U.S. patent application number 13/230133 was filed with the patent office on 2012-01-05 for dpp iv inhibitor formulations.
This patent application is currently assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH. Invention is credited to Anja KOHLRAUSCH, Patrick ROMER, Gerd SEIFFERT.
Application Number | 20120003313 13/230133 |
Document ID | / |
Family ID | 36972901 |
Filed Date | 2012-01-05 |
United States Patent
Application |
20120003313 |
Kind Code |
A1 |
KOHLRAUSCH; Anja ; et
al. |
January 5, 2012 |
DPP IV INHIBITOR FORMULATIONS
Abstract
The present invention relates to pharmaceutical compositions of
DPP IV inhibitors with an amino group, their preparation and their
use to treat diabetes mellitus.
Inventors: |
KOHLRAUSCH; Anja; (Biberach
an der Riss, DE) ; ROMER; Patrick; (Ochsenhausen,
DE) ; SEIFFERT; Gerd; (Laupheim, DE) |
Assignee: |
BOEHRINGER INGELHEIM INTERNATIONAL
GMBH
Ingelheim am Rhein
DE
|
Family ID: |
36972901 |
Appl. No.: |
13/230133 |
Filed: |
September 12, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11744701 |
May 4, 2007 |
|
|
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13230133 |
|
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Current U.S.
Class: |
424/480 ; 264/6;
424/474; 514/263.21 |
Current CPC
Class: |
A61K 9/2059 20130101;
A61K 9/28 20130101; A61K 31/517 20130101; A61K 31/522 20130101;
A61K 9/2077 20130101; A61P 3/10 20180101; A61K 9/2054 20130101;
A61K 9/2013 20130101; A61P 3/00 20180101; A61P 3/04 20180101; A61P
3/06 20180101; A61P 19/02 20180101; A61K 9/0053 20130101; A61K
9/2866 20130101; A61P 29/00 20180101; A61K 9/2813 20130101; A61P
37/06 20180101; A61K 9/2009 20130101; A61K 9/2853 20130101; A61K
9/2893 20130101; A61K 9/2027 20130101; A61P 19/10 20180101; A61P
43/00 20180101 |
Class at
Publication: |
424/480 ; 264/6;
424/474; 514/263.21 |
International
Class: |
A61K 9/36 20060101
A61K009/36; A61P 43/00 20060101 A61P043/00; A61K 31/52 20060101
A61K031/52; B29B 9/16 20060101 B29B009/16; A61K 9/28 20060101
A61K009/28 |
Foreign Application Data
Date |
Code |
Application Number |
May 4, 2006 |
EP |
06009201 |
Claims
1. A pharmaceutical composition comprising as an active ingredient
a DPP IV inhibitor compound of formula ##STR00015## in an amount of
0.5 mg, 1 mg, 2.5 mg, 5 mg or 10 mg, or a salt thereof, a first
diluent, a second diluent, a binder, a disintegrant and a
lubricant, 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; and wherein the DPP IV inhibitor compound is present in
an amount 0.5-20% based on the total weight of DPP IV inhibitor
compound, first diluent, second diluent, binder, disintegrant and
lubricant.
2. The pharmaceutical composition of claim 1 further comprising an
additional disintegrant.
3. The pharmaceutical composition of claim 2, wherein the
additional disintegrant is crospovidone.
4. The pharmaceutical composition of claim 1 further comprising a
glidant.
5. The pharmaceutical composition of claim 4, wherein the glidant
is colloidal silicon dioxide.
6. The pharmaceutical composition of claim 1 comprising
TABLE-US-00013 40-88% diluent 1, 3-40% diluent 2, 1-5% binder,
5-15% disintegrant, and 0.1-4% lubricant
7. The pharmaceutical composition of claim 1 comprising
TABLE-US-00014 0.5-7% active ingredient 50-75% diluent 1, 5-15%
diluent 2, .sup. 2-4% binder, 8-12% disintegrant, and 0.5-2%
lubricant
8. The pharmaceutical composition according to claim 1 in the
dosage form of a capsule, a tablet, or a film-coated tablet.
9. The pharmaceutical composition of claim 8 comprising 2-4% film
coat.
10. The pharmaceutical composition of claim 9, wherein the film
coat comprises a film-forming agent, a plasticizer, a glidant and
optionally one or more pigments.
11. The pharmaceutical composition of claim 10, wherein the film
coat comprises hydroxypropylmethylcellulose (HPMC), polyethylene
glycol (PEG), talc, titanium dioxide and iron oxide.
12. A process for the preparation of a pharmaceutical composition
according to claim 1 comprising a. dissolving the binder in a
solvent to produce a granulation liquid; b. blending the DPP-IV
inhibitor, a diluent, and the 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.degree. 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 the lubricant to the granulate for final
blending.
13. The process according to claim 12 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
tablets.
14. The process according to claim 12, wherein part of the
excipients are added extragranular prior to the final blending of
step g.
15. The process according to claim 12, wherein the granulate
produced in steps a-e is produced in a one pot high shear
granulation process and subsequent drying in a one pot
granulator.
16. The pharmaceutical composition according to claim 1, wherein
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine is comprised in an amount of 5
mg.
17. The pharmaceutical composition according to claim 16 in the
form of a capsule, a tablet, or a film-coated tablet.
18. The pharmaceutical composition of claim 16, wherein the
composition is in the form of a film-coated tablet, and wherein the
film coat comprise 2-4% wt % based the weight of the uncoated
tablet.
19. The pharmaceutical composition of claim 18, wherein the film
coat comprises a film-forming agent, a plasticizer, a glidant and
optionally one or more pigments.
20. The pharmaceutical composition of claim 19, wherein the film
coat comprises hydroxypropylmethylcellulose (HPMC), polyethylene
glycol (PEG), talc, titanium dioxide and iron oxide.
21. The pharmaceutical composition according to claim 16, which is
an oral dosage form in the form of a tablet.
22. The pharmaceutical composition according to claim 16, which is
an oral dosage form in form of a film-coated tablet.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 11/744,701, filed May 4, 2007, which claims priority of EP 06
009 201, filed Mary 4, 2006, each of which is hereby incorporated
by reference in its entirety.
1. FIELD OF THE INVENTION
[0002] 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
[0003] 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
[0004] 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.
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] 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.
[0011] 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.
[0012] As an optional glidant colloidal silicon dioxide can be
used.
[0013] 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.
[0014] 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.
[0015] Typical pharmaceutical compositions comprise (% by
weight)
TABLE-US-00001 0.5-20%.sup. active ingredient 40-88% diluent 1,
3-40% diluent 2, 1-5% binder, 5-15% disintegrant, and 0.1-4%
lubricant.
[0016] Preferred pharmaceutical compositions comprise (% by
weight)
TABLE-US-00002 0.5-7% active ingredient 50-75% diluent 1, 5-15%
diluent 2, .sup. 2-4% binder, 8-12% disintegrant, and 0.5-2%
lubricant
[0017] 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
hydroxypropylmethyl-cellulose (HPMC), polyethylene glycol (PEG),
talc, titanium dioxide and optionally iron oxide.
[0018] 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)
##STR00001##
or formula (II)
##STR00002##
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.
[0019] Preferred DPP IV inhibitor compounds are the following
compounds and salts thereof: [0020]
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine (compare WO 2004/018468, example
2(142):
[0020] ##STR00003## [0021]
1-[([1,5]naphthyridin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amin-
o-piperidin-1-yl)-xanthine (compare WO 2004/018468, example
2(252)):
[0021] ##STR00004## [0022]
1-[(Quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piper-
idin-1-yl)-xanthine (compare WO 2004/018468, example 2(80)):
[0022] ##STR00005## [0023]
2-((R)-3-Amino-piperidin-1-yl)-3-(but-2-yinyl)-5-(4-methyl-quinazolin-2-y-
lmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (compare WO
2004/050658, example 136):
[0023] ##STR00006## [0024]
1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyln-1-yl)-8-[(2-ami-
no-2-methyl-propyl)-methylamino]-xanthine (compare WO 2006/029769,
example 2(1)):
[0024] ##STR00007## [0025]
1-[(3-Cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amin-
o-piperidin-1-yl)-xanthine (compare WO 2005/085246, example
1(30)):
[0025] ##STR00008## [0026]
1-(2-Cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-y-
l)-xanthine (compare WO 2005/085246, example 1(39)):
[0026] ##STR00009## [0027]
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)):
[0027] ##STR00010## [0028]
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)):
[0028] ##STR00011## [0029]
1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-am-
ino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example
1(81)):
[0029] ##STR00012## [0030]
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)):
[0030] ##STR00013## [0031]
1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-pipe-
ridin-1-yl)-xanthine (compare WO 2005/085246, example 1(83)):
##STR00014##
[0032] 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.
[0033] 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.
[0034] 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.
[0035] Thus an exemplary wet granulation process for the
preparation of a pharmaceutical composition according to the
present invention comprises [0036] a. dissolving a binder such as
copovidone in a solvent such as purified water at ambient
temperature to produce a granulation liquid; [0037] b. blending a
DPP-IV inhibitor, a diluent, and a disintegrant in a suitable
mixer, to produce a pre-mix; [0038] c. moistening the pre-mix with
the granulation liquid and subsequently granulating the moistened
pre-mix for example in a high shear mixer; [0039] d. optionally
sieving the granulated pre-mix through a sieve with a mesh size of
at least 1.0 mm and preferably 3 mm; [0040] e. drying the granulate
at about 40-75.degree. C. and preferably 55-65.degree. 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; [0041] 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
[0042] g. adding preferably sieved lubricant to the granulate for
final blending for example in a cube mixer.
[0043] 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 (crospovidone)
can be added extragranular prior to final blending of step g.
[0044] 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.
[0045] For the preparation of capsules the final blend is further
filled into capsules.
[0046] 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.
[0047] 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
[0048] 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:
TABLE-US-00003 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
TABLE-US-00004 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
[0049] 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:
TABLE-US-00005 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
TABLE-US-00006 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
[0050] 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.degree. 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:
TABLE-US-00007 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
[0051] 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.degree. 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.
[0052] 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:
TABLE-US-00008 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
[0053] 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.degree. 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.
[0054] 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:
TABLE-US-00009 Component mg mg mg mg mg Active ingredient 0.500
1.000 2.500 5.000 10.000 Mannitol 27.500 27.000 67.500 135.000
130.000 Pregelatinized starch 20.000 20.000 50.000 100.000 100.000
Copovidone 1.500 1.500 3.750 7.500 7.500 Magnesium stearate 0.500
0.500 1.250 2.500 2.500 Total tablet mass 50.000 50.000 125.000
250.000 250.000
Example 6
Tablet Formulation Variants
[0055] 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.degree. 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.
[0056] 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.
[0057] 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
TABLE-US-00010 [0058] 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
TABLE-US-00011 [0059] 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
TABLE-US-00012 [0060] 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 93.000 103.333 185.000 102.778
(film-coated tablet)
* * * * *