DPP IV inhibitor formulations

SIGNATURE OF THE APPLICANT

Dr. Maria Rosa Fabara Vera

SIGNATURE OF ATTORNEY

Dr. Maria Rosa Fabara Vera

TECHNICAL MEMORY

DPP IV Inhibitor Formulations

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

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-terminus of a number of proteins that possess a proline residue at their N-terminus. or alanine. Due to this property, DPP-IV inhibitors interfere with the plasma level of bioactive peptides, including the GLP-1 peptide, and are considered promising drugs for the treatment of diabetes mellitus.

In attempts to prepare pharmaceutical compositions of selected DPP-IV inhibitors, DPP-IV inhibitors with a primary or secondary amino group have been found to exhibit incompatibilities, degradation problems, or extraction problems with a number of common excipients, such as microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, sucrose, lactose, and maltodextrins. Although the compounds are themselves very stable, they do react with many excipients used in solid dosage forms and with excipient impurities, especially in the close contact provided in tablets and in high excipient/drug ratios. The amino group appears to react with reducing sugars and other reactive carbonyl groups, as well as with carboxylic acid functional groups formed, for example, on the surface of microcrystalline cellulose by oxidation. These unforeseen difficulties are primarily seen in the low dosage ranges that are required due to the surprising potency of the selected inhibitors. Thus, pharmaceutical compositions are required to overcome these technical problems associated with the unexpected potency of selected DPP-IV inhibitory compounds.

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

Suitable diluents for a pharmaceutical composition according to the invention are powdered cellulose, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol. Among those diluents, the preferred ones are mannitol and pregelatinized starch.

Preferred diluents as second diluents are the aforementioned pregelatinized starch and low substituted hydroxypropyl cellulose (L-HPC) diluents, which exhibit additional binding properties.

Suitable lubricants for a pharmaceutical composition according to the invention are talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate. The preferred lubricant is magnesium stearate.

Suitable binders for a pharmaceutical composition according to the invention are copovidone (copolymers of vinyl pyrrolidone with other vinyl derivatives), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone) (povidone), pregelatinized starch and low substituted hydroxypropyl cellulose. (L-HPC), with copovidone and pregelatinized starch being preferred.

The aforementioned binders pregelatinized starch and L-HPC have additional diluting and disintegrating properties and can also be used as a second diluent or disintegrant.

Suitable disintegrants for a pharmaceutical composition according to the present invention are corn starch, crospovidone, low substituted hydroxypropyl cellulose (L-HPC) or pregelatinized starch, with corn starch being preferred.

Colloidal silicon dioxide may be used as an optional slip agent.

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

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

Typical pharmaceutical compositions comprise (wt%)

0.5-20% active ingredient

40-88% thinner 1,

3-40% thinner 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% thinner 1,

5-15% thinner 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 forms of capsules, tablets or film-coated tablets. Typically, the coating film represents 2-4%, preferably 3%, of the composition, comprising a film-forming agent, a plasticizer, a glidant and optionally one or more pigments. By way of example, a coating composition may comprise hydroxypropyl methyl cellulose (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 inhibitors and salts thereof defined by formula (I)

<img file="ECSP088800A_D0001.tif" />

wherein R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methylquinazolin-2 -¡l)methyl, 2-Cyano-benzyl, (3-cyano-quinol¡n-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl) lo, (4-methylpyrimidin-2-yl)methyl or (4,6-dimethyl-pyrimidin-2-yl)methyl, and R2 is 3-(R)-amino-piperidin-1-yl, ( 2-amino-2-methylpropylj-methylamino or (2-(S)-amino-propyl)-methylamino.

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

• 1 -[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-(ñ)-am¡no-piperid¡n -1-yl)-xanthine (compare WO 2004/018468, example 2(142)):

<img file="ECSP088800A_D0002.tif" />

• 1 -[([1,5] n afti ridi n-2-il)met¡l]-3-met¡l-7-(2-buti η -1 -¡l)-8-((fi) -3-amino-p¡perdin-1-yl)-xanthine (compare WO 2004/018468, example 2(252)):

<img file="ECSP088800A_D0003.tif" />

• 1 -[(quinazolin-2-yl) methyl]-3-methyl I-7-(2-butyn-1 -yl)-8-(( phy)-3-am in o-pi peridin-1 -il)-xant¡na (compare WO 2004/018468, example 2(80)):

<img file="ECSP088800A_D0004.tif" />

• 2-((R)-3-amino-piper¡din-1 -yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5 -dihydroimidazo[4,5-d]pyridazin-4-one (compare WO 2004/050658, example 136):

<img file="ECSP088800A_D0005.tif" />

<img file="ECSP088800A_D0006.tif" />

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

<img file="ECSP088800A_D0007.tif" />

No.

N • 1 -[(3-cyano-quinolin-2-¡l)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((fi)-3-amino-piper din-1-yl)-xanthine (compare WO 2005/085246, example 1(30)):

<img file="ECSP088800A_D0008.tif" />

<img file="ECSP088800A_D0009.tif" />

• 1 -(2-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-am¡no-p¡per¡d¡n-1- il)-xanthine (compare WO 2005/085246, example 1(39)):

<img file="ECSP088800A_D0010.tif" />

<img file="ECSP088800A_D0011.tif" />

• 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)):

<img file="ECSP088800A_D0012.tif" />

<img file="ECSP088800A_D0013.tif" />

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

<img file="ECSP088800A_D0014.tif" />

<img file="ECSP088800A_D0015.tif" />

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

<img file="ECSP088800A_D0016.tif" />

• 1 -[(4,6-dimet¡lp¡r¡m¡d¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1 -yl) -8-((fi)-3-amino-piperdin-1-yl)xanthine (compare WO 2005/085246, example 1(82)):

<img file="ECSP088800A_D0017.tif" />

• 1 -[(qu inoxali n-6-yl) methyl]-3-methyl I-7-(2-butyn-1 -yl)-8-(( phy)-3-am in o-pi peridin-1 -il)-xant¡na (compare WO 2005/085246, example 1(83)):

<img file="ECSP088800A_D0018.tif" />

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

In the wet granulation process the granulation liquid is a solvent, such as water, ethanol, methanol, isopropanol or acetone, preferably being 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 the exception of the lubricant, are premixed and granulated with the aqueous granulating liquid by use of a high shear granulator. The wet granulation step is followed by an optional wet sieving step, followed by drying and dry sieving of the granules. For drying, for example, a fluid bed dryer can then be used.

The dried granules are sieved through a suitable sieve. After the addition of the other excipients, with the exception of the lubricant, the mixture is mixed in a suitable conventional mixer, such as a free fall mixer, followed by the addition of the lubricant, such as magnesium stearate, and the final mixing in the mixer.

Thus, by way of example, a wet granulation process for the preparation of a pharmaceutical composition according to the present invention, comprises

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

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

c. moistening the premix with the granulating liquid and subsequently granulating the wet premix in, for example, a high shear mixer;

d. optionally, sieve the granulated premix through a sieve with a mesh size of at least 1.0 mm and preferably 3 mm;

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

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

g. adding to the granulate a lubricant, preferably sieved, to carry out the final mixing in, for example, a mixing tank.

In an alternative process, a part of the excipients, such as a part of the disintegrant (for example, corn starch) or diluent (for example, pregelatinized starch), or an additional disintegrant (crospovidone), can be added extragranularly, prior to the final mixing of stage g.

In another alternative version of the process, the granulate produced in steps a to e is produced in the vessel used in the high shear granulation process and subsequently dried in the vessel of a granulator.

For the preparation of capsules, the final mixture is subsequently filled into capsules.

For the preparation of tablets or tablet cores, the final blend is subsequently compressed into tablets of the chosen tablet core weight and with suitable size and impact resistance, using a suitable tablet press.

For the preparation of film-coated tablets, a coating suspension is prepared and the compressed cores of the tablets 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, one option is to use an external lubrication system.

examples

Example 1 - Formulation for direct compression

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

<td>Component</td><td>mg/ tablet 0</td><td>%/compress 0</td><td>mg/ tablet 0</td><td>%/compress 0</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>Total</td><td> 50,000</td><td> 100,000</td><td> 125,000</td><td> 100,000</td>

<td>Component</td><td>mg/ tablet</td><td>%/ compressed</td><td>mg/ tablet</td><td>%/ compressed</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>Total</td><td> 250,000</td><td> 100,000</td><td> 500,000</td><td> 100,000</td>

Example 2 - Alternative formulation for direct compression

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

<td>Component</td><td>mg/ tablet 0</td><td>%/compress 0</td><td>mg/ tablet 0</td><td>%/compress 0</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></td><td> 46,400</td><td> 77,333</td><td> 46,900</td><td> 78,177</td>

<td>Anhydrous</td><td></td><td></td><td></td><td></td>

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

<td>low substitution</td><td></td><td></td><td></td><td></td>

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

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

<td>Component</td><td>mg/ tablet 0</td><td>%/compress 0</td><td>mg/ tablet 0</td><td>%/compress 0</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>hydroxypropyl cellulose</td><td> 120,000</td><td> 20,000</td><td> 90,000</td><td> 20,000</td>

<td>low substitution</td><td></td><td></td><td></td><td></td>

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

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

Example 3 - Formulation of tablets

Copovidone is dissolved in purified water at room temperature to produce the granulation liquid. A DPP IV inhibitor active ingredient with a primary amino group, mannitol and a part of the pregelatinized starch are mixed in a suitable mixer in order to produce the premix. The premix is ​​moistened with the granulating liquid and then granulated. The wet granulate is optionally sieved through a sieve with a mesh size of 1.6-3.0 mm. The granulate is dried at a temperature of 55°C in a suitable dryer to a residual moisture content corresponding to a loss of 2-5% during drying. The dried granulate is sieved through a sieve with a mesh size of 1.0 mm. The granules are mixed with a part of the pregelatinized starch in a suitable mixer. Magnesium stearate is added to this mixture after passing through a 1.0 mm sieve to remove lumps. Subsequently, the final blend is produced by final blending in a suitable mixer and subjected to pressure to form tablets. The following composition of tablets can be obtained:

<td>Component</td><td>mg/tablet</td><td>%/compressed</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>Whole (granulated)</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>Total</td><td> 600,000</td><td> 100,000</td>

Example 4 - Formulation of coated tablets

Copovidone is dissolved in purified water at room temperature to produce the granulation liquid. A DPP IV inhibitor active ingredient with a primary amino group, mannitol, pregelatinized starch and corn starch are mixed in a suitable mixer to produce the premix. The premix is ​​moistened with the granulating liquid and then granulated using a high shear mixer. The wet granulate is optionally sieved through a sieve with a mesh size of 1.6-3.0 mm. The granulate is dried at a temperature of approximately 60 °C in a fluid bed dryer until a loss in drying value of 2-4% is obtained. The Final Blend is subjected to pressure to form the cores of the tablets.

To form the coating suspension, hydroxypropyl methyl cellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are slurried in purified water, in a suitable mixer and at room temperature. The tablet cores are coated with the coating suspension to a weight of about 3% to produce film-coated tablets. The following tablet compositions can be obtained:

<td>Component</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>Cornstarch</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 mass (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>talcum powder</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 Mass (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 - Formulation of tablets

Copovidone is dissolved in purified water at room temperature to produce the granulation liquid. A DPP IV inhibitor active ingredient with a primary amino group, mannitol and pregelatinized starch are mixed in a suitable mixer in order to produce the premix. The premix is ​​moistened with the granulating liquid and then granulated. The wet granulate is optionally sieved through a suitable sieve. The granulate is dried at a temperature of about 50⁹C in a suitable dryer until obtaining a loss in the drying value of 35%. 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 mixer and the final blend is pressed into tablets. The following tablet compositions can be obtained:

<td>Component</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>Total mass 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 - Variants of the tablet formulation

Copovidone is dissolved in purified water at room temperature to produce the granulation liquid. A DPP IV inhibitor active ingredient with a primary amino group and a part of the mannitol, pregelatinized starch and corn starch are mixed in a suitable mixer to produce the premix. The premix is ​​moistened with the granulating liquid and then granulated. The wet granulate is sieved through a suitable sieve. The granulate is dried at an air inlet temperature of approximately 60°C in a fluid bed dryer until a loss in drying value of 1-4% is obtained. The dried granulate is sieved through a sieve with a mesh size of 1.0 mm.

The magnesium stearate is passed through a sieve to remove lumps and added to the granulate. Additionally, the remaining part of the excipients is added in an extragranular way at this stage of the process. Subsequently, the final blend is produced by final blending in a suitable mixer and subjected to pressure to form tablet cores.

To form the coating suspension, hydroxypropyl methyl cellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are slurried in purified water, in a suitable mixer and at room temperature. The tablet cores are coated with the coating suspension to a weight of about 3% to produce film-coated tablets. The following variants of the formulation can be obtained:

Example 6.1 - Variants of the formulation with extragranular excipients

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

<td>mg/ tablet</td><td>%/ Compressed</td><td>mg/ tablet</td><td>%/ Compressed</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>Cornstarch</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>Whole (granulated)</td><td> 34,650</td><td> 38,500</td><td> 79,650</td><td> 88,500</td>

<td>Cornstarch</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 - Variants of the formulation with an additional extragranular disintegrant

<td>Component</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>Cornstarch</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 mass (granulate)</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 mass (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>talcum powder</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 Mass (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 Dosage Formulations D

<td>Component</td><td>mg/ tablet 0</td><td>%/compress 0</td><td>mg/ tablet 0</td><td>%/compress 0</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>Cornstarch</td><td> 9,000</td><td> 10,000</td><td> 18,000</td><td> 10,000</td>

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

<td>Whole (granulated)</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>Hydroxypropyl methyl cellulose</td><td> 1,500</td><td> 1,667</td><td> 2,500</td><td> 1,389</td>

<td>Poly(ethylene 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>talcum powder</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 (film-coated tablet)</td><td> 93,000</td><td> 103,333</td><td> 185,000</td><td> 102,778</td>

CLAIMS