U.S. patent application number 13/724624 was filed with the patent office on 2013-05-23 for pharmaceutical compositions.
This patent application is currently assigned to AstraZeneca AB. The applicant listed for this patent is Simon Banks. Invention is credited to Simon Banks.
Application Number | 20130131087 13/724624 |
Document ID | / |
Family ID | 39107049 |
Filed Date | 2013-05-23 |
United States Patent
Application |
20130131087 |
Kind Code |
A1 |
Banks; Simon |
May 23, 2013 |
Pharmaceutical Compositions
Abstract
The present invention relates to pharmaceutical compositions
and, more particularly, to a pharmaceutical composition containing
the compound {1S-[1.alpha., 2.alpha.,
3.beta.(1S*,2R*),5.beta.]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino-
}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethox-
y)cyclopentane-1,2-diol.
Inventors: |
Banks; Simon;
(Leicestershire, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Banks; Simon |
Leicestershire |
|
GB |
|
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
39107049 |
Appl. No.: |
13/724624 |
Filed: |
December 21, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11841030 |
Aug 20, 2007 |
|
|
|
13724624 |
|
|
|
|
60823083 |
Aug 21, 2006 |
|
|
|
Current U.S.
Class: |
514/261.1 ;
544/254 |
Current CPC
Class: |
A61K 47/38 20130101;
A61K 47/02 20130101; A61K 47/36 20130101; A61P 37/02 20180101; A61P
43/00 20180101; A61P 7/00 20180101; A61P 7/02 20180101; A61K 9/2018
20130101; A61P 9/10 20180101; A61K 31/519 20130101; A61K 47/10
20130101; A61K 9/2009 20130101; A61P 9/00 20180101 |
Class at
Publication: |
514/261.1 ;
544/254 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 47/38 20060101 A61K047/38; A61K 47/36 20060101
A61K047/36; A61K 47/10 20060101 A61K047/10; A61K 47/02 20060101
A61K047/02; C07D 487/04 20060101 C07D487/04 |
Claims
1-16. (canceled)
17. An oral pharmaceutical composition comprising: {1S-[1.alpha.,
2.alpha.,
3.beta.(1S*,2R*),5.beta.]}-3-(7-{[2-(3,4-difluorophenyl)cyclopr-
opyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hy-
droxyethoxy)cyclopentane-1,2-diol substantially present in the form
of Polymorph II in an amount of 20 to 45% by weight of the
pharmaceutical composition as a whole; mannitol in an amount of 20
to 45% by weight of the pharmaceutical composition as a whole;
dibasic calcium phosphate dihydrate in an amount of 10 to 30% by
weight of the pharmaceutical composition as a whole; hydroxypropyl
cellulose in an amount of 3 to 6% by weight of the pharmaceutical
composition as a whole; sodium starch glycolate in an amount of 2
to 6% by weight of the pharmaceutical composition as a whole; and
one or more lubricants in an amount of 0.5 to 3% by weight of the
pharmaceutical composition as a whole.
18. An oral solid pharmaceutical composition comprising: a solid
core comprising (1) {1S-[1.alpha., 2.alpha.,
3.beta.(1S*,2R*),5.beta.]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino-
}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethox-
y)cyclopentane-1,2-diol in an amount of 90 mg; and (2) means for
releasing substantially all 90 mg of said 1,2-diol from the solid
pharmaceutical composition after oral administration.
19. The solid pharmaceutical composition of claim 18, wherein the
1,2-diol is substantially as Polymorph II.
20. The solid pharmaceutical composition of claim 18, wherein at
least 90% of the 1,2-diol is Polymorph II.
21. The solid pharmaceutical composition of claim 19, wherein the
1,2-diol is at least 95% Polymorph II.
22. The solid pharmaceutical composition of claim 18, wherein at
least 90% of the 90 mg of the 1,2-diol is released from the solid
pharmaceutical composition.
23. The solid pharmaceutical composition of claim 21, wherein at
least 90% of the 90 mg of the 1,2-diol is released from the solid
pharmaceutical composition.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. provisional
application Ser. No. 60/823,083 filed Aug. 21, 2006, which is
incorporated herein by reference is its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to pharmaceutical compositions
and, more particularly, to a pharmaceutical composition containing
{1S-[1.alpha., 2.alpha.,
3.beta.(1S*,2R*),5.beta.]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino-
}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethox-
y)cyclopentane-1,2-diol.
BACKGROUND OF THE INVENTION
[0003] The compound of formula (I):
##STR00001##
is conventionally named {S-[1.alpha., 2.alpha.,
3.beta.(1S*,2R*),5.beta.]}-3-(7-{[3,4-difluorophenyl)cyclopropyl]amino}-5-
-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)c-
yclopentane-1,2-diol, and hereinafter will be referred to as the
"Agent."
[0004] The Agent is disclosed as an ADP-receptor antagonist in
International Patent Application number PCT/SE99/02256 (publication
number WO00/34283) and International Patent Application number
PCT/SE01/01239 (publication number WO01/92262). It has been found
that adenosine 5'-diphosphate (ADP) acts as a key mediator of
thrombosis. ADP-induced platelet aggregation is mediated by the
P.sub.2T receptor subtype located on the platelet membrane. The
P.sub.2T receptor (also known as P2Y.sub.ADP or P2T.sub.AC) is
primarily involved in mediating platelet aggregation/activation and
is a G-protein coupled receptor which is as yet uncloned. The
pharmacological characteristics of this receptor have been
described, for example, in Humphries et al., Br. J. Pharmacology,
1994, 113, 1057-1063, and Fagura et al., Br. J. Pharmacology, 1998,
124, 157-164. It has been shown that antagonists at this receptor
offer significant improvements over other anti-thrombotic agents
(see, J. Med. Chem., 1999, 42, 213).
SUMMARY OF THE INVENTION
[0005] The present invention provides pharmaceutical compositions
comprising: {1S-[1.alpha., 2.alpha.,
3.beta.(1S*,2R*),5.beta.]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino-
}-5-(propylthio-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy-
)cyclopentane-1,2-diol; one or more fillers selected from mannitol,
sorbitol, dibasic calcium phosphate dihydrate, dibasic calcium
phosphate anhydrate, and tribasic calcium phosphate, or any mixture
thereof; one or more binders selected from hydroxypropyl cellulose,
alginic acid, carboxymethylcellulose sodium, copovidone, and
methylcellulose, or any mixture thereof; one or more disintegrants
selected from sodium starch glycolate, croscarmellose sodium, and
crospovidone, or any mixture thereof; and one or more
lubricants.
[0006] In some embodiments, the filler is a mixture of mannitol and
dibasic calcium phosphate dihydrate. In any of the foregoing
embodiments, the binder is hydroxypropyl cellulose. In any of the
foregoing embodiments, the disintegrant is sodium starch glycolate.
In any of the foregoing embodiments, the lubricant is magnesium
stearate or sodium stearyl fumarate. In any of the foregoing
embodiments, {1S-[1.alpha., 2.alpha.,
3.beta.(1S*,2R*),5.beta.]}-3-(7-{[2-(3,4-difluorophenyl)cyclopr-
opyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hy-
droxyethoxy)cyclopentane-1,2-diol is present in an amount of 20 to
45% by weight. In any of the foregoing embodiments, the filler is
present in an amount of 20 to 70% by weight. In any of the
foregoing embodiments, the binder is present in an amount of 3 to
6% by weight. In any of the foregoing embodiments, the disintegrant
is present in an amount of 2 to 6% by weight. In any of the
foregoing embodiments, the lubricant is present in an amount of 0.5
to 1% by weight. In any of the foregoing embodiments,
{1S-[1.alpha., 2.alpha.,
3.beta.(1S*,2R*),5.beta.]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino-
}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethox-
y)cyclopentane-1,2-diol is substantially present in the form of
Polymorph II. In any of the foregoing embodiments, {1S-[1.alpha.,
2.alpha.,
3.beta.(1S*,2R*),5.beta.]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino-
}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethox-
y)cyclopentane-1,2-diol is substantially present in the form of
Polymorph III. In any of the foregoing embodiments, the filler is a
mixture of mannitol and dibasic calcium phosphate dehydrate, the
binder is hydroxypropyl cellulose, the disintegrant is sodium
starch glycolate, and the lubricant is magnesium stearate or sodium
stearyl fumarate. In any of the foregoing embodiments,
{1S-[1.alpha., 2.alpha.,
3.beta.(1S*,2R*),5.beta.]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino-
}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethox-
y)cyclopentane-1,2-diol is present in an amount of 20 to 45% by
weight, mannitol is present in an amount of 20 to 45% by weight,
dibasic calcium phosphate dihydrate is present in an amount of 10
to 30% by weight, hydroxypropylcellulose is present in an amount of
3 to 6% by weight, sodium starch glycolate is present in an amount
of 2 to 6% by weight, and one or more lubricants is present in an
amount of 0.5 to 3% by weight. In any of the foregoing embodiments,
the pharmaceutical composition has been prepared by a wet
granulation process or a high shear wet granulation process.
DESCRIPTION OF EMBODIMENTS
[0007] The pharmaceutical compositions of the present invention are
suitable for oral administration. One of the qualities that is
desirable in a pharmaceutical composition suitable for oral
administration is bioavailability. The bioavailability of a drug is
the relative amount of an administered dose that reaches the
systemic circulation in an unchanged form. Therefore,
bioavailability is important in determining the therapeutically
active concentration at the site of action. Both drug release from
the formulation and the stability of the formulation will affect
its bioavailability. It is therefore important that the drug
formulation should release substantially all of the drug (see
Aulton M E, Pharmaceutics--The Science of Dosage Form Design,
2.sup.nd Edition, 2002, Churchill Livingstone). Bioavailability can
be measured using tests know in the art such as, for example, using
a standard United States Pharmacopoiea (USP) dissolution apparatus
and a standard `bio-relevant` dissolution medium such as, for
example, FaSSIF (Pharm. Res., 2000, 17, 439-444).
[0008] There are pharmaceutical, compositions containing the Agent
that retain some of the Agent and hence reduce its
bioavailability.
[0009] We have now discovered a novel pharmaceutical composition of
the Agent that has advantageous properties and which solves one or
more of the problems associated with formulation of the Agent. In a
first aspect, we have discovered a pharmaceutical composition that
is suitable for oral administration and that releases substantially
all of the Agent. In one aspect, the pharmaceutical composition
releases at least 90% of the Agent. In another aspect, the
pharmaceutical composition releases at least 95% of the Agent. In
yet another aspect, the pharmaceutical composition releases at
least 97% of the Agent.
[0010] Accordingly, the invention provides a pharmaceutical
composition comprising: the Agent; one or more fillers selected
from mannitol, sorbitol, dibasic calcium phosphate dihydrate,
dibasic calcium phosphate anhydrate, and tribasic calcium
phosphate, or any mixture thereof; one or more binders selected
from hydroxypropyl cellulose, alginic acid, carboxymethylcellulose
sodium, copovidone, and methylcellulose, or any mixture thereof;
one or more disintegrants selected from sodium starch glycolate,
croscarmellose sodium, and crospovidone, or any mixture thereof;
and one or more lubricants.
[0011] In one aspect, the pharmaceutical composition contains from
1 to 50% by weight of the Agent. In some embodiments, it contains
20 to 45% by weight of the Agent.
[0012] The filler may be a "soluble" filler or an "insoluble"
filler. A "soluble" filler is a filler that is substantially
soluble in water at ambient temperature. An "insoluble" filler is a
filler that has low or slow solubility in water at ambient
temperature.
[0013] In one aspect, the pharmaceutical composition contains one
or more "soluble" fillers. In another aspect, the pharmaceutical
composition contains one "soluble" filler. In one aspect, the
pharmaceutical composition contains one or more "insoluble"
fillers. In another aspect, the pharmaceutical composition contains
one "insoluble" filler.
[0014] In one aspect, the pharmaceutical composition contains at
least one "soluble" filler selected from mannitol, sorbitol,
maltodextrin, maltose, and dextrin. In one aspect, the "soluble"
filler is mannitol or sorbitol. In another aspect, the "soluble"
filler is mannitol.
[0015] In another aspect, the pharmaceutical composition contains
one or more "insoluble" fillers selected from dibasic calcium
phosphate dihydrate, dibasic calcium phosphate anhydrate, partially
pre-gelled starch, and tribasic calcium phosphate. In one aspect,
the "insoluble" filler is selected from dibasic calcium phosphate
dihydrate, dibasic calcium phosphate anhydrate, and tribasic
calcium phosphate. In another aspect, the "insoluble" filler is
dibasic calcium phosphate dihydrate.
[0016] In another aspect, the filler is a mixture of mannitol and
dibasic calcium phosphate dihydrate.
[0017] In another aspect, the pharmaceutical composition contains
from 1 to 90% by weight of filler. In some embodiments, it contains
20 to 70% by weight of filler. In another aspect, the
pharmaceutical composition contains from 1 to 70% by weight of
"soluble" filler. In some embodiments, it contains 20 to 45% by
weight of "soluble" filler. In another aspect, the pharmaceutical
composition contains from 1 to 30% by weight of "insoluble" filler.
In some embodiments, it contains 10 to 30% by weight of "insoluble"
filler.
[0018] In one aspect, the pharmaceutical composition contains one
or more binders. In another aspect, the pharmaceutical composition
contains one binder. In another aspect, the binder is hydroxypropyl
cellulose.
[0019] In another aspect, the pharmaceutical composition contains
from 2 to 8% by weight of binder. In some embodiments, it contains
3 to 6% by weight of binder.
[0020] In one aspect, the pharmaceutical composition contains one
or more disintegrants. In another aspect, the pharmaceutical
composition contains one disintegrant. In one aspect, the
disintegrant is sodium starch glycolate or croscarmellose sodium.
In one aspect, the disintegrant is sodium starch glycolate.
[0021] In another aspect, the pharmaceutical composition contains
from 2 to 6% by weight of disintegrant.
[0022] In one aspect, the pharmaceutical composition contains one
or more lubricants. In another aspect, the pharmaceutical
composition contains one lubricant. Suitable lubricants include,
for example, magnesium stearate, stearic acid, palmitic acid,
calcium stearate, carnauba wax, hydrogenated vegetable oils,
mineral oil, polyethylene glycols, and sodium stearyl fumarate. In
one aspect, the lubricant is magnesium stearate or sodium stearyl
fumarate. In another aspect, the lubricant is magnesium
stearate.
[0023] Typically, one or more lubricants will be present in an
amount 0.5 to 3%, and especially 0.5 to 1% by weight.
[0024] Additional conventional excipients, which may be added,
include preservatives, stabilisers, anti-oxidants, silica flow
conditioners, antiadherents, or glidants.
[0025] Other suitable lubricants and additional excipients which
may be used are described in Handbook of Pharmaceutical Excipients,
2.sup.nd Edition, American Pharmaceutical Association; The Theory
and Practice of Industrial Pharmacy, 2nd Edition, Lachman, Leon,
1976; Pharmaceutical Dosage Forms: Tablets Volume 1, 2.sup.nd
Edition, Lieberman, Hebert A., et al, 1989; Modern Pharmaceutics,
Banker, Gilbert and Rhodes, Christopher T, 1979; and Remington's
Pharmaceutical Sciences, 15.sup.th Edition, 1975.
[0026] It will be appreciated that a particular excipient may act
as both a binder and a filler, or as a binder, a filler and a
disintegrant. Typically, the combined amount of filler, binder, and
disintegrant comprises, for example, 50 to 90% by weight of the
composition.
[0027] In another aspect, the invention relates to a pharmaceutical
composition comprising the Agent, mannitol, dibasic calcium
phosphate dihydrate, hydroxypropylcellulose, sodium starch
glycolate, and one or more lubricants.
[0028] In another aspect, the invention relates to a pharmaceutical
composition comprising: the Agent in an amount of 20 to 45% by
weight; mannitol in an amount of 20 to 45% by weight; dibasic
calcium phosphate dihydrate in an amount of 10 to 30% by weight;
hydroxypropylcellulose in an amount of 3 to 6% by weight; sodium
starch glycolate in an amount of 2 to 6% by weight; and one or more
lubricants in an amount of 0.5 to 3% by weight.
[0029] It is desirable that the physical properties of these
compositions are stable on storage, as changes in for instance,
disintegration times, dissolution rates or tablet hardness among
others can affect product performance. It is possible that
decreases in dissolution rate on storage under international
Council for Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) stability
testing conditions, used to assign product shelf life, can reduce
the bioavailability of the Agent. Physical property stability can
be measured by USP methodologies for disintegration times and
dissolution testing.
[0030] It is also desirable that the compositions are chemically
stable as degradation by oxidation, hydrolysis, isomerisation,
photolysis, polymerization, or any other method of degradation,
either as a result of mixing with excipients or by any other
method, could lead to a reduction in bioavailability. Chemical
stability can be measured by a suitable, stability indicating
chromatographic method for determining degradation products (see
Aulton M E, Pharmaceutics--The Science of Dosage Form Design,
2.sup.nd Edition, 2002, Churchill Livingstone).
[0031] In another aspect, we have discovered a pharmaceutical
composition that is suitable for oral administration that releases
substantially all of the Agent and has a desirable stability
profile.
[0032] In one aspect the invention relates to a pharmaceutical
composition prepared by wet granulation. Granulation is a process
by which primary particles (powders) are made to adhere to form
larger, multiparticulate entities called granules. Granulation
normally commences after initial dry mixing of the powdered
ingredients so that a fairly uniform distribution of ingredients
through the mix is achieved. Granulation methods can be divided
into two types, wet granulation methods that utilize a liquid to
form the granules and dry methods that do not.
[0033] In dry granulation methods, primary powder particles are
aggregated under pressure (or compaction). There are two main
processes: a large tablet (also known as a slug) is produced with a
heavy duty tablet press or the powder particles are compressed
between two rollers to produce a sheet or `ribbon` of material
(process known as roller compaction). In both cases, the compacted
material is milled using a suitable milling technique to produce
granular material. The granules can then be compressed in a
standard tablet press to produce tablets.
[0034] Wet granulation involves massing the primary powder
particles using a granulating fluid. The fluid contains a solvent,
which can be removed by drying, and is non-toxic. The granulating
fluid can be used alone or more typically with a binding agent
(binder) to ensure article adhesion in the dry state. Binding
agents cart be added to the system as a binder solution (as part of
the granulating fluid) or as dry material mixed with the primary
powder particles. There are three main types of wet granulator,
shear granulators (such as planetary mixers), high shear mixer
granulators (such as Fielder or Diosna) and Fluid Bed Granualtors
(such as Aeromatic or Glatt).
[0035] In another aspect, we have discovered a pharmaceutical
composition prepared by a wet granulation process that is suitable
for oral administration that releases substantially all of the
Agent and a desirable stability profile.
[0036] In another aspect, the invention relates to a pharmaceutical
composition prepared by a wet granulation process comprising the
Agent, mannitol dibasic calcium phosphate dihydrate,
hydroxypropylcellulose, sodium starch glycolate, and one or more
lubricants.
[0037] In another aspect, the invention relates to a pharmaceutical
composition prepared by high shear wet granulation. High shear wet
granulation is a process that involves intensive dry mixing of
primary powders and subsequent addition of granulating fluid, which
results in the formation of granules. The granulating fluid
contains a volatile solvent (usually water) and may also include a
binder, ensuring particle adhesion (binders may also be added dry
as powders to the bulk of the formulation to be granulated).
Granules possess major advantages compared to powders, which they
are composed of, in terms of improved flow properties, reduced risk
of segregation, and increased homogeneity (information taken from
Aulton M E, Pharmaceutics--The Science of Dosage Form Design,
2.sup.nd Edition, 2002, Churchill Livingstone).
[0038] In one aspect, the pharmaceutical composition is in a solid
dosage form, such as a tablet or capsule. In another aspect, the
pharmaceutical composition is in the form of a tablet.
[0039] In another aspect the invention relates to a pharmaceutical
composition prepared by a high shear wet granulation process
comprising the Agent, mannitol, dibasic calcium phosphate
dihydrate, hydroxypropylcellulose, sodium starch glycolate, and one
or more lubricants.
[0040] The Agent exists in an amorphous form and in four different
substantially crystalline forms (see International Patent
Application number PCT/SE01/01239 (publication number WO01/92262)).
In another aspect, the invention relates to a pharmaceutical
composition as hereinabove define in which the Agent is in a
crystalline form.
[0041] In yet another aspect, the invention relates to a
pharmaceutical composition comprising the Agent substantially as
Polymorph II. In yet another aspect, the invention relates to a
pharmaceutical composition comprising the Agent substantially as
Polymorph III. In some embodiments, the Agent is at least 90%
Polymorph II or Polymorph III. In some embodiments, the Agent is at
least 95% polymorph II or Polymorph III. In some embodiments, the
Agent is at least 99% Polymorph II or Polymorph III. In some
embodiments, the Agent is at least 99.9% Polymorph II or Polymorph
III.
[0042] Compositions of the invention, which are of particular
interest, include, for example, the specific embodiments set out
hereinafter in the accompanying Example. It will be appreciated
that modifications of the wet granulation techniques, including the
order of addition of the components and their screening and
blending prior to compression into tablets, may be carried out
according to principles well known in the art.
[0043] A further aspect of the present invention comprises a method
of preparing a pharmaceutical composition, which comprises admixing
the Agent with; one or more fillers selected front mannitol,
sorbitol, maltodextrin, maltose, dextrin, dibasic calcium phosphate
dihydrate, dibasic calcium phosphate anhydrate, partially
pre-gelled starch, and tribasic calcium phosphate, or any mixture
thereof; one or more binders selected from hydroxyl propyl
cellulose, hydroxyl propyl methylcellulose, alginic acid,
carboxymethylcellulose sodium, copovidone, and methylcellulose, or
any mixture thereof; one or more disintegrants selected from sodium
starch glycolate, croscarmellose sodium, and crospovidone, or any
mixture thereof; and one or more lubricants.
[0044] The following pharmaceutical composition is intended to
illustrate the invention. It should be understood that the example
is for illustrative purposes only and is not to be construed as
limiting the invention in any manner.
EXAMPLES
Example 1
Pharmaceutical Composition
TABLE-US-00001 [0045] Quantity per unit dose Quantity Ingredient
Unit dose (mg) (% w/w or w/v) The Agent 90.00 30.00 Mannitol 126.00
42.00 Dibasic calcium 63.00 21.00 phosphate dihydrate Hydroxypropyl
9.00 3.00 cellulose Sodium starch 9.00 3.00 glycolate Magnesium
stearate 3.00 1.00 Core tablet weight 300.000 100.00
A high shear wet granulator (Fielder GP1 with 10 L bowl) was used
to dry mix the Agent, mannitol, dibasic calcium phosphate
dihydrate, hydroxypropyl cellulose, and sodium starch glycolate in
amounts to give 2.5 kg of total formulation, for 4 minutes. Water
was added via a pressure pot at approximately 50 g/minute to
approximately 25% w/w. The total mixing time was approximately 10
minutes.
[0046] The fluid bed was dried using a Glatt GPCG1 at 60.degree. C.
to a product temperature of 42.degree. C. The resulting granule was
milled by Quadro Comil 197. The milled granules were blended with
magnesium stearate and tablets were compressed from the blend.
[0047] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims. Each reference
(including, but not limited to, journal articles, U.S. and non-U.S.
patents, patent application publications. international patent
application publications, and the like) cited in the present
application is incorporated herein by reference in its
entirety.
* * * * *