1. FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions of selected DPP IV inhibitors, their preparation and their use to treat selected medical conditions.

2. DESCRIPTION OF THE PRIOR ART

The enzyme DPP-IV (dipeptidyl peptidase IV) also known as CD26 is a serine protease known to lead to the cleavage of a dipeptide from the N-terminal end of a number of proteins having at their N-terminal end a prolin or alanin residue. Due to this property DPP-IV inhibitors interfere with the plasma level of bioactive peptides including the peptide GLP-1 and are considered to be promising drugs for the treatment of diabetes mellitus.

DETAILED DESCRIPTION OF THE INVENTION

In attempts to prepare pharmaceutical compositions of selected DPP-IV inhibitors it has been observed, that the DPP-IV inhibitors with a primary or secondary amino group show incompatibilities, degradation problems, or extraction problems with a number of customary excipients such as microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, saccharose, lactose, maltodextrines. Though the compounds themselves are very stable, they react with many excipients used in solid dosage forms and with impurities of excipients, especially in tight contact provided in tablets and at high excipient/drug ratios. The amino group appears to react with reducing sugars and with other reactive carbonyl groups and with carboxylic acid functional groups formed for example at the surface of microcrystalline cellulose by oxidation. These unforeseen difficulties are primarily observed in low dosage ranges which are required due to the surprising potency of the selected inhibitors. Thus, pharmaceutical compositions are required so solve these technical problems associated with the unexpected potency of selected DPP-IV inhibitor compounds.

A pharmaceutical composition according to the present invention is intended for the treatment of to achieve glycemic control in a type 1 or type 2 diabetes mellitus patient and comprises a DPP-IV inhibitor with an amino group, especially a free or primary amino group, as an active ingredient, a first and second diluent, a binder, a disintegrant and a lubricant. An additional disintegrant and an additional glidant are a further option. Additionally the compositions can be used to treat rheumatoid arthritis, obesity and osteoporosis as well as to support allograft transplantation.

Diluents suitable for a pharmaceutical composition according to the invention are cellulose powder, dibasic calciumphosphate anhydrous, dibasic calciumphosphate dihydrate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol. Among those diluents mannitol and pregelatinized starch are preferred.

Diluents preferred as the second diluent are the above mentioned diluents pregelatinized starch and low-substituted hydroxypropylcellulose (L-HPC) which show additional binder properties.

Lubricants suitable for a pharmaceutical composition according to the invention are talc, polyethyleneglycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate. The preferred lubricant is magnesium stearate.

Binders suitable for a pharmaceutical composition according to the invention are copovidone (copolymerisates of vinylpyrrolidon with other vinylderivates), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone), pregelatinized starch, low-substituted hydroxypropylcellulose (L-HPC), copovidone and pregelatinized starch being preferred.

The above mentioned binders pregelatinized starch and L-HPC show additional diluent and disintegrant properties and can also be used as the second diluent or the disintegrant.

Disintegrants suitable for a pharmaceutical composition according to the present invention are corn starch, crospovidone, low-substituted hydroxypropylcellulose (L-HPC) or pregelatinized starch, corn starch being preferred.

As an optional glidant colloidal silicon dioxide can be used.

An exemplary composition according to the present invention comprises the diluent mannitol, pregelatinized starch as a diluent with additional binder properties, the binder copovidone, the disintegrant corn starch, and magnesium stearate as the lubricant.

Dosage forms prepared with a pharmaceutical compositions according to the present invention contain active ingredients in dosage ranges of 0.1-100 mg. Preferred dosages are 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.

Typical pharmaceutical compositions comprise (% by weight)

0.5-20%
active ingredient

40-88%
diluent 1,

3-40%
diluent 2,

1-5%
binder,

5-15%
disintegrant, and

0.1-4%
lubricant.

Preferred pharmaceutical compositions comprise (% by weight)

0.5-7%
active ingredient

50-75%
diluent 1,

5-15%
diluent 2,

2-4%
binder,

8-12%
disintegrant, and

0.5-2%
lubricant

The pharmaceutical compositions according to the invention are intended for oral use and can be used in the dosage form of a capsule, a tablet or a film-coated tablet. Typically the film coat represents 2-4%, preferably 3% of the composition and comprises a film-forming agent, a plasticizer, a glidant and optionally one or more pigments. An exemplary coat composition may comprise hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and optionally iron oxide.

Preferred active ingredients in the context of the present invention are DPP-IV inhibitors with a primary amino group and salts thereof such as any DPP-IV inhibitor and salt thereof defined by formula (I)

[Image Omitted]

or formula (II)

[Image Omitted]

wherein R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl], (quinoxalin-6-yl)methyl, (4-Methyl-quinazolin-2-yl)methyl, 2-Cyano-benzyl, (3-Cyano-quinolin-2-yl)methyl, (3-Cyano-pyridin-2-yl)methyl, (4-Methyl-pyrimidin-2-yl)methyl, or (4,6-Dimethyl-pyrimidin-2-yl)methyl, and R2 is 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino or (2-(S)-amino-propyl)-methylamino.

Preferred DPP IV inhibitor compounds are the following compounds and salts thereof:

- 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (compare WO 2004/018468, example 2(142):

[Image Omitted]

- 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2004/018468, example 2(252)):

[Image Omitted]

- 1-[(Quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2004/018468, example 2(80)):

[Image Omitted]

- 2-((R)-3-Amino-piperidin-1-yl)-3-(but-2-yinyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (compare WO 2004/050658, example 136):

[Image Omitted]

- 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyin-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine (compare WO 2006/029769, example 2(1)):

[Image Omitted]

- 1-[(3-Cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(30)):

[Image Omitted]

- 1-(2-Cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(39)):

[Image Omitted]

- 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine (compare WO 2006/029769, example 2(4)):

[Image Omitted]

- 1-[(3-Cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(52)):

[Image Omitted]

- 1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(81)):

[Image Omitted]

- 1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(82)):

[Image Omitted]

- 1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(83)):

[Image Omitted]

To prepare compositions according to the invention a granulate can be prepared by a wet granulation process. Alternative methods for granulation of active ingredient and excipients with a granulation liquid are fluid bed granulation or one-pot granulation.

In the wet granulation process the granulation liquid is a solvent such as water, ethanol, methanol, isopropanol, acetone, preferably purified water, and contains a binder such as copovidone. The solvent is a volatile component, which does not remain in the final product. The active ingredient and the other excipients with exception of the lubricant are premixed and granulated with the aqueous granulation liquid using a high shear granulator. The wet granulation step is followed by an optional wet sieving step, drying and dry sieving of the granules. For example a fluid bed dryer can then be used for drying.

The dried granules are sieved through an appropriate sieve. After addition of the other excipients with exception of the lubricant the mixture is blended in a suitable conventional blender such as a free fall blender followed by addition of the lubricant such as magnesium stearate and final blending in the blender.

Thus an exemplary wet granulation process for the preparation of a pharmaceutical composition according to the present invention comprises

a. dissolving a binder such as copovidone in a solvent such as purified water at ambient temperature to produce a granulation liquid;

b. blending a DPP-IV inhibitor, a diluent, and a disintegrant in a suitable mixer, to produce a pre-mix;

c. moistening the pre-mix with the granulation liquid and subsequently granulating the moistened pre-mix for example in a high shear mixer;

d. optionally sieving the granulated pre-mix through a sieve with a mesh size of at least 1.0 mm and preferably 3 mm;

e. drying the granulate at about 40-75° C. and preferably 55-65° C. inlet air temperature for example in a fluid bed dryer until the desired loss on drying value in the range of 1-5% is obtained;

f. delumping the dried granulate for example by sieving through a sieve with a mesh size of 0.6 mm-1.6 mm, preferably 1.0 mm; and

g. adding preferably sieved lubricant to the granulate for final blending for example in a cube mixer.

In an alternative process part of the excipients such as part of a disintegrant (e.g. corn starch) or a diluent (e.g. pregelatinized starch) or an additional disintegrant (crospovidone) can be added extragranular prior to final blending of step g.

In another alternative version of the process the granulate produced in steps a to e is produced in a one pot high shear granulation process and subsequent drying in a one pot granulator.

For the preparation of capsules the final blend is further filled into capsules.

For the preparation of tablets or tablet cores the final blend is further compressed into tablets of the target tablet core weight with appropriate size and crushing strength, using an appropriate tablet press.

For the preparation of film-coated tablets a coating suspension is prepared and the compressed tablet cores are coated with the coating suspension to a weight gain of about 2-4%, preferably about 3%, using a standard film coater. The film-coating solvent is a volatile component, which does not remain in the final product. To reduce the required amount of lubricant in the tablets it is an option to use an external lubrication system.

EXAMPLES
Example 1—Formulation for Direct Compression

An active DPP IV inhibitor ingredient with a primary amino group and all other excipients with exception of magnesium stearate are blended in a high shear blender. This pre-mix is sieved through a 1 mm sieve. After addition of magnesium stearate the pre-mix is blended in a free fall blender to produce the final blend. The final blend is compressed into tablets using a suitable tablet press. The following compositions can be obtained:

Component
mg/tablet
%/tablet
mg/tablet
%/tablet

Active ingredient
1.000
2.000
2.500
2.000

Mannitol
43.250
86.500
108.125
86.500

Pregelatinized starch
5.000
10.000
12.500
10.000

Magnesium stearate
0.750
1.500
1.875
1.500

Total
50.000
100.000
125.000
100.000

Component
mg/tablet
%/tablet
mg/tablet
%/tablet

Active ingredient
5.000
2.000
10.000
2.000

Mannitol
216.250
86.500
432.500
86.500

Pregelatinized starch
25.000
10.000
50.000
10.000

Magnesium stearate
3.750
1.500
7.500
1.500

Total
250.000
100.000
500.000
100.000

Example 2—Alternative Formulation for Direct Compression

An active DPP IV inhibitor ingredient with a primary amino group and all other excipients with exception of magnesium stearate are blended in a high shear blender. This pre-mix is sieved through a 1 mm sieve. After addition of magnesium stearate the pre-mix is blended in a free fall blender to produce the final blend. The final blend is compressed into tablets using a suitable tablet press. The following compositions can be obtained:

Component
mg/tablet
%/tablet
mg/tablet
%/tablet

Active ingredient
1.000
1.667
0.500
0.833

Dibasic
46.400
77.333
46.900
78.177

calciumphosphate,

anhydrous

Low-substituted
12.000
20.000
12.000
20.000

hydroxypropylcellulose

Magnesium stearate
0.600
1.000
0.600
1.000

Total
60.000
100.000
60.000
100.000

Component
mg/tablet
%/tablet
mg/tablet
%/tablet

Active ingredient
10.000
1.667
10.000
2.222

Dibasic
464.000
77.333
344.000
76.788

calciumphosphate,

anhydrous

Low-substituted
120.000
20.000
90.000
20.000

hydroxypropylcellulose

Magnesium stearate
6.000
1.000
6.000
1.000

Total
600.000
100.000
450.000
100.000

Example 3—Tablet Formulation

Copovidone is dissolved in purified water at ambient temperature to produce a granulation liquid. An active DPP IV inhibitor ingredient with a primary amino group, mannitol and part of the pregelatinized starch are blended in a suitable mixer, to produce a pre-mix. The pre-mix is moistened with the granulation liquid and subsequently granulated. The moist granulate is optionally sieved through a sieve with a mesh size of 1.6-3.0 mm. The granulate is dried at 55° C. in a suitable dryer to a residual moisture content corresponding to 2-5% loss on drying. The dried granulate is sieved through a sieve with a mesh size of 1.0 mm. The granulate is blended with part of the pregelatinized starch in a suitable mixer. Magnesium stearate is added to this blend after passing through a 1.0 mm sieve for delumping. Subsequently the final blend is produced by final blending in a suitable mixer and compressed into tablets. The following tablet composition can be obtained:

Component
mg/tablet
%/tablet

Active ingredient
10.000
1.667

Pregelatinized starch
210.000
35.000

Mannitol
236.000
39.333

Copovidone
18.000
3.000

Total (granulate)
474.000
79.000

Pregelatinized starch
120.000
20.000

Magnesium stearate
6.000
1.000

Total
600.000
100.000

Example 4—Coated Tablet Formulation

Copovidone is dissolved in purified water at ambient temperature to produce a granulation liquid. An active DPP IV inhibitor ingredient with a primary amino group, mannitol, pregelatinized starch and corn starch are blended in a suitable mixer to produce the pre-mix. The pre-mix is moistened with the granulation liquid and subsequently granulated using a high shear mixer. The moist granulate is optionally sieved through a sieve with a mesh size of 1.6-3.0 mm. The granulate is dried at about 60° C. in a fluid bed dryer until a loss on the drying value of 2-4% is obtained. The Final Blend is compressed into tablet cores.

Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are suspended in purified water in a suitable mixer at ambient temperature to produce a coating suspension. The tablet cores are coated with the coating suspension to a weight gain of about 3% to produce film-coated tablets. The following tablet compositions can be obtained:

Component
mg
mg
mg
mg
mg

Active ingredient
0.500
1.000
2.500
5.000
10.000

Mannitol
67.450
66.950
65.450
130.900
125.900

Pregelatinized starch
9.000
9.000
9.000
18.000
18.000

Corn starch
9.000
9.000
9.000
18.000
18.000

Copovidone
2.700
2.700
2.700
5.400
5.400

Magnesium stearate
1.350
1.350
1.350
2.700
2.700

Total Mass
90.000
90.000
90.000
180.000
180.000

(tablet core)

HPMC
1.500
1.500
1.500
2.500
2.500

PEG
0.150
0.150
0.150
0.250
0.250

Titanium dioxide
0.750
0.750
0.750
1.250
1.250

Talc
0.525
0.525
0.525
0.875
0.875

Iron oxide, yellow
0.075
0.075
0.075
0.125
0.125

Total Mass
93.000
93.000
93.000
185.000
185.000

(coated tablet)

Example 5—Tablet Formulation

Copovidone is dissolved in purified water at ambient temperature to produce a granulation liquid. An active DPP IV inhibitor ingredient with a primary amino group, mannitol and pregelatinized starch are blended in a suitable mixer to produce a pre-mix. The pre-mix is moistened with the granulation liquid and subsequently granulated. The moist granulate is optionally sieved through a suitable sieve. The granulate is dried at about 50° C. in a suitable dryer until a loss on drying value of 3-5% is obtained. The dried granulate is sieved through a sieve with a mesh size of 1.0 mm.

Magnesium stearate is passed through a 1.0 mm sieve and added to the granulate. Subsequently the final blend is produced by final blending in a suitable blender and the final blend is compressed into tablets. The following tablet compositions can be obtained:

Component
mg
mg
mg
mg
mg

Active
0.500
1.000
2.500
5.000
10.000

ingredient

Mannitol
27.500
27.000
67.500
135.000
130.000

Pregelatinized
20.000
20.000
50.000
100.000
100.000

starch

Copovidone
1.500
1.500
3.750
7.500
7.500

Magnesium
0.500
0.500
1.250
2.500
2.500

stearate

Total tablet
50.000
50.000
125.000
250.000
250.000

mass

Example 6—Tablet Formulation Variants

Copovidone is dissolved in purified water at ambient temperature to produce a granulation liquid. An active DPP IV inhibitor ingredient with a primary amino group and a part of mannitol, pregelatinized starch and corn starch are blended in a suitable mixer, to produce a pre-mix. The pre-mix is moistened with the granulation liquid and subsequently granulated. The moist granulate is sieved through a suitable sieve. The granulate is dried at about 60° C. inlet air temperature in a fluid bed dryer until a loss on drying value of 1-4% is obtained. The dried granulate is sieved through a sieve with a mesh size of 1.0 mm.

Magnesium stearate is passed through a sieve for delumping and added to the granulate. Additionally the remaining part of the excipients are added extragranular at this process step. Subsequently the final blend is produced by final blending in a suitable blender and compressed into tablet cores.

Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are suspended in purified water in a suitable mixer at ambient temperature to produce a coating suspension. The tablet cores are coated with the coating suspension to a weight gain of about 3% to produce film-coated tablets. The following formulation variants can be obtained:

Example 6.1—Formulation Variants with Extragranular Excipients

Formulation E
Formulation F

Component
mg/Tablet
%/Tablet
mg/Tablet
%/Tablet

Active ingredient
1.000
1.111
1.000
1.111

Mannitol
23.300
25.889
66.950
74.389

Pregelatinized starch
4.500
5.000
4.500
5.000

Corn starch
4.500
5.000
4.500
5.000

Copovidone
1.350
1.500
2.700
3.000

Total (granulate)
34.650
38.500
79.650
88.500

Corn starch
4.500
5.000
4.500
5.000

Pregelatinized starch
4.500
5.000
4.500
5.000

Mannitol
45.000
50.000

Magnesium stearate
1.350
1.500
1.350
1.500

Total (tablet core)
90.000
100.000
90.000
100.000

Example 6.2—Formulation Variants with Additional Extragranular Disintegrant

Component
mg
mg
mg
mg
mg

Active ingredient
0.500
1.000
2.500
5.000
10.000

Mannitol
67.450
66.950
65.450
130.900
125.900

Pregelatinized starch
9.000
9.000
9.000
18.000
18.000

Corn starch
9.000
9.000
9.000
18.000
18.000

Copovidone
2.700
2.700
2.700
5.400
5.400

Total Mass
88.650
88.650
88.650
177.300
177.300

(granulate)

Magnesium stearate
1.350
1.350
1.350
2.700
2.700

Crospovidone
2.000
2.000
2.000
4.000
4.000

Total Mass
92.000
92.000
92.000
184.000
184.000

(tablet core)

HPMC
1.500
1.500
1.500
2.500
2.500

PEG
0.150
0.150
0.150
0.250
0.250

Titanium dioxide
0.750
0.750
0.750
1.250
1.250

Talc
0.525
0.525
0.525
0.875
0.875

Iron oxide, yellow
0.075
0.075
0.075
0.125
0.125

Total Mass
95.000
95.000
95.000
189.000
189.000

(coated tablet)

Example 6.3—High Dose Formulations D

Component
mg/tablet
%/tablet
mg/tablet
%/tablet

Active ingredient
25.000
27.778
50.000
27.778

Mannitol
40.700
45.222
81.400
45.222

Pregelatinized starch
9.000
10.000
18.000
10.000

Corn starch
9.000
10.000
18.000
10.000

Copovidone
2.700
3.000
5.400
3.000

Total (granulate)
86.400
96.000
172.800
96.000

Crospovidone
2.700
3.000
5.400
3.000

Magnesium stearate
0.900
1.000
1.800
1.000

Total (tablet core)
90.000
100.000
180.000
100.000

Hydroxypropyl
1.500
1.667
2.500
1.389

methylcellulose

Polyethylene glycol
0.150
0.167
0.250
0.139

Titanium dioxide
0.750
0.833
1.250
0.694

Talcum
0.525
0.583
0.875
0.486

Iron oxide yellow
0.075
0.083
0.125
0.069

Total (film-coated tablet)
93.000
103.333
185.000
102.778