Pharmaceutical preparation
The present invention relates to a solid pharmaceutical preparation of 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile, a method of making same, and medical uses thereof.
1. A composite comprising a solid dispersion of 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile, or a pharmaceutically acceptable salt thereof, in a polymeric matrix,
wherein the polymeric matrix comprises hydroxypropyl methylcellulose acetate succinate and/or cellulose acetate phthalate.
2. The composite according to claim 1 , wherein the solid dispersion is a solid solution.
3. The composite according to claim 1 , wherein 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile is present in the polymeric matrix in a range of from 4 to 50 percent (w/w), based upon the total weight of the composite.
4. The composite according to claim 1 , wherein the composite has a mean particle size characterized by a d 50 value in the range from 1 μm to 300 μm.
5. A granulate comprising the composite according to claim 1 , wherein the granulate has a particle size characterized by a d 50 vlue of 1000 μm or less.
6. A pharmaceutical preparation comprising the composite according to claim 1 .
7. The pharmaceutical preparation according to claim 6 , which is a pharmaceutical preparation for oral administration.
8. The pharmaceutical preparation according to claim 6 , which is an immediate release preparation.
9. The pharmaceutical preparation according to claim 6 , which is a capsule comprising the composite and optionally one or more pharmaceutically acceptable excipients.
10. The pharmaceutical preparation according to claim 9 , which contains 40 to 100% (w/w) of the composite; and 0 to 60% (w/w) of at least one pharmaceutically acceptable excipient, based upon the total weight of all material contained in the capsule.
11. The pharmaceutical preparation according to claim 6 , which is a tablet comprising optionally one or more pharmaceutically acceptable excipient selected from a filler, a disintegrant, a glidant and a lubricant.
12. The pharmaceutical preparation according to claim 11 , which comprises:
25 to 100% (w/w) of the composite;
0 to 45% (w/w) of a filler;
0 to 20% (w/w) of disintegrant;
0 to 5% (w/w) of a lubricant;
0 to 7,5% (w/w) of glidant; and
a total of 0 to 20% (w/w) of one or more additional pharmaceutically acceptable excipients,
based upon the total weight of the tablet.
13. The pharmaceutical preparation according to claim 11 , which comprises:
60 to 80% (w/w) of the composite;
10 to 30% (w/w) of a filler;
4 to 15% (w/w) of disintegrant;
0 to 3% (w/w) of a lubricant;
0 to 5% (w/w) of a glidant; and
a total of 0 to 10% (w/w) of one or more additional pharmaceutically acceptable excipients,
based upon the total weight of the tablet.
14. The pharmaceutical preparation according to claim 11 , which comprises:
65 to 75% (w/w) of the composite;
15 to 25% (w/w) of a filler;
5 to 10% (w/w) of disintegrant;
0.25 to 2% (w/w) of a lubricant;
0.5 to 2% (w/w) of a glidant; and
a total of 0 to 10% (w/w) of one or more additional pharmaceutically acceptable excipients,
based upon the total weight of the tablet.
15. The pharmaceutical preparation according to claim 11 , wherein the filler is selected from lactose and/or microcrystalline cellulose, the disintegrant is selected from crospovidone, carboxymethylcellulose and salts and derivatives thereof, 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.
16. A method for preparing the composite according to claim 1 , the method comprising: spray-drying, co-precipitation or lyophilization.
17. A method for preparing the composite according to claim 1 , the method comprising:
(a) dissolving 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile and the polymer of the polymeric matrix to be formed, and optionally one or more pharmaceutically acceptable excipient in a solvent to form a solution,
(b) spray-drying the solution to form the composite, and
(c) optionally drying the composite.
18. A method for preparing a pharmaceutical preparation, which is a tablet, comprising
(a) conducting the method according to claim 16 to form the composite;
(b) optionally granulating a mixture of the composite and one or more pharmaceutically acceptable excipients;
(c) mixing the composite and one or more pharmaceutically acceptable excipients;
(d) tableting the mixture prepared by (b) or the granulate prepared by (c); and
(e) optionally film coating of the tablets prepared by (d).
19. A method for preparing a pharmaceutical preparation, which is a capsule, comprising
(a) conducting the method according to claim 16 to form the composite;
(b) optionally mixing the composite and one or more pharmaceutically acceptable excipient and optionally granulating the mixture obtained;
(c) filling the mixture or granulate prepared by (b) or the composite prepared by (a) into capsules.
20. A method of treating cancer comprising administering to a subject in need thereof the pharmaceutical preparation according to claim 6 , optionally together with radiotherapy.
21. The method according to claim 20 , wherein the treatment further comprises chemotherapy.
22. The composite according to claim 1 , wherein 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile is present in the polymeric matrix in a range of from 10 to 30 percent (w/w), based upon the total weight of the composite.
23. The composite according to claim 1 , wherein 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile is present in the polymeric matrix in a range of from 15 to 25 percent (w/w) based upon the total weight of the composite.
24. The composite according to claim 1 , wherein the composite has a mean particle size that is characterized by a d 50 value in the range from 20 μm to 200 μm.
25. A granulate comprising the composite according to claim 1 , wherein the granulate has a particle size that is characterized by a d 50 value of 500 μm or less.