically acceptable excipients.

15) A pharmaceutical preparation according to claim 14, which is a capsule, which contains 40 to 100% (w/w) of the solid preparation; and 0 to 60% (w/w) of at least one pharmaceutically acceptable excipient, preferably selected from a filler, a glidant, a disintegrant and a lubricant, based upon the total weight of all material contained in the capsule.

16) A pharmaceutical preparation according to claim 11, which is a tablet and which in addition to the pharmaceutically acceptable excipients present in the solid preparation optionally comprises one or more pharmaceutically acceptable excipient selected from a filler, a disintegrant, a glidant and a lubricant.

17) A pharmaceutical preparation according to claim 16, which is a tablet comprising the solid preparation and optionally further excipients, which tablet, based upon its total weight, comprises: i) 20 to 80% (w/w) 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 pharmaceutical acceptable salt thereof; ii) 10 to 70% (w/w) of a filler; iii) 0 to 20% (w/w) of a binder; iv) 0 to 20% (w/w) of disintegrant; v) 0 to 5% (w/w) of a lubricant; vi) 0 to 7.5% (w/w) of glidant; and vii) a total of 0 to 20% (w/w) of one or more additional pharmaceutically acceptable excipients.

18) A pharmaceutical preparation according to claim 16, which is a tablet comprising the solid preparation and optionally further excipients, which tablet based upon its total weight comprises: i) 30 to 70% (w/w) 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 pharmaceutical acceptable salt thereof; ii) 20 to 60% (w/w) of a filler; iii) 0 to 10% (w/w) of a binder; iv) 0.25 to 10% (w/w) of disintegrant; v) 0 to 4% (w/w) of a lubricant; vi) 0 to 5% (w/w) of a glidant; and vii) a total of 0 to 10% (w/w) of one or more additional pharmaceutically acceptable excipients.

19) A pharmaceutical preparation according to claim 16, which is a tablet comprising: i) 35 to 60% (w/w) 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 pharmaceutical acceptable salt thereof; ii) 40 to 60% (w/w) of a filler; iii) 0 to 5% (w/w) of a binder; iv) 0.5 to 5% (w/w) of disintegrant; v) 0.25 to 3% (w/w) of a lubricant; vi) 0 to 2% (w/w) of a glidant; and vii) a total of 0 to 10% (w/w) of one or more additional pharmaceutically acceptable excipients.

20) A pharmaceutical preparation according to claim 16, wherein the filler is mannitol, the binder is microcrystalline cellulose, the disintegrant is selected from crospovidone, carboxy starch glycolate, carboxymethylcellulose and salts and derivatives thereof, especially croscarmellose sodium, the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, glycerol fatty acid esters and sodium stearyl fumarate and/or the glidant is selected from colloidal silicon dioxide and derivatives thereof.

21) A method for preparing the solid preparation according to claim 1, the method comprising dry granulating.

22) The method for preparing the solid preparation according to claim 21, the method comprising: (a) mixing 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutical acceptable salt thereof and a filler and optionally one or more further pharmaceutically acceptable excipient; (b) dry granulating the mixture prepared by step (a) to form the solid preparation; and (c) optionally milling.

23) A method for preparing the solid preparation according to claim 21, wherein dry granulating is roller compacting.

24) A method for preparing a pharmaceutical preparation, which is a tablet, comprising a solid preparation according to claim 1, comprising (a) dry granulating to form the solid preparation; (b) mixing the solid preparation and one or more pharmaceutically acceptable excipients; (c) tableting the mixture prepared by step (b); and (d) optionally film coating of the tablets prepared by step (c).

25) A method for preparing a pharmaceutical preparation, which is a capsule, comprising a solid preparation according to claim 1, comprising (a) dry granulating to form the solid preparation; (b) optionally mixing the solid preparation and one or more pharmaceutically acceptable excipient; and (c) filling the solid preparation prepared by step (a) or the mixture prepared by step (b) into capsules.

26) A method for use in the treatment of cancer optionally together with radiotherapy, comprising administering to a host in need thereof an effective amount of a pharmaceutical preparation according to claim 11.

27) The method according to claim 26, wherein the treatment further comprises chemotherapy.

28) The method according to claim 26, wherein the treatment further comprises immunotherapy.

Description

DETAILED DESCRIPTION OF THE INVENTION

Brief Description of the Figures

[0108] FIG. 1 shows dissolution curves for formulation prototypes (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-dihydro-pyridazin-3-yl)-benzonitrile. Dissolution conditions are the following: 900 mL acetate buffer of pH=4.5 with 5 mmol/L sodium chloride and 0.1% Tween 80 using a paddle apparatus with 75 rpm at 37° C.

[0109] FIG. 2 shows dissolution curves of the examples 12-19 in the dissolution medium acetate buffer pH 4.5+3 mmol/NaCl+0.1% Tween showing satisfying dissolution. Example 12: filled circles; Example 13: open circles; Example 14: filled triangles; Example 15: open triangles; Example 16: filled squares; Example 17: open squares; filled rhombus: Example 18; open rhombus: Example 19.

[0110] FIG. 3 shows the comparison of 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (black dots) with corn starch (open dots) regarding its elastic properties.

[0111] FIG. 4. shows the comparison of 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile with different pharmaceutically used fillers. 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-dihydro-pyridazin-3-yl)-benzonitrile.

PREFORMULATION EXAMPLES

Examples Assessing Wet Granulation Techniques

Example A)

[0112] Example A (open triangles in FIG. 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%), Crospovidone (3.76%) are manufactured by a high-shear granulation process. Afterwards, the resulting granules are sieved over 1.0 mm sieve and subsequently blended with Crospovidone (2.35%), povidone 25 (1.41%), magnesium stearate (0.94%), talcum (0.94%) and silicon dioxide (0.47%) and processed to tablets on a single punch press with a resistance to crushing of approx. 125 N, a disintegration time of <10 minutes and a total weight of approx. 645 mg.

Example B)

[0113] Example B (filled circles in FIG. 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%) has been manufactured by a high-shear granulation process. Afterwards, the resulting granules were sieved over 1.0 mm sieve and subsequently blended with carboxymethyl starch sodium (1.93%), magnesium stearate (0.97%) and silicon dioxide (0.48%) and processed to tablets on a single punch press with a resistance to crushing of approx. 144 N, a disintegration time of <8 minutes and a total weight of approx. 259 mg.

Example C)

[0114] Example C (filled triangles in FIG. 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%) has been manufactured by fluid bed granulation process a person skilled in the art would choose. Afterwards, the resulting granules were sieved over 0.8 mm sieve and subsequently blended with pregelatinized starch (9.89%), magnesium stearate (0.99%), carboxymethyl starch sodium (2.47%) and silicon dioxide (0.49%) and processed to tablets on a single punch press. Afterwards, the tablets were coated using a commercially available preformulated film-coating mixture based on polyvinyl alcohol, with the coating being present to 1.13% in the whole formulation. Resulting tablets showed a resistance to crushing of approx. 159 N, a disintegration time of <6 minutes and a total weight of approx. 755 mg.

Example D)

[0115] Example D (open circles in FIG. 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%) has been manufactured by fluid bed granulation process a person skilled in the art would choose.

[0116] Afterwards, the resulting granules were sieved over 0.8 mm sieve and subsequently blended with starch 1500 (9.89%), magnesium stearate (0.99%), carboxymethyl starch sodium (1.98%) and silicon dioxide (0.49%) and processed to tablets on a single punch press to tablet cores of approx. 741.8 mg.

[0117] Afterwards, the tablets were coated using a commercially available preformulated film-coating mixture based on polyvinylalcohol, with the coating being present to 1.13% in the whole formulation. Resulting tablets showed a resistance to crushing of approx. 159 N, a disintegration time of <6 minutes and a total weight of approx. 750 mg.

[0118] As can be seen from FIG. 1 the tablets that are manufactured with granulates that are prepared by high shear granulation (Examples A and B) do not show satisfying in-vitro release properties. Further, tablets that are manufactured with granulates that are prepared by fluid bed granulation (Examples C and D) show better in-vitro release properties than the high shear granulation prototypes (Examples A and B) but they are limited in their maximum achievable drug load.

Examples Assessing the Material Property Young's Modulus

[0119] Young's modulus is assessed as an indicator for material stiffness (the higher Young's modulus, the more rigid a substance is) whereby its measurement is done in dependence of the solid fraction, which is complementary to porosity (i.e. solid fraction=1−porosity fraction). With this, a solid fraction of 1 indicates no porosity, i.e. no air entrapped in the solid phase. Pharmaceutical relevant solid fractions usually range from 0.75 to 0.85. Porosities have been determined by nitrogen pycnometry.

[0120] The measurements to determine the Young's modulus are conducted on a commercially available instrumented single punch press (Romaco Kilian StylOne system) with ultrasound-assisted measurement punches. For this purpose, neat substances are compacted between the upper and the lower punch, leading to densification of the material. The ultrasound velocity in the sample in dependence of the degree of densification is recorded and used for calculation of Youngs modulus of the specific substance.

[0121] For this investigation, following neat materials are selected:

TABLE-US-00001 Example Material E 3-(1-{3-[5-(1-Methyl-piperidin-4- ylmethoxy)-pyrimidin-2-yl]-benzyl}- 6-oxo-1,6-dihydro-pyridazin-3-yl)- benzonitrile F Corn starch G dicalcium phosphate H Mannitol I Lactose

[0122] As can be seen in FIG. 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) shows similar properties as corn starch (open dots), a substance which is known for its high elasticity and therewith unfavorable compression properties. Furthermore, FIG. 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 distinct lower Young's moduli compared to widely used pharmaceutical fillers (dicalcium phosphate, mannitol and lactose),

Formulation Examples

Example E

[0123] Exemplary Solid Preparation Formulations

[0124] D.sub.50 values are recorded as described above and are in the range of 70-530 μm.

[0125] Bulk densities are determined using a 100 mL beaker according to DIN 53468.

Example 1

[0126] The ingredients are weighed (batch size of 103.2 kg) and sieved through a 1.0 mm sieve. The blend is produced by mixing all ingredients except magnesium stearate in a commercially available bin blender (e.g. Servolift) for 15 min with 12 rpm. The magnesium stearate is added afterwards and the whole mixture is blended again for 5 min with 12 rpm. The mixture is transferred afterwards to a roller compactor for manufacturing of the solid preparation. The roller compactor (Gerteis Macropactor) is run with the following settings: Compaction force 12 kN/cm, gap width 2.5 mm, roll speed 3.0 rpm. The resulting granules are sieved through a 0.8 mm sieve.

Example 2

[0127] The ingredients are weighed (batch size of 2.4 kg) and sieved through a 1.0 mm sieve except for magnesium stearate. The blend is produced by mixing all ingredients except magnesium stearate in a commercially available Turbula T50A blender for 15 min with. The magnesium stearate is sieved over 0.5 mm and is added afterwards to the mixture, which is then blended again for 5 min. The mixture is transferred afterwards to a roller compactor for manufacturing of the solid preparation. The roller compactor (Alexanderwerk WP120P) is run with the following settings: Compaction force 4.0 kN/cm, gap width 1.0 mm, roll speed 4.0 rpm. The resulting granules are sieved through a 1.0 mm sieve.

Examples 3-8

[0128] The ingredients are weighed (batch size of 1.0 kg) and sieved through a 1.0 mm sieve. The blend is produced by mixing all ingredients in a commercially available Servolift bin blender for 15 min with 12 rpm. The mixture is transferred afterwards to a roller compactor for manufacturing of the solid preparation. The roller compactor (Gerteis Minipactor) is run with the following settings: Compaction force 3.0 kN/cm, gap width 3.0 mm, roll speed 3.0 rpm. The resulting granules are sieved through a 1.0 mm sieve.

Example 9

[0129] The ingredients are weighed (batch size of 33.2 kg) and sieved through a 1.0 mm sieve. The blend is produced by mixing all ingredients in a commercially available Servolift bin blender for 15 min with 12 rpm. The mixture is transferred afterwards to a roller compactor for manufacturing of the solid preparation. The roller compactor (Gerteis Macropactor) is run with the following settings: Compaction force 4.5 kN/cm, gap width 3.0 mm, roll speed 3.0 rpm. The resulting granules are sieved through a 0.8 mm sieve.

TABLE-US-00002 Solid Bulk preparation % density # Composition (w/w) [g/cm.sup.3] 1 Solid preparation consisting of 0.63 3-(1-{3-[5-(1-Methyl-piperidin-4- 52.08 ylmethoxy)-pyrimidin-2-yl]-benzyl}- 6-oxo-1,6-dihydro-pyridazin-3-yl)- benzonitrile Mannitol (Parteck M100) 44.42 Silicon dioxide (Aerosil 200) 2.00 Crospovidone (Kollidon CL SF) 1.00 Mg.-stearate 0.50 2 Solid preparation consisting of 0.65 3-(1-{3-[5-(1-Methyl-piperidin-4- 70.0 ylmethoxy)-pyrimidin-2-yl]-benzyl}- 6-oxo-1,6-dihydro-pyridazin-3-yl)- benzonitrile Mannitol (Parteck M100) 28.0 Silicon dioxide (Aerosil 200) 0.5 Crospovidone (Kollidon CL SF) 1.0 Mg.-stearate 0.5 3 Solid preparation consisting of 0.60 3-(1-{3-[5-(1-Methyl-piperidin-4- 31.6 ylmethoxy)-pyrimidin-2-yl]-benzyl}- 6-oxo-1,6-dihydro-pyridazin-3-yl)- benzonitrile Mannitol (Parteck M100) 66.9 Crospovidone (Kollidon CL SF) 1.0 Mg.-stearate 0.5 4 Solid preparation consisting of 0.61 3-(1-{3-[5-(1-Methyl-piperidin-4- 31.6 ylmethoxy)-pyrimidin-2-yl]-benzyl}- 6-oxo-1,6-dihydro-pyridazin-3-yl)- benzonitrile Lactose (SuperTab 30GR) 66.9 Crospovidone (Kollidon CL SF) 1.0 Mg.-stearate 0.5 5 Solid preparation consisting of 0.59 3-(1-{3-[5-(1-Methyl-piperidin-4- 31.6 ylmethoxy)-pyrimidin-2-yl]-benzyl}- 6-oxo-1,6-dihydro-pyridazin-3-yl)- benzonitrile Isomalt (Galeniq IQ 721) 66.9 Crospovidone (Kollidon CL SF) 1.0 Mg.-stearate 0.5 6 Solid preparation consisting of 0.59 3-(1-{3-[5-(1-Methyl-piperidin-4- 37.5 ylmethoxy)-pyrimidin-2-yl]-benzyl}- 6-oxo-1,6-dihydro-pyridazin-3-yl)- benzonitrile Mannitol (Parteck M100) 56.0 Crospovidone (Kollidon CL SF) 1.0 Mg.-stearate 0.5 Microcrystalline Cellulose (Type 5.0 101) 7 Solid preparation consisting of 0.63 3-(1-{3-[5-(1-Methyl-piperidin-4- 37.5 ylmethoxy)-pyrimidin-2-yl]-benzyl}- 6-oxo-1,6-dihydro-pyridazin-3-yl)- benzonitrile Lactose (SuperTab 30GR) 56.0 Crospovidone (Kollidon CL SF) 1.0 Mg.-stearate 0.5 Microcrystalline Cellulose (Type 5.0 101) 8 Solid preparation consisting of 0.61 3-(1-{3-[5-(1-Methyl-piperidin-4- 37.5 ylmethoxy)-pyrimidin-2-yl]-benzyl}- 6-oxo-1,6-dihydro-pyridazin-3-yl)- benzonitrile Isomalt (Galeniq IQ 721) 56.0 Crospovidone (Kollidon CL SF) 1.0 Mg.-stearate 0.5 Microcrystalline Cellulose (Type 5.0 101) 9 Solid preparation consisting of 0.56 3-(1-{3-[5-(1-Methyl-piperidin-4- 37.5 ylmethoxy)-pyrimidin-2-yl]-benzyl}- 6-oxo-1,6-dihydro-pyridazin-3-yl)- benzonitrile Mannitol (Parteck M100) 55.8 Crospovidone (Kollidon CL SF) 1.2 Microcrystalline Cellulose (Type 5.0 101) Mg.-stearate 0.5

[0130] Exemplary Tablet Formulations

[0131] Disintegration and friability test are described in the European Pharmacopoeia, Version 9.8, sections 2.9.1 (Disintegration) and section 2.9.7 (Friability of uncoated tablets).

Example 10

[0132] The solid preparation from Example 1 is blended for 15 min with the Crospovidone. The magnesium stearate is added afterwards and the whole mixture is blended again for 5 min with 12 rpm. The whole mixture is tableted with a rotary tablet press, utilizing 18.8×9.2 mm punches, a pre-compression force of 1.6 kN and a main compression force of 17.1 kN at a tableting speed of 20000 units/hours.

Example 11

[0133] The solid preparation from Example 2 is blended for 10 min with the ingredients. The whole mixture is tableted with a single punch press, utilizing 18×8 mm punches and compression force of 12 kN at a tableting speed of 1860 units/hours. Values for disintegration time and friability are for a resistance to crushing of 100 N.

Example 12

[0134] The solid preparation from Example 3 is blended for 15 min at 12 rpm with all ingredients. The whole mixture is tableted with a single punch press utilizing 19×9 mm punches and compression force of 15 kN at a tableting speed of 1500 units/hours. Values for disintegration time and friability are for a resistance to crushing of 150 N.

Example 13

[0135] The solid preparation from Example 4 is blended for 15 min at 12 rpm with all ingredients. The whole mixture is tableted with a single punch press utilizing 19×9 mm punches and compression force of 21 kN at a tableting speed of 2460 units/hours. Values for disintegration time and friability are for a resistance to crushing of 110 N.

Example 14

[0136] The solid preparation from Example 5 is blended for 15 min at 12 rpm with all ingredients. The whole mixture is tableted with a single punch press utilizing 19×9 mm punches and compression force of 17 kN at a tableting speed of 2520 units/hours. Values for disintegration time and friability are for a resistance to crushing of 160 N.

Example 15

[0137] The solid preparation from Example 6 is blended for 15 min at 12 rpm with all ingredients. The whole mixture is tableted with a single punch press utilizing 19×9 mm punches and compression force of 17 kN at a tableting speed of 2460 units/hours. Values for disintegration time and friability are for a resistance to crushing of 150 N.

Example 16

[0138] The solid preparation from Example 7 is blended for 15 min at 12 rpm with all ingredients. The whole mixture is tableted with a single punch press utilizing 19×9 mm punches and compression force of 17 kN at a tableting speed of 2460 units/hours. Values for disintegration time and friability are for a resistance to crushing of 110 N.

Example 17

[0139] The solid preparation from Example 8 is blended for 15 min at 12 rpm with all ingredients. The whole mixture is tableted with a single punch press utilizing 19×9 mm punches and compression force of 17 kN at a tableting speed of 2460 units/hours. Values for disintegration time and friability are for a resistance to crushing of 150 N.

Example 18

[0140] The solid preparation from Example 6 is blended for 15 min at 12 rpm with all ingredients. The whole mixture is tableted with a single punch press utilizing 19×9 mm punches and compression force of 15 kN at a tableting speed of 2460 units/hours. Values for disintegration time and friability are for a resistance to crushing of 165 N.

Example 19

[0141] The solid preparation from Example 8 is blended for 15 min at 12 rpm with all ingredients. The whole mixture is tableted with a single punch press utilizing 19×9 mm punches and compression force of 15 kN at a tableting speed of 2460 units/hours. Values for disintegration time and friability are for a resistance to crushing of 170 N.

Example 20

[0142] The solid preparation from Example 7 is blended for 15 min at 12 rpm with all ingredients. The whole mixture is tableted with a single punch press utilizing 19×9 mm punches and compression force of 17 kN at a tableting speed of 2460 units/hours. Values for disintegration time and friability are for a resistance to crushing of 150 N.

Example 21

[0143] The solid preparation from Example 9 is blended for 15 min at 12 rpm with all ingredients. The whole mixture is tableted with a rotary tablet press, utilizing 18×9 mm punches, a pre-compression force of 5.0 kN and a main compression force of 13.0 kN at a tableting speed of 30000 units/hours.

TABLE-US-00003 Example/ Disinte- Fria- Formu- % gration bility lation # Composition (w/w) time [s] [%] 10 Solid preparation as listed 96.00 64 0.16 in example #1 Crospovidone (Kollidon 2.00 CL SF) Mg.-stearate 2.00 Solid preparation compressed to tablets and subsequently coated 11 Solid preparation as listed 98.5 94 0.28 in example #2 Silicon dioxide (Aerosil 0.5 200) Mg.-stearate 1.0 Solid preparation compressed to tablets, potentially coated 12 Solid preparation as listed 95.0 51 0.11 in example #3 Crospovidone (Kollidon 2.0 CL SF) Mg.-stearate 2.0 Silicon dioxide (Aerosil 1.0 200) 13 Solid preparation as listed 95.0 42 0.20 in example #4 Crospovidone (Kollidon 2.0 CL SF) Mg.-stearate 2.0 Silicon dioxide (Aerosil 1.0 200) 14 Solid preparation as listed 95.0 337 0.13 in example #5 Crospovidone (Kollidon 2.0 CL SF) Mg.-stearate 2.0 Silicon dioxide (Aerosil 1.0 200) 15 Solid preparation as listed 95.0 49 0.13 in example #6 Crospovidone (Kollidon 2.0 CL SF) Mg.-stearate 2.0 Silicon dioxide (Aerosil 1.0 200) 16 Solid preparation as listed 95.0 41 0.22 in example #7 Crospovidone (Kollidon 2.0 CL SF) Mg.-stearate 2.0 Silicon dioxide (Aerosil 1.0 200) 17 Solid preparation as listed 95.0 302 0.13 in example #8 Crospovidone (Kollidon 2.0 CL SF) Mg.-stearate 2.0 Silicon dioxide (Aerosil 1.0 200) 18 Solid preparation as listed 80.0 66 0.12 in example #6 Mannitol (Parteck M200) 10.0 Crospovidone (Kollidon 2.0 CL SF) Mg.-stearate 2.0 Silicon dioxide (Aerosil 1.0 200) Microcrystalline Cellulose 5.0 (Type 102) 19 Solid preparation as listed 80.0 345 0.11 in example #8 Isomalt (Galeniq IQ 721) 10.0 Crospovidone (Kollidon 2.0 CL SF) Mg.-stearate 2.0 Silicon dioxide (Aerosil 1.0 200) Microcrystalline Cellulose 5.0 (Type 102) 20 Solid preparation as listed 80.0 n.a. n.a. in example #7 Lactose (Tablettose 100) 10.0 Crospovidone (Kollidon 2.0 CL SF) Mg.-stearate 2.0 Silicon dioxide (Aerosil 1.0 200) Microcrystalline Cellulose 5.0 (Type 102) 21 Solid preparation as listed 85.0 80 0.08 in example #9 Mannitol (Parteck M 200) 10.0 Crospovidone (Kollidon 2.0 CL SF) Silicon dioxide (Aerosil 1.0 200) Mg.-stearate 2.0

[0144] Exemplary Capsule Formulations

[0145] Disintegration test is described in the European Pharmacopoeia, Version 9.8, sections 2.9.1 (Disintegration).

Example 22: Exemplary Capsule Formulations

[0146] HPMC capsules containing the different solid preparations from examples 1-9 are prepared by mixing such preparations with the further excipients as depicted below and filling such mixtures into the capsule shells. The disintegration of the capsule formulations is below 9 minutes.

TABLE-US-00004 Example/ Formulation # Composition % (w/w) 22 Solid preparation as described in the 98.75 examples 1-9 Silicon dioxide (Aerosil 200) 1 Magnesium stearate 0.25