Pharmaceutical preparation

Patent metadata

Field	Value
Publication number	US-11478459-B2
Application number	US-201816637822-A
Country	US
Kind code	B2
Filing date	Aug 8, 2018
Priority date	Aug 11, 2017
Publication date	Oct 25, 2022
Grant date	Oct 25, 2022

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Merck Patent Gmbh

Inventors

• Geissler Simon
• Schiller Stefan
• Harms Meike
• Kubas Holger
• Weigandt Markus
• Lange Michael

Classifications

• A61K9/1641

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers · CPC title

• A61K9/0053 Primary

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K9/2027

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• A61K9/1652

  Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623) · CPC title

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title