Dpp iv inhibitor formulations

European).

EP 2 023 902 T4

Z-7394/10

Formulations containing DPP-IV inhibitors

Description

The present invention relates to pharmaceutical compositions containing selected DPP IV inhibitors, their preparation and their use for the treatment of selected disease states.

It is known that the enzyme DPP-IV (dipeptidyl peptidase IV) also known as CD26 is a serine protease having the ability to detach the dipeptide from the Nterminal end of many proteins having a proline or alanine residue at this end. Because of this property, DPP-IV inhibitors affect the plasma concentration of bioactive peptides, including GLP-1 peptide, and are therefore considered to be promising drugs for the treatment of diabetes.

During research into the development of pharmaceutical compositions containing selected DPP-IV inhibitors, it was observed that DPP-IV inhibitors containing primary or secondary amino groups behave incompatible with many commonly used excipients such as microcrystalline cellulose, sodium starch glycolate (sodium carboxymethyl starch ether) , croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, sucrose, lactose or maltodextrin, causing degradation or extraction problems. These compounds, although very stable as such, do, however, react with many excipients used to make solid dosage forms, as well as with impurities present in these excipients, especially in direct contact with tablets, and in cases where the excipient / drug ratio is of high value. Amine groups have been shown to react with reducing sugars as well as with other reactive carbonyl groups and with carboxylic acid functional groups formed, for example, on the surface of microcrystalline cellulose by oxidation. These unforeseen problems were noted primarily in the case of low-dose preparations that are required because of the surprising high activity of some inhibitors. Therefore, pharmaceutical compositions are needed to solve technical problems caused by the unexpectedly high activity of some DPP-IV inhibitors.

The pharmaceutical composition of the present invention is intended for administration to provide glycemic regulation in patients with type 1 or type 2 diabetes and contains as active ingredient a DPP-IV inhibitor with an amino group, especially a free or primary amino group, first and second diluents. binding, disintegrating and lubricating agent. Additional disintegrant and additional glidant are another option. The compositions can also be used in the treatment of rheumatoid arthritis, obesity and osteoporosis, as well as adjunct to allogeneic transplants.

Diluents suitable for use in the compositions of the invention include cellulose powder, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch, or xylitol. Of these diluents, mannitol and pre-gelatinized starch are particularly preferred.

Pre-gelatinized starch and low substituted hydroxypropyl cellulose (L-HPC), which additionally have binding properties, are preferred as the second diluent.

Lubricants suitable for use in the pharmaceutical composition of the invention are talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil, or magnesium stearate. Magnesium stearate is a particularly preferred lubricant.

Suitable binders for use in the pharmaceutical composition of the invention are copovidone (copolymerizates of vinylpyrrolidone with other vinyl derivatives), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (povidone), pre-gelatinized starch, low-substituted hydroxy cellulose which copovidone and pre-gelatinized starch are particularly preferred.

Among the binders mentioned above, pregelatinized starch and L10 HPC additionally have the properties of a diluent and disintegrant and can therefore also be used as a second diluent or as a disintegrant.

Disintegrants suitable for use in the pharmaceutical composition of the present invention are corn starch, crospovidone, low substituted hydroxypropyl cellulose (L-HPC), or pregelatinized starch, with corn starch being particularly preferred.

Colloidal silicon dioxide can be used as an optional lubricant.

An exemplary composition of the present invention contains mannitol as a diluent, pregelatinized starch as a second diluent having additional binding properties, copovidone as a binder, corn starch as a disintegrant and magnesium stearate as a lubricant.

Dosage forms prepared from the compositions of the present invention contain active ingredients in doses ranging from 0.1-100 mg. 0.5 mg doses are preferred,

1 mg, 2.5 mg, 5 mg and 10 mg.

Typical pharmaceutical compositions contain (in wt.%)

<td> 0,5-20 %</td><td>active ingredient,</td>

<td> 40 - 88 %</td><td>thinner 1,</td>

<td> 3 - 40 %</td><td>thinner 2,</td>

<td> 1 - 5 %</td><td>binding agent,</td>

<td> 5 - 15 %</td><td>disintegrant and</td>

<td> 0,1 - 4 %</td><td>lubricant.</td>

Preferably the pharmaceutical compositions contain (in wt.%)

<td> 0,5 - 7 %</td><td>active ingredient,</td>

<td> 50 - 75 %</td><td>thinner 1</td>

<td> 5 - 15 %</td><td>thinner 2,</td>

<td> 2 - 4 %</td><td>binding agent,</td>

<td> 8 - 12 %</td><td>disintegrant and</td>

<td> 0,5 - 2 %</td><td>lubricant.</td>

The compositions of the invention are intended for oral use and may be administered in the form of a capsule, tablet, or coated tablet dosage form. Generally, the coating layer is 2-4%, preferably, 3% of the composition and contains a film former, plasticizer, glidant and optionally one or more dyes. An exemplary coating composition may contain hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and optionally iron oxide.

Preferably, the active ingredients in the context of the present invention are DPP-IV inhibitors having primary amine groups and salts thereof such as any DPP-IV inhibitor and its salt represented by formula (I)

<img file="PL2023902T4_D0001.tif" />

or formula (II)

<img file="PL2023902T4_D0002.tif" />

in which R1 is ([1,5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methylquinazolin-2-yl) methyl,

2-cyano-benzyl, (3-cyanoquinolin-2-yl) -methyl, (3-cyanopyridin-2-yl) methyl, (4-methylpyrimidin-2-yl) methyl, or (4,6-dimethylpyrimidin-2 -yl) methyl and R2 is 3- (R) -aminopiperidin-1-yl, (2-amino-2-methylpropyl) methylamino, or (2- (S) -aminopropyl) methylamino.

The following compounds and their salts are preferred as DPP-IV inhibitors:

• 1 - [(4-Methylquinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3 (R) -aminopiperidin-1-yl) xanthine ( compare with example 2 (142) of WO 2004/018468)

<img file="PL2023902T4_D0003.tif" />

• 1 - [([1,5] Naphthyridin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - ((R) -3aminopiperidin-1-yl) - xanthine (compare with example 2 (252) of WO 2004/018468)

<img file="PL2023902T4_D0004.tif" />

• 1 - [(Chinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - ((R) -3aminopiperidin-1-yl) xanthine (compare with an example 2 (80) from WO 2004/018468):

<img file="PL2023902T4_D0005.tif" />

• 2 - ((R) -3-Aminopiperidin-1-yl) -3- (but-2-ynyl) -5- (4-methylquinazolin-2-ylmethyl) -3,5-dihydroimidazo [4,5-d ] pyridazine-4-one (compare with example 136 of WO 2004/050658):

<img file="PL2023902T4_D0006.tif" />

• 1 - [(4-Methylquinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - [(2 amino-2-methylpropyl) methylamino] xanthine (compare with example 2 (1) of WO 2006/029769):

<img file="PL2023902T4_D0007.tif" />

• 1 - [(3-Cyanoquinolin-2-yl) methyl-3-methyl-7- (2-butin-1-yl) -8 - ((R) -3aminopiperidin-1-yl) xanthine (compare with example 1 (30) of WO 2005/085246):

<img file="PL2023902T4_D0008.tif" />

• 1- (2-Cyanobenzyl) -3-methyl-7- (2-butin-1-yl) -8 - ((R) -3aminopiperidin-1-yl) xanthine (compare with example 1 (39) of WO 2005/085246):

<img file="PL2023902T4_D0009.tif" />

• 1 - [(4-Methylquinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - [(S) (2-aminopropyl) methylamino] xanthine ( compare with example 2 (4) of WO 2006/029769):

<img file="PL2023902T4_D0010.tif" />

1 - [(3-Cyanopyridin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - ((R) -3aminopiperidin-1-yl) xanthine (compare with example 1 (52) of WO 2005/085246):

<img file="PL2023902T4_D0011.tif" />

• 1 - [(4-Methylpyrimidin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - ((R) 3-aminopiperidin-1-yl) xanthine (compare with example 1 (81) of WO 2005/085246):

<img file="PL2023902T4_D0012.tif" />

• 1 - [(4,6-Dimethylpyrimidin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 ((R) -3-aminopiperidin-1-yl) - xanthine (compare with example 1 (82) of WO 2005/085246):

<img file="PL2023902T4_D0013.tif" />

• 1 - [(Quinoxalin-6-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - ((R) -3aminopiperidin-1-yl) xanthine (compare with an example 1 (83) from WO 2005/085246):

<img file="PL2023902T4_D0014.tif" />

To prepare a composition according to the invention, granules can be prepared in a wet granulation process. Alternative methods for granulating the active ingredient and excipients with the granulation fluid include fluidized bed granulation, or one tank granulation.

In the wet granulation process, the granulation liquid is a solvent such as water, ethanol, methanol, isopropanol, acetone, preferably purified water, and the liquid contains a binder such as copovidone. The solvent is a volatile component that is no longer present in the final product. The active ingredient and other excipients, with the exception of the lubricant, are premixed and granulated with an aqueous granulation liquid in a fast rotary granulator. The wet granulation step optionally followed by a wet sieving step followed by drying the granules and dry sieving. For example, a fluid bed dryer can be used for drying.

The dried granules are sieved through a suitable screen. After the addition of other excipients, except for the lubricant, the mixture is mixed in a conventional mixer (blender) such as a free fall mixer, followed by the addition of a lubricant such as magnesium stearate, followed by final blending.

Thus, an exemplary wet granulation process to produce the pharmaceutical composition of the present invention includes:

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

b. mixing the DPP-IV inhibitor, diluent and disintegrant in a suitable mixer to produce a premix (premixture);

c. wetting the premix with a granulation liquid and then granulating the wetted premix, for example in a high speed mixer;

d. optionally sieving the granular premix through a mesh size of at least 1.0 mm, preferably 3 mm;

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

f. removing lumps from the dry 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 to the granulate a lubricant, preferably sieved, to carry out final mixing, for example in a cube mixer.

According to an alternative method, part of the excipients, such as part of the disintegrant (e.g., corn starch), or diluent (e.g. pre-gelatinized starch), or an additional disintegrant (crospovidone) in the extragranulated form are added before the final mixing stage g.

According to another alternative version of the method, the granulate prepared in stages a to e is produced by a granulation process in a single hopper high speed granulator and then dried in a single hopper granulator.

To make capsules, the capsules are filled with the final mixture obtained.

To make tablets or tablet cores, the final blend obtained is compressed into tablets with a core weight suitable for the target tablet and of suitable size and crush strength using a suitable tablet press.

To make coated tablets, a coating suspension is prepared and the compressed tablet cores are coated with this suspension to achieve a weight gain of about 2-4%, preferably about 3%, using a standard coating apparatus. The solvent used in the coating is a volatile component and is no longer present in the final product. In order to reduce the necessary content of lubricant in tablets, it is possible to use an external lubricant system.

Examples

Example 1 - Formulation for direct compression

The active ingredient being a DPP IV inhibitor containing a primary amine group and all other excipients, except for magnesium stearate, is mixed in a high speed blender. The premix is ​​sieved through a 1 mm sieve. After the addition of magnesium stearate, the premix is ​​mixed in a freezer blender until the final blend is obtained. The final blend is compressed into tablets using a suitable tablet press. The following compositions can be prepared in this way:

<td>Ingredient</td><td>mg / tablet</td><td>% / Tablet</td><td>mg / tablet</td><td>% / Tablet</td>

<td>Active ingredient</td><td> 1,000</td><td> 2,000</td><td> 2,500</td><td> 2,000</td>

<td>mannitol</td><td> 43,250</td><td> 86,500</td><td> 108,125</td><td> 86,500</td>

<td>Pregelatinized starch</td><td> 5,000</td><td> 10,000</td><td> 12,500</td><td> 10,000</td>

<td>Magnesium stearate</td><td> 0,750</td><td> 1,500</td><td> 1,875</td><td> 1,500</td>

<td>Together</td><td> 50,000</td><td> 100,000</td><td> 125,000</td><td> 100,000</td>

<td>Ingredient</td><td>mg / tablet</td><td>% / Tablet</td><td>mg / tablet</td><td>% / Tablet</td>

<td>Active ingredient</td><td> 5,000</td><td> 2,000</td><td> 10,000</td><td> 2,000</td>

<td>mannitol</td><td> 216,250</td><td> 86,500</td><td> 432,500</td><td> 86,500</td>

<td>Pregelatinized starch</td><td> 25,000</td><td> 10,000</td><td> 50,000</td><td> 10,000</td>

<td>Magnesium stearate</td><td> 3,750</td><td> 1,500</td><td> 7,500</td><td> 1,500</td>

<td>Together</td><td> 250,000</td><td> 100,000</td><td> 500,000</td><td> 100,000</td>

Example 2 - Alternative formulation for direct compression The active ingredient being a DPP IV inhibitor containing a primary amine group and all other excipients, except for magnesium stearate, is mixed in a high speed blender. The premix is ​​sieved through a 1 mm sieve. After the addition of magnesium stearate, the premix is ​​mixed in a blender to free fall to obtain the final blend. The final blend is compressed into tablets using a suitable tablet press. The following compositions can be prepared in this way:

<td>Ingredient</td><td>mg / tablet</td><td>% / Tablet</td><td>mg / tablet</td><td>% / Tablet</td>

<td>Active ingredient</td><td> 1,000</td><td> 1,667</td><td> 0,500</td><td> 0,833</td>

<td>Dibasic calcium phosphate,</td><td></td><td></td><td></td><td></td>

<td>anhydrous</td><td> 46,400</td><td> 77,333</td><td> 46,900</td><td> 78,177</td>

<td>Low substituted</td><td></td><td></td><td></td><td></td>

<td>hydroxypropyl</td><td> 12,000</td><td> 20,000</td><td> 12,000</td><td> 20,000</td>

<td>Magnesium stearate</td><td> 0,600</td><td> 1,000</td><td> 0,600</td><td> 1,000</td>

<td>Together</td><td> 60,000</td><td> 100,000</td><td> 60,000</td><td> 100,000</td>

<td>Ingredient</td><td>mg / tablet</td><td>% / Tablet</td><td>mg / tablet</td><td>% / Tablet</td>

<td>Active ingredient</td><td> 10,000</td><td> 1,667</td><td> 10,000</td><td> 2,222</td>

<td>Dibasic calcium phosphate,</td><td></td><td></td><td></td><td></td>

<td>anhydrous</td><td> 464,000</td><td> 77,333</td><td> 344,000</td><td> 76,788</td>

<td>Low substituted</td><td></td><td></td><td></td><td></td>

<td>hydroxypropyl</td><td> 120,000</td><td> 20,000</td><td> 90,000</td><td> 20,000</td>

<td>Magnesium stearate</td><td> 6,000</td><td> 1,000</td><td> 6,000</td><td> 1,000</td>

<td>Together</td><td> 600,000</td><td> 100,000</td><td> 450,000</td><td> 100,000</td>

Example 3 - Tablet formulation

Copovidone is dissolved in purified water at ambient temperature to prepare the granulation liquid. The active ingredient DPP IV inhibitor containing a primary amine group, mannitol and a portion of pregelatinized starch are mixed in a suitable mixer to form a premixture.

The premix is ​​wetted with a granulation liquid and then granulated.

The wet granulate is optionally sieved through a 1.6-3.0 mm sieve. The granulate is dried at 55 ° C in a suitable dryer until the residual moisture content corresponds to 2-5% loss on drying. The dry granulate is sieved through a 1.0 mm sieve. The granulate is mixed in a suitable mixer with part of the pregelatinized starch. Magnesium stearate is added to the resulting mixture after sieving through a 1.0 mm sieve to remove lumps.

The final blend obtained by final mixing in a suitable mixer is compressed into tablets. You can get tablets with the following composition:

<td>Ingredient</td><td>mg / tablet</td><td>% / Tablet</td>

<td>Active ingredient</td><td> 10,000</td><td> 1,667</td>

<td>Pregelatinized starch</td><td> 210,000</td><td> 35,000</td>

<td>mannitol</td><td> 236,000</td><td> 39,333</td>

<td>copovidone</td><td> 18,000</td><td> 3,000</td>

<td>Total (granules)</td><td> 474,000</td><td> 79,000</td>

<td>Pregelatinized starch</td><td> 120,000</td><td> 20,000</td>

<td>Magnesium stearate</td><td> 6,000</td><td> 1,000</td>

<td>Together</td><td> 600,000</td><td> 100,000</td>

Example 4 - Film-coated tablet formulation

Copovidone is dissolved in purified water at ambient temperature to prepare the granulation liquid. The active ingredient DPP IV inhibitor containing a primary amine group, mannitol, pregelatinized starch and cornstarch are mixed in a suitable mixer to form a premixture. The premix is ​​wetted using a granulation liquid and then granulated in a high speed mixer. The wet granulate is optionally sieved through a 1.6-3.0 mm sieve. The granulate is dried at 60 ° C in a fluid bed dryer until the loss on drying is 2-4%. The final blend is compressed into tablet cores.

To obtain the coating suspension, hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are suspended at ambient temperature in purified water in a suitable mixer. To make coated tablets, the tablet cores are coated with a coating suspension until a weight gain of about 3% is achieved. You can get tablets with the following composition:

<td>Ingredient</td><td>mg</td><td>mg</td><td>mg</td><td>mg</td><td>mg</td>

<td>Active ingredient</td><td> 0,500</td><td> 1,000</td><td> 2,500</td><td> 5,000</td><td> 10,000</td>

<td>mannitol</td><td> 67,450</td><td> 66,950</td><td> 65,450</td><td> 130,900</td><td> 125,900</td>

<td>Pregelatinized starch</td><td> 9,000</td><td> 9,000</td><td> 9,000</td><td> 18,000</td><td> 18,000</td>

<td>Corn starch</td><td> 9,000</td><td> 9,000</td><td> 9,000</td><td> 18,000</td><td> 18,000</td>

<td>copovidone</td><td> 2,700</td><td> 2,700</td><td> 2,700</td><td> 5,400</td><td> 5,400</td>

<td>Magnesium stearate</td><td> 1,350</td><td> 1,350</td><td> 1,350</td><td> 2,700</td><td> 2,700</td>

<td>Total weight (tablet core)</td><td> 90,000</td><td> 90,000</td><td> 90,000</td><td> 180,000</td><td> 180,000</td>

<td>HPMC</td><td> 1,500</td><td> 1,500</td><td> 1,500</td><td> 2,500</td><td> 2,500</td>

<td>PEG</td><td> 0,150</td><td> 0,150</td><td> 0,150</td><td> 0,250</td><td> 0,250</td>

<td>Titanium dioxide</td><td> 0,750</td><td> 0,750</td><td> 0,750</td><td> 1,250</td><td> 1,250</td>

<td>Talc</td><td> 0,525</td><td> 0,525</td><td> 0,525</td><td> 0,875</td><td> 0,875</td>

<td>Iron oxide, yellow</td><td> 0,075</td><td> 0,075</td><td> 0,075</td><td> 0,125</td><td> 0,125</td>

<td>Total weight (coated tablet)</td><td> 93,000</td><td> 93,000</td><td> 93,000</td><td> 185,000</td><td> 185,000</td>

Example 5 - Tablet formulation

Copovidone is dissolved in purified water at ambient temperature to prepare the granulation liquid. The active ingredient being a DPP IV inhibitor containing a primary amine group, mannitol, pregelatinized starch is mixed in a suitable mixer to form a premixture. The premix is ​​wetted with a granulating liquid and then granulated. The wet granulate is optionally sieved through a suitable screen. The granulate is dried at 50 ° C in a suitable dryer until the loss on drying is 3-5%. The dried granulate is sieved through a 1.0 mm sieve

Magnesium stearate is sieved through a 1.0 mm sieve and added to the granulate. As a result of final mixing in a suitable blender, a final blend is prepared, which is compressed into tablets. You can make tablets with the following composition:

<td>Ingredient</td><td>mg</td><td>mg</td><td>mg</td><td>mg</td><td>mg</td>

<td>Active ingredient</td><td> 0,500</td><td> 1,000</td><td> 2,500</td><td> 5,000</td><td> 10,000</td>

<td>mannitol</td><td> 27,500</td><td> 27,000</td><td> 67,500</td><td> 135,000</td><td> 130,000</td>

<td>Pregelatinized starch</td><td> 20,000</td><td> 20,000</td><td> 50,000</td><td> 100,000</td><td> 100,000</td>

<td>copovidone</td><td> 1,500</td><td> 1,500</td><td> 3,750</td><td> 7,500</td><td> 7,500</td>

<td>Magnesium stearate</td><td> 0,500</td><td> 0,500</td><td> 1,250</td><td> 2,500</td><td> 2,500</td>

<td>The total weight of the tablet</td><td> 50,000</td><td> 50,000</td><td> 125,000</td><td> 250,000</td><td> 250,000</td>

Example 6 - Tablet formulation variants

Copovidone is dissolved in purified water at ambient temperature to prepare the granulation liquid. The active ingredient DPP IV inhibitor containing a primary amine group, part of mannitol, pregelatinized starch and cornstarch are mixed in a suitable mixer to form a premixture. The premix is ​​wetted with a granulating liquid and then granulated. The wet granulate is sieved through a suitable screen. The granulate is dried at an inlet air temperature of about 60 ° C in a fluid bed dryer until the loss on drying is 1-4%.

The dried granulate is sieved through a 1.0 mm sieve

Magnesium stearate is sieved through a sieve to remove lumps and then added to the granulate. In addition, the remainder of the excipients in the form of extragranulate are added at this stage of the process. The final blend is prepared by final blending in a suitable blender. This mix is ​​compressed into tablet cores.

To obtain the coating suspension, hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are suspended at ambient temperature in purified water in a suitable mixer. To make coated tablets, the tablet cores are coated with a coating suspension until a weight gain of about 3% is achieved. The following formulation variants can be made:

Example 6.1 - Formulation variants with extragranulated excipients

<td rowspan="2">Ingredient</td><td colspan="2">Formulation E</td><td colspan="2">Formulation F</td>

<td>mg / tablet</td><td>% pills</td><td>mg / tablet</td><td>% pills</td>

<td>Active ingredient</td><td> 1,000</td><td> 1,111</td><td> 1,000</td><td> 1,111</td>

<td>mannitol</td><td> 23,300</td><td> 25,889</td><td> 66,950</td><td> 74,389</td>

<td>Pregelatinized starch</td><td> 4,500</td><td> 5,000</td><td> 4,500</td><td> 5,000</td>

<td>Corn starch</td><td> 4,500</td><td> 5,000</td><td> 4,500</td><td> 5,000</td>

<td>copovidone</td><td> 1,350</td><td> 1,500</td><td> 2,700</td><td> 3,000</td>

<td>Total (granules)</td><td> 34,650</td><td> 38,500</td><td> 79,650</td><td> 88,500</td>

<td>Corn starch</td><td> 4,500</td><td> 5,000</td><td> 4,500</td><td> 5,000</td>

<td>Pregelatinized starch</td><td> 4,500</td><td> 5,000</td><td> 4,500</td><td> 5,000</td>

<td>mannitol</td><td> 45,000</td><td> 50,000</td><td></td><td></td>

<td>Magnesium stearate</td><td> 1,350</td><td> 1,500</td><td> 1,350</td><td> 1,500</td>

<td>Total (tablet core)</td><td> 90,000</td><td> 100,000</td><td> 90,000</td><td> 100,000</td>

Example 6.2 - Formulation variants with an additional extragranulated disintegrant

<td>Ingredient</td><td>mg</td><td>mg</td><td>mg</td><td>mg</td><td>mg</td>

<td>Active ingredient</td><td> 0,500</td><td> 1,000</td><td> 2,500</td><td> 5,000</td><td> 10,000</td>

<td>mannitol</td><td> 67,450</td><td> 66,950</td><td> 65,450</td><td> 130,900</td><td> 125,900</td>

<td>Pregelatinized starch</td><td> 9,000</td><td> 9,000</td><td> 9,000</td><td> 18,000</td><td> 18,000</td>

<td>Corn starch</td><td> 9,000</td><td> 9,000</td><td> 9,000</td><td> 18,000</td><td> 18,000</td>

<td>copovidone</td><td> 2,700</td><td> 2,700</td><td> 2,700</td><td> 5,400</td><td> 5,400</td>

<td>Total weight (granules)</td><td> 88,650</td><td> 88,650</td><td> 88,650</td><td> 177,300</td><td> 177,300</td>

<td>Magnesium stearate</td><td> 1,350</td><td> 1,350</td><td> 1,350</td><td> 2,700</td><td> 2,700</td>

<td>crospovidone</td><td> 2,000</td><td> 2,000</td><td> 2,000</td><td> 4,000</td><td> 4,000</td>

<td>Total weight (tablet core)</td><td> 92,000</td><td> 92,000</td><td> 92,000</td><td> 184,000</td><td> 184,000</td>

<td>HPMC</td><td> 1,500</td><td> 1,500</td><td> 1,500</td><td> 2,500</td><td> 2,500</td>

<td>PEG</td><td> 0,150</td><td> 0,150</td><td> 0,150</td><td> 0,250</td><td> 0,250</td>

<td>Titanium dioxide</td><td> 0,750</td><td> 0,750</td><td> 0,750</td><td> 1,250</td><td> 1,250</td>

<td>Talc</td><td> 0,525</td><td> 0,525</td><td> 0,525</td><td> 0,875</td><td> 0,875</td>

<td>Iron oxide, yellow</td><td> 0,075</td><td> 0,075</td><td> 0,075</td><td> 0,125</td><td> 0,125</td>

<td>Total weight (coated tablet)</td><td> 95,000</td><td> 95,000</td><td> 95,000</td><td> 189,000</td><td> 189,000</td>

Example 6.3 - High dose formulations

<td>Ingredient</td><td>mg / tablet</td><td>% / Tablet</td><td>mg / tablet</td><td>% / Tablet</td>

<td>Active ingredient</td><td> 25,000</td><td> 27,778</td><td> 50,000</td><td> 27,778</td>

<td>mannitol</td><td> 40,700</td><td> 45,222</td><td> 81,400</td><td> 45,222</td>

<td>Pregelatinized starch</td><td> 9,000</td><td> 10,000</td><td> 18,000</td><td> 10,000</td>

<td>Corn starch</td><td> 9,000</td><td> 10,000</td><td> 18,000</td><td> 10,000</td>

<td>Kopo Widoń</td><td> 2,700</td><td> 3,000</td><td> 5,400</td><td> 3,000</td>

<td>Total (granules)</td><td> 86,400</td><td> 96,000</td><td> 172,800</td><td> 96,000</td>

<td>crospovidone</td><td> 2,700</td><td> 3,000</td><td> 5,400</td><td> 3,000</td>

<td>Magnesium stearate</td><td> 0,900</td><td> 1,000</td><td> 1,800</td><td> 1,000</td>

<td>Total (tablet core)</td><td> 90,000</td><td> 100,000</td><td> 180,000</td><td> 100,000</td>

<td>Hydroxy propyl and ethyl acetate</td><td> 1,500</td><td> 1,667</td><td> 2,500</td><td> 1,389</td>

<td>Polyethylene glycol</td><td> 0,150</td><td> 0,167</td><td> 0,250</td><td> 0,139</td>

<td>Titanium dioxide</td><td> 0,750</td><td> 0,833</td><td> 1,250</td><td> 0,694</td>

<td>Talc</td><td> 0,525</td><td> 0,583</td><td> 0,875</td><td> 0,486</td>

<td>Yellow iron oxide</td><td> 0,075</td><td> 0,083</td><td> 0,125</td><td> 0,069</td>

<td>Total (coated tablet)</td><td> 93,000</td><td> 103,333</td><td> 185,000</td><td> 102,778</td>

BOEHRINGER INGELHEIM INTERNATIONAL GMBH, Germany Representative:

EP 2 023 902 T4

Z-7394/10