111111111111111111111111111111111!!J!!110111,11F1111111111111111111111110111111
`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2008/0107731 Al
`Kohlrausch et al. (cid:9)
`May 8, 2008
`(43) Pub. Date: (cid:9)
`
`(54) DPP IV INHIBITOR FORMULATIONS
`
`(30) (cid:9)
`
`Foreign Application Priority Data
`
`(76) Inventors:
`
`Anj a Kohlrausch, Biberach (DE);
`Patrick Romer, Reinstetten (DE);
`Gerd Seiffert, Baustetten (DE)
`
`Correspondence Address:
`MICHAEL P. MORRIS
`BOEHRINGER INGELHEIM CORPORATION
`900 RIDGEBURY ROAD, P. O. BOX 368
`RIDGEFIELD, CT 06877-0368
`
`(21) Appl. No.: (cid:9)
`
`11/744,701
`
`(22) Filed: (cid:9)
`
`May 4, 2007
`
`May 4, 2006 (EP) (cid:9)
`Publication Classification
`
` 06 009 201
`
`(51) Int. Cl.
`A61K 9/28 (cid:9)
`(2006.01)
`A61K 9/14 (cid:9)
`(2006.01)
`A61K 47/02 (cid:9)
`(2006.01)
`A61K 47/36 (cid:9)
`(2006.01)
`A61K 47/38 (cid:9)
`(2006.01)
`A61K 47/44 (cid:9)
`(2006.01)
` 424/474; 514/769; 514/781; 514/772;
`(52) U.S. Cl. (cid:9)
`514/778; 514/777; 514/772.3; 514/770; 424/489
`ABSTRACT
`
`(57) (cid:9)
`
`The present invention relates to pharmaceutical compositions
`of DPP IV inhibitors with an amino group, their preparation
`and their use to treat diabetes mellitus.
`
`Mylan EX 1011, Page 1
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`US 2008/0107731 Al (cid:9)
`
`May 8, 2008
`
`1
`
`DPP IV INHIBITOR FORMULATIONS
`
`BACKGROUND OF THE INVENTION
`
`[0001] This Application claims priority of EP 06 009 201,
`which is hereby incorporated by reference in its entirety.
`[0002] 1. Field of the Invention
`[0003] The present invention relates to pharmaceutical
`compositions of selected DPP IV inhibitors, their preparation
`and their use to treat selected medical conditions.
`[0004] 2. Description of the Prior Art
`[0005] 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
`
`[0006]
`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, croscar-
`mellose 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 com-
`pounds.
`[0007] 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 ingre-
`dient, 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.
`[0008] Diluents suitable for a pharmaceutical composition
`according to the invention are cellulose powder, dibasic cal-
`ciumphosphate anhydrous, dibasic calciumphosphate dihy-
`drate, erythritol, low substituted hydroxypropyl cellulose,
`mannitol, pregelatinized starch or xylitol. Among those dilu-
`ents mannitol and pregelatinized starch are preferred.
`[0009] Diluents preferred as the second diluent are the
`above mentioned diluents pre-gelatinized starch and low-
`substituted hydroxypropylcellulose (L-HPC) which show
`additional binder properties.
`[0010] Lubricants suitable for a pharmaceutical composi-
`tion according to the invention are talc, polyethyleneglycol,
`
`calcium behenate, calcium stearate, hydrogenated castor oil
`or magnesium stearate. The preferred lubricant is magnesium
`stearate.
`[0011] 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.
`[0012] The above mentioned binders pregelatinized starch
`and L-HPC show additional diluent and disintegrant proper-
`ties and can also be used as the second diluent or the disinte-
`grant.
`[0013] Disintegrants suitable for a pharmaceutical compo-
`sition according to the present invention are corn starch,
`crospovidone, low-substituted hydroxypropylcellulose
`(L-HPC) or pregelatinized starch, corn starch being pre-
`ferred.
`[0014] As an optional glidant colloidal silicon dioxide can
`be used.
`[0015] 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 magne-
`sium stearate as the lubricant.
`[0016] Dosage forms prepared with a pharmaceutical com-
`positions according to the present invention contain active
`ingredients in dosage ranges of 0.1-100 mg. Preferred dos-
`ages are 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.
`[0017] Typical pharmaceutical compositions comprise (%
`by weight)
`
`0.5-20%
`40-88%
`3-40%
`1-5%
`5-15%
`0.1-4%
`
`active ingredient
`diluent 1,
`diluent 2,
`binder,
`disintegrant, and
`lubricant.
`
`[0018] Preferred pharmaceutical compositions comprise
`(% by weight)
`
`0.5-7%
`50-75%
`5-15%
`2-4%
`8-12%
`0.5-2%
`
`active ingredient
`diluent 1,
`diluent 2,
`binder,
`disintegrant, and
`lubricant
`
`[0019] 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 plasti-
`cizer, a glidant and optionally one or more pigments. An
`exemplary coat composition may comprise hydroxypropyl-
`methyl-cellulose (HPMC), polyethylene glycol (PEG), talc,
`titanium dioxide and optionally iron oxide.
`
`Mylan EX 1011, Page 2
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`2
`
`[0020] 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)
`
`[0024] 1-[(Quinazolin-2-yl)methyl]-3-methyl-7-(2-bu-
`tyn-l-y1)-8-((R)-3-amino-piperidin-l-y1)-xanthine
`(compare WO 2004/018468, example 2(80)):
`
`(I)
`
`0
`
`0
`
`or formula (II)
`
`R2
`
`I
`
`N
`
`0
`
`0
`
`N (cid:9)
`
`R2
`
`III ) (cid:9)
`N
`
`wherein R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-
`2-yl)methyl], (quinoxalin-6-yl)methyl, (4-Methyl-quinazo-
`lin-2-yl)methyl, 2-Cyano-benzyl, (3-Cyano-quinolin-2-yl)
`methyl, (cid:9)
`(3-Cyano-pyridin-2-yl)methyl, (cid:9)
`(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-propy1)-methylamino or (2-(S)-amino-propyl)-
`methylamino.
`[0021] Preferred DPP IV inhibitor compounds are the fol-
`lowing compounds and salts thereof:
`[0022] 1- [(4-methyl-quinazolin-2-yl)methyl] -3 -methyl-
`7 -(2-butyn-1 -y1)-8-(3- (R)-amino -piperidin-1 -y1)-xan-
`thine (compare WO 2004/018468, example 2(142):
`
`0
`
`N\
`
`N
`
`N
`
`[0025] 2-((R)-3 -Amino -piperidin-1 -y1)-3 -(but-2 -yiny1)-
`5- (4 -methyl-quinazolin-2 -ylmethyl)-3,5 -dihydro -imi-
`dazo[4,5-d]pyridazin-4-one (compare WO 2004/
`050658, example 136):
`
`N
`
`0
`
`N
`
`I (cid:9)
`N (cid:9)
`
`I
`
`N
`\ (cid:9)
`
`
`
`[0026] 1-[(4-Methyl-quinazolin-2-yl)methyl] -3-me-
`thy1-7-(2-butyin-l-y1)-8-[(2-amino-2-methyl-propyl)-
`methylamino]-xanthine (compare WO 2006/029769,
`example 2(1)):
`
`0 %
`
`N%
`
`N N /
`
`Ni
`N \
`
`°
`
`ON
`
`) N
`N
`
`N
`
`[0027] 1-[(3-Cyano-quinolin-2-yl)methyl]-3-methyl-7-
`(2-butyn-l-y1)-84(R)-3-amino-piperidin-l-y1)-xan-
`thine (compare WO 2005/085246, example 1(30)):
`
`[0023] 1-[([1,5]naphthyridin-2-yl)methyl] -3-methy1-7-
`(2-butyn-l-y1)-84(R)-3-amino-piperidin-l-y1)-xan-
`thine (compare WO 2004/018468, example 2(252)):
`
`N
`II
`
`0
`
`0
`
`ON
`
`N
`
`N vN
`
`N
`
`N
`
`0 (cid:9)
`
`N
`
`N
`
`[0028] 1-(2-Cyano-benzy1)-3-methy1-7-(2-butyn-1-y1)-
`8-((R)-3-amino-piperidin-1-y1)-xanthine (compare WO
`2005/085246, example 1(39)):
`
`Mylan EX 1011, Page 3
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`US 2008/0107731 Al
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`May 8, 2008
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`3
`
`0
`
`N
`
`N\ /
`N
`
`ONN
`
`N
`
`[0029] 1-[(4-Methyl-quinazolin-2-yl)methyl] -3-me-
`
`thy1-7-(2-butyn-l-y1)-8-[(S)-(2-amino-propy1)-methy-
`
`lamino]-xanthine (compare WO 2006/029769, example
`
`2(4)):
`
`0
`
`oN (cid:9)
`
`N/
`)
`N
`
`N
`
`[0030] 1-[(3-Cyano-pyridin-2-y1 )methy1]-3-methy1-7-
`
`(2-butyn-1-y1 )-8-((R)-3-amino-piperidin-l-y1)-xan-
`
`thine (compare WO 2005/085246, example 1(52)):
`
`N
`
`II
`
`0
`
`N
`
`[0031] 1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-
`
`7-(2-butyn-l-y1)-8-((R)-3-amino-piperidin-l-y1)-xan-
`
`thine (compare WO 2005/085246, example 1(81)):
`
`0
`
`N
`
`[0032] 1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-me-
`
`thyl-7-(2-butyn-l-y1)-8-((R)-3-amino-piperidin-l-y1)-
`
`xanthine (compare WO 2005/085246, example 1(82)):
`
`0
`
`N
`
`I >
`(" N N
`
`N/
`
`N
`
`[0033] 1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-bu-
`tyn-l-y1)-8-((R)-3-amino-piperidin-l-y1)-xanthine
`(compare WO 2005/085246, example 1(83)):
`
`0
`
`/
`
`N
`
`[0034] 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.
`[0035]
`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 pre-
`mixed 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.
`[0036] The dried granules are sieved through an appropri-
`ate sieve. After addition of the other excipients with exception
`of the lubricant the mixture is blended in a suitable conven-
`tional blender such as a free fall blender followed by addition
`of the lubricant such as magnesium stearate and final blend-
`ing in the blender.
`[0037] Thus an exemplary wet granulation process for the
`preparation of a pharmaceutical composition according to the
`present invention comprises
`[0038] a. dissolving a binder such as copovidone in a
`solvent such as purified water at ambient temperature to
`produce a granulation liquid;
`[0039] b. blending a DPP-IV inhibitor, a diluent, and a
`disintegrant in a suitable mixer, to produce a pre-mix;
`[0040] c. moistening the pre-mix with the granulation
`liquid and subsequently granulating the moistened pre-
`mix for example in a high shear mixer;
`[0041] d. optionally sieving the granulated pre-mix
`through a sieve with a mesh size of at least 1.0 mm and
`preferably 3 mm;
`[0042] 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;
`
`Mylan EX 1011, Page 4
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`4
`
`[0043] 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
`[0044] g. adding preferably sieved lubricant to the granu-
`late for final blending for example in a cube mixer.
`[0045] In an alternative process part of the exipients such as
`part of a disintegrant (e.g. corn starch) or a diluent (e.g.
`pregelatinized starch) or an additional disintegrant (crospovi-
`done) can be added extragranular prior to final blending of
`step g.
`[0046] In another alternative version of the process the
`granulate produced in steps a toe is produced in a one pot high
`shear granulation process and subsequent drying in a one pot
`granulator.
`[0047] For the preparation of capsules the final blend is
`further filled into capsules.
`[0048] 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.
`[0049] 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
`
`[0050] An active DPP IV inhibitor ingredient with a pri-
`mary 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 com-
`pressed into tablets using a suitable tablet press. The follow-
`ing compositions can be obtained:
`
`Component
`
`mg/tablet
`
`%/tablet
`
`mg/tablet
`
`%/tablet
`
`Active ingredient
`Mannitol
`Pregelatinized starch
`Magnesium stearate
`
`1.000
`43.250
`5.000
`0.750
`
`2.000
`86.500
`10.000
`1.500
`
`2.500
`108.125
`12.500
`1.875
`
`2.000
`86.500
`10.000
`1.500
`
`Total
`
`50.000
`
`100.000
`
`125.000
`
`100.000
`
`Component
`
`mg/tablet
`
`%/tablet
`
`mg/tablet
`
`%/tablet
`
`Active ingredient
`Mannitol
`Pregelatinized starch
`Magnesium stearate
`
`5.000
`216.250
`25.000
`3.750
`
`2.000
`86.500
`10.000
`1.500
`
`10.000
`432.500
`50.000
`7.500
`
`2.000
`86.500
`10.000
`1.500
`
`Total
`
`250.000
`
`100.000
`
`500.000
`
`100.000
`
`Example 2
`
`Alternative Formulation for Direct Compression
`
`[0051] An active DPP IV inhibitor ingredient with a pri-
`mary 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 com-
`pressed into tablets using a suitable tablet press. The follow-
`ing compositions can be obtained:
`
`Component
`
`mg/tablet %/tablet mg/tablet %/tablet
`
`Active ingredient
`Dibasic
`calciumphosphate,
`anhydrous
`Low-substituted
`hydroxypropylcellulose
`Magnesium stearate
`
`1.000
`46.400
`
`1.667
`77.333
`
`0.500
`46.900
`
`0.833
`78.177
`
`12.000
`
`20.000
`
`12.000
`
`20.000
`
`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
`Dibasic
`calciumphosphate,
`anhydrous
`Low-substituted
`hydroxypropylcellulose
`Magnesium stearate
`
`10.000
`464.000
`
`1.667
`77.333
`
`10.000
`344.000
`
`2.222
`76.788
`
`120.000
`
`20.000
`
`90.000
`
`20.000
`
`6.000
`
`1.000
`
`6.000
`
`1.000
`
`Total
`
`600.000
`
`100.000
`
`450.000
`
`100.000
`
`Example 3
`
`Tablet Formulation
`
`[0052] Copovidone is dissolved in purified water at ambi-
`ent 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 moist-
`ened 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:
`
`Mylan EX 1011, Page 5
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`US 2008/0107731 Al (cid:9)
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`5
`
`Component
`
`mg/tablet
`
`%/tablet
`
`Active ingredient
`Pregelatinized starch
`Mannitol
`Copovidone
`
`Total (granulate)
`Pregelatinized starch
`Magnesium stearate
`
`10.000
`210.000
`236.000
`18.000
`
`474.000
`120.000
`6.000
`
`1.667
`35.000
`39.333
`3.000
`
`79.000
`20.000
`1.000
`
`Total
`
`600.000
`
`100.000
`
`Example 4
`
`Coated Tablet Formulation
`
`[0053] Copovidone is dissolved in purified water at ambi-
`ent 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 moist-
`ened 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.
`[0054] Hydroxypropyl methylcellulose, polyethylene gly-
`col, 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 composi-
`tions can be obtained:
`
`Component
`
`mg
`
`mg
`
`mg
`
`mg
`
`mg
`
`Active ingredient
`Mannitol
`Pregelatinized starch
`Corn starch
`Copovidone
`Magnesium stearate
`
`0.500
`67.450
`9.000
`9.000
`2.700
`1.350
`
`1.000
`66.950
`9.000
`9.000
`2.700
`1.350
`
`2.500
`65.450
`9.000
`9.000
`2.700
`1.350
`
`10.000
`5.000
`130.900 125.900
`18.000
`18.000
`18.000
`18.000
`5.400
`5.400
`2.700
`2.700
`
`Total Mass
`(tablet core)
`HPMC
`PEG
`Titanium dioxide
`Talc
`Iron oxide, yellow
`
`Total Mass
`(coated tablet)
`
`90.000
`
`90.000
`
`90.000
`
`180.000 180.000
`
`1.500
`0.150
`0.750
`0.525
`0.075
`
`1.500
`0.150
`0.750
`0.525
`0.075
`
`1.500
`0.150
`0.750
`0.525
`0.075
`
`2.500
`0.250
`1.250
`0.875
`0.125
`
`2.500
`0.250
`1.250
`0.875
`0.125
`
`93.000
`
`93.000
`
`93.000
`
`185.000 185.000
`
`Example 5
`
`Tablet Formulation
`
`[0055] Copovidone is dissolved in purified water at ambi-
`ent 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 granu-
`late is sieved through a sieve with a mesh size of 1.0 mm.
`[0056] 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 ingredient
`Mannitol
`Pregelatinized starch
`Copovidone
`Magnesium stearate
`
`0.500
`27.500
`20.000
`1.500
`0.500
`
`1.000
`27.000
`20.000
`1.500
`0.500
`
`10.000
`5.000
`2.500
`67.500 135.000 130.000
`50.000 100.000 100.000
`3.750
`7.500
`7.500
`1.250
`2.500
`2.500
`
`Total tablet mass
`
`50.000
`
`50.000
`
`125.000
`
`250.000 250.000
`
`Example 6
`
`Tablet Formulation Variants
`
`[0057] Copovidone is dissolved in purified water at ambi-
`ent 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 subse-
`quently 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.
`[0058] Magnesium stearate is passed through a sieve for
`delumping and added to the granulate. Additionally the
`remaining part of the exipients 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.
`[0059] Hydroxypropyl methylcellulose, polyethylene gly-
`col, 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 vari-
`ants can be obtained:
`
`Example 6.1
`
`Formulation Variants with Extragranular Excipients
`
`[0060]
`
`Formulation E (cid:9)
`
`Formulation F
`
`Component (cid:9)
`
`mg/Tablet %/Tablet mg/Tablet %/Tablet
`
`Active ingredient
`Mannitol
`
`1.000 (cid:9)
`23.300 (cid:9)
`
`1.111
`25.889
`
`1.000 (cid:9)
`66.950 (cid:9)
`
`1.111
`74.389
`
`Mylan EX 1011, Page 6
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`US 2008/0107731 Al (cid:9)
`
`May 8, 2008
`
`6
`
`-continued
`
`Formulation E
`
`Formulation F
`
`Component
`
`mg/Tablet %/Tablet mg/Tablet %/Tablet
`
`Pregelatinized starch
`Corn starch
`Copovidone
`
`Total (granulate)
`Corn starch
`Pregelatinized starch
`Mannitol
`Magnesium stearate
`
`4.500
`4.500
`1.350
`
`34.650
`4.500
`4.500
`45.000
`1.350
`
`5.000
`5.000
`1.500
`
`38.500
`5.000
`5.000
`50.000
`1.500
`
`4.500
`4.500
`2.700
`
`79.650
`4.500
`4.500
`
`5.000
`5.000
`3.000
`
`88.500
`5.000
`5.000
`
`1.350
`
`1.500
`
`Total (tablet core)
`
`90.000
`
`100.000
`
`90.000
`
`100.000
`
`Example 6.2
`
`Formulation Variants with Additional Extragranular
`Disintegrant
`
`[0061]
`
`Component
`
`mg
`
`mg
`
`mg
`
`mg
`
`mg
`
`Active ingredient
`Mannitol
`Pregelatinized starch
`Corn starch
`Copovidone
`
`0.500
`67.450
`9.000
`9.000
`2.700
`
`1.000
`66.950
`9.000
`9.000
`2.700
`
`2.500
`65.450
`9.000
`9.000
`2.700
`
`10.000
`5.000
`130.900 125.900
`18.000
`18.000
`18.000
`18.000
`5.400
`5.400
`
`Total Mass
`(granulate)
`Magnesium stearate
`Crospovidone
`
`Total Mass
`(tablet core)
`HPMC
`PEG
`Titanium dioxide
`Talc
`Iron oxide, yellow
`
`Total Mass
`(coated tablet)
`
`88.650
`
`88.650
`
`88.650
`
`177.300 177.300
`
`1.350
`2.000
`
`1.350
`2.000
`
`1.350
`2.000
`
`2.700
`4.000
`
`2.700
`4.000
`
`92.000
`
`92.000
`
`92.000
`
`184.000 184.000
`
`1.500
`0.150
`0.750
`0.525
`0.075
`
`1.500
`0.150
`0.750
`0.525
`0.075
`
`1.500
`0.150
`0.750
`0.525
`0.075
`
`2.500
`0.250
`1.250
`0.875
`0.125
`
`2.500
`0.250
`1.250
`0.875
`0.125
`
`95.000
`
`95.000
`
`95.000
`
`189.000 189.000
`
`Example 6.3
`
`High Dose Formulations D
`
`[0062]
`
`Component
`
`Active ingredient
`Mannitol
`Pregelatinized starch
`Corn starch
`Copovidone
`Total (granulate)
`Crospovidone
`Magnesium stearate
`
`mg/
`tablet %/tablet mg/tablet %/tablet
`
`25.000
`40.700
`9.000
`9.000
`2.700
`86.400
`2.700
`0.900
`
`27.778
`45.222
`10.000
`10.000
`3.000
`96.000
`3.000
`1.000
`
`50.000
`81.400
`18.000
`18.000
`5.400
`172.800
`5.400
`1.800
`
`27.778
`45.222
`10.000
`10.000
`3.000
`96.000
`3.000
`1.000
`
`Total (tablet core)
`Hydroxypropyl methylcellulose
`
`90.000 100.000
`1.500
`1.667
`
`180.000
`2.500
`
`100.000
`1.389
`
`Component
`
`Polyethylene glycol
`Titanium dioxide
`Talcum
`Iron oxide yellow
`
`-continued
`
`mg/
`tablet %/tablet mg/tablet %/tablet
`
`0.150
`0.750
`0.525
`0.075
`
`0.167
`0.833
`0.583
`0.083
`
`0.250
`1.250
`0.875
`0.125
`
`0.139
`0.694
`0.486
`0.069
`
`Total ( film-coated tablet)
`
`93.000 103.333
`
`185.000
`
`102.778
`
`What is claimed is:
`1. A pharmaceutical composition comprising as an active
`ingredient a DPP IV inhibitor compound with an amino group
`or a salt thereof, a first diluent, a second diluent, a binder, a
`disintegrant and a lubricant.
`2. The pharmaceutical composition of claim 1, wherein the
`first and second diluents are independently cellulose powder,
`dibasic calciumphosphate anhydrous, dibasic calciumphos-
`phate dihydrate, erythritol, low substituted hydroxypropyl
`cellulose, mannitol, pregelatinized starch, or xylitol,
`3. The pharmaceutical composition of claim 1, wherein the
`lubricant is talc, polyethyleneglycol, calcium behenate, cal-
`cium stearate, hydrogenated castor oil, or Magnesium stear-
`ate.
`4. The pharmaceutical composition of claim 1, wherein the
`binder is copovidone (copolymerisates of vinylpyrrolidon
`with other vinylderivates), hydroxypropyl methylcellulose
`(HPMC), hydroxypropylcellulose (HPC), or polyvinylpyr-
`rolidon (Povidone).
`5. The pharmaceutical composition of claim 1, wherein the
`disintegrant is corn starch.
`6. The pharmaceutical composition of claim 1, wherein the
`first diluent is mannitol, the second diluent is pregelatinized
`starch, the binder is copovidone, the disintegrant is corn
`starch, and the lubricant is magnesium stearate.
`7. The pharmaceutical composition of claim 1 further com-
`prising an additional disintegrant.
`8. The pharmaceutical composition of claim 7, wherein the
`additional disintegrant is crospovidone.
`9. The pharmaceutical composition of claim 1 further com-
`prising a glidant.
`10. The pharmaceutical composition of claim 9, wherein
`the glidant is colloidal silicon dioxide.
`11. The pharmaceutical composition of claim 1 comprising
`
`0.5-20%
`40-88%
`3-40%
`1-5%
`5-15%
`0.1-4%
`
`active ingredient
`diluent 1,
`diluent 2,
`binder,
`disintegrant, and
`lubricant.
`
`12. The pharmaceutical composition of claim 1 comprising
`
`0.5-7%
`50-75%
`5-15%
`2-4%
`
`active ingredient
`diluent 1,
`diluent 2,
`binder,
`
`Mylan EX 1011, Page 7
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`US 2008/0107731 Al (cid:9)
`
`May 8, 2008
`
`7
`
`-continued
`
`8-12%
`0.5-2%
`
`disintegrant, and
`lubricant
`
`13. The pharmaceutical composition according to claim 1
`in the dosage form of a capsule, a tablet, or a film-coated
`tablet.
`14. The pharmaceutical composition of claim 13 compris-
`ing 2-4% film coat.
`15. The pharmaceutical composition of claim 1, wherein
`the film coat comprises a film-forming agent, a plasticizer, a
`glidant and optionally one or more pigments.
`16. The pharmaceutical composition of claim 15, wherein
`the film coat comprises hydroxypropylmethylcellulose
`(HPMC), polyethylene glycol (PEG), talc, titanium dioxide
`and iron oxide.
`17. A process for the preparation of a pharmaceutical com-
`position according to claim 1 comprising
`a. dissolving a binder in a solvent to produce a granulation
`liquid;
`b. blending a DPP-IV inhibitor, a diluent, and a disintegrant
`to produce a pre-mix;
`
`c. moistening the pre-mix with the granulation liquid and
`subsequently granulating the moistened pre-mix;
`d. optionally sieving the granulated pre-mix through a
`sieve with a mesh size of at least 1.0 mm;
`e. drying the granulate at about 40-75° C. until the desired
`loss on drying value in the range of 1-5% is obtained;
`f. sieving the dried granulate through a sieve with a mesh
`size of at least 0.6 mm;
`g. adding lubricant to the granulate for final blending.
`18. The process according to claim 17 further comprising
`h. compressing the final blend into tablet cores;
`i. preparing a coating suspension;
`j. coating the tablet cores with the coating suspension to a
`weight gain of about 2-4% to produce film-coated tab-
`lets.
`19. The process according to claim 17, wherein part of the
`exipients are added extragranular prior to the final blending of
`step g.
`20. The process according to claim 17, wherein the granu-
`late produced in steps a-e is produced in a one pot high shear
`granulation process and subsequent drying in a one pot
`granulator.
`
`Mylan EX 1011, Page 8
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)