DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation

• US 9,415,016 B2
• Filed: 08/27/2015
• Issued: 08/16/2016
• Est. Priority Date: 04/03/2008
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Egusa, Kenji, Friedl, Thomas, Braun, Michael, Fujita, Hikaru, Maruyama, Megumi, Nishioka, Takaaki
• Primary Examiner(s): Arnold, Ernst V
• Assistant Examiner(s): Chang, Kyung Sook
• Application Number:
  US14/836,996
• Publication Number:
  US 20150366812A1
• Time in Patent Office: 355 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61K 9/2813 Inorganic compounds
• CPC Class Codes: A61K 9/282 Organic compounds, e.g. fats
• CPC Class Codes: A61K 9/2866 : Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to pharmaceutical compositions comprising fixed dose combinations of a DPP-4 inhibitor drug and a partner drug, processes for the preparation thereof, and their use to treat certain diseases.

Claims

1. A pharmaceutical composition comprising or made from:

(a) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in a dosage of 2.5 mg or 5 mg,

(b) metformin hydrochloride,

(c) one or more pharmaceutical excipients, and

(d) a basic amino acid having an intramolecular amino group and alkaline characteristics, which basic amino acid is present in an amount sufficient to suppress degradation of said 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,

wherein the pharmaceutical composition is a tablet comprising a film-coat; and

wherein the pharmaceutical composition comprises the following amounts (% by weight of total coated tablet mass);

0.1-0.5% of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, and 47-85% of metformin hydrochloride.

2. The pharmaceutical composition according to claim 1, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is stabilized against chemical degradation.

3. The pharmaceutical composition according to claim 1, wherein the basic amino acid having an intramolecular amino group and alkaline characteristics is selected from L-arginine, L-lysine and L-histidine.

4. The pharmaceutical composition according to claim 1, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is present in a dosage strength of 5 mg.

5. The pharmaceutical composition according to claim 1, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is present in a dosage strength of 2.5 mg.

6. The pharmaceutical composition according to claim 1, wherein metformin hydrochloride is present in a dosage range from about 100 mg to about 1500 mg.

7. The pharmaceutical composition according to claim 6, wherein metformin hydrochloride is present in a dosage strength of 250, 500, 625, 750, 850, or 1000 mg.

8. The pharmaceutical composition according to claim 6, wherein metformin hydrochloride is present in a dosage strength of 500 mg, 850 mg, or 1000 mg.

9. The pharmaceutical composition according to claim 1, wherein the basic amino acid having an intramolecular amino group and alkaline characteristics is L-arginine.

10. The pharmaceutical composition according to claim 9, wherein L-arginine is present from about 1 mg to about 25 mg.

11. The pharmaceutical composition according to claim 9, wherein L-arginine is present from about 1 mg to about 50 mg.

12. The pharmaceutical composition according to claim 9, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine and L-arginine are present in a weight ratio from about 1:

20 to about 10;

1.

13. The pharmaceutical composition according to claim 9, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine and L-arginine are present in a weight ratio from about 1:

15 to about 10;

1.

14. The pharmaceutical composition according to claim 9, wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine and L-arginine are present in a weight ratio from about 1:

10 to about 10;

1.

15. The pharmaceutical composition according to claim 1, wherein the excipients are selected from the group consisting of one or more fillers, a binder, a lubricant, and a glidant.

16. The pharmaceutical composition according to claim 1, comprising copovidone as binder.

17. The pharmaceutical composition according to claim 16, further comprising one or more of the following:

the filler corn starch, the lubricant magnesium stearate, and the glidant colloidal anhydrous silica.

18. The pharmaceutical composition according to claim 1, wherein the tablet is a mono-layer tablet.

19. The pharmaceutical composition according to claim 1, wherein the film-coat comprises a film-coating agent, a plasticizer, optionally a glidant, and optionally one or more pigments.

20. The pharmaceutical composition according to claim 1, in which the pharmaceutical composition is a mono-layer tablet, wherein one or more of the following applies:

the percentage of metformin hydrochloride is about 85% by weight of total tablet core,

the percentage of DPP-4 inhibitor is about 0.2%-0.4% by weight of total tablet core,

the percentage of L-arginine is about 2% by weight of total tablet core,

the tablet crushing strength is higher than or equal 100 N,

the tablet friability is lower than or equal 0.5%,

the tablet thickness is from about 5.7 to about 8.4 mm,

the tablet core weight is from about 590 to about 1180 mg, and

the tablet disintegration time is lower than or equal 15 minutes.

21. The pharmaceutical composition according to claim 1, which is an immediate release dosage form, characterized in that in a dissolution test after 45 minutes at least 75% by weight of each of the active ingredients is dissolved.

24. The pharmaceutical composition according to claim 1 comprising the active ingredients in a dosage strength of 2.5 mg of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine and 500 mg of metformin hydrochloride.

25. The pharmaceutical composition according to claim 1 comprising the active ingredients in a dosage strength of 2.5 mg of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine and 850 mg of metformin hydrochloride.

26. The pharmaceutical composition according to claim 1 comprising the active ingredients in a dosage strength of 2.5 mg of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine and 1000 mg of metformin hydrochloride.

27. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises the following amount (% by weight of total coated tablet mass):

0.07-2.2% of L-arginine.

22. A solid pharmaceutical composition which is a mono-layer tablet comprising:

1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in a dosage of 2.5 mg,

metformin hydrochloride,

L-arginine in an amount sufficient to suppress degradation of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, and

one or more fillers and one or more binders,

wherein the percentage of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is about 0.2%-0.4% by weight of total tablet core.

23. The solid pharmaceutical composition according to claim 22, further comprising one or more glidants and/or one or more lubricants.