U.S. patent application number 11/202715 was filed with the patent office on 2006-03-09 for extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof.
This patent application is currently assigned to Boehringer Ingelheim International GmbH. Invention is credited to Wolfram Eisenreich, Thomas Friedl.
Application Number | 20060051417 11/202715 |
Document ID | / |
Family ID | 34926161 |
Filed Date | 2006-03-09 |
United States Patent
Application |
20060051417 |
Kind Code |
A1 |
Friedl; Thomas ; et
al. |
March 9, 2006 |
Extended release tablet formulation containing pramipexole or a
pharmaceutically acceptable salt thereof
Abstract
An extended release tablet formulation comprising pramipexole or
a pharmaceutically acceptable salt thereof in a matrix, the matrix
comprising at least two water swelling polymers, wherein one of the
polymers is pregelatinized starch, and wherein another one of the
polymers is an anionic polymer.
Inventors: |
Friedl; Thomas;
(Ochsenhausen, DE) ; Eisenreich; Wolfram; (Ulm,
DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim International
GmbH
Ingelheim
DE
|
Family ID: |
34926161 |
Appl. No.: |
11/202715 |
Filed: |
August 12, 2005 |
Current U.S.
Class: |
424/468 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/2866 20130101; A61P 25/00 20180101; A61K 9/2027 20130101;
A61K 9/14 20130101; A61P 25/16 20180101; A61P 43/00 20180101; A61K
9/2031 20130101; A61K 9/2886 20130101; A61P 25/28 20180101; A61K
31/428 20130101; A61P 25/14 20180101; A61K 9/2846 20130101; A61K
9/2059 20130101 |
Class at
Publication: |
424/468 |
International
Class: |
A61K 9/22 20060101
A61K009/22 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 13, 2004 |
EP |
04019248.6 |
Claims
1. An extended release tablet formulation comprising pramipexole or
a pharmaceutically acceptable salt thereof in a matrix comprising:
(a) pregelatinized starch; and (b) an anionic polymer.
2. The extended release tablet formulation according to claim 1,
wherein the anionic polymer is selected from the group consisting
of optionally crosslinked acrylic acid polymers, methacrylic acid
polymers, alginates, and carboxymethyl cellulose.
3. The extended release tablet formulation according to claim 2,
wherein the anionic polymer is an optionally crosslinked acrylic
acid polymer, and wherein the content of the optionally crosslinked
acrylic acid polymer in the matrix is from about 0.25 wt.-% to
about 25 wt.-%.
4. The extended release tablet formulation according to claim 3,
wherein the anionic polymer is an optionally crosslinked acrylic
acid polymer, and wherein the content of the optionally crosslinked
acrylic acid polymer in the matrix is from about 0.5 wt.-% to about
15 wt.-%.
5. The extended release tablet formulation according to claim 4,
wherein the anionic polymer is an optionally crosslinked acrylic
acid polymer, and wherein the content of the optionally crosslinked
acrylic acid polymer in the matrix is from about 1 wt.-% to about
10 wt.-%.
6. The extended release tablet formulation according to claim 1,
further comprising a water swelling polymer which is not
pregelatinized starch or an anionic polymer.
7. The extended release tablet formulation according to claim 6,
wherein the water swelling polymer which is not pregelatinized
starch or an anionic polymer is hydroxypropyl cellulose or
hydroxypropyl methyl cellulose.
8. The extended release tablet formulation according to claim 7,
wherein the water swelling polymer which is not pregelatinized
starch or an anionic polymer is hydroxypropyl methyl cellulose.
9. The extended release tablet formulation according to claim 8,
wherein the content of hydroxypropyl methyl cellulose in the matrix
is from about 10 wt.-% to about 75 wt.-%.
10. The extended release tablet formulation according to claim 9,
wherein the content of hydroxypropyl methyl cellulose in the matrix
is from about 25 wt.-% to about 65 wt.-%.
11. The extended release tablet formulation according to claim 1,
wherein the matrix comprises about: (a) 0.05 to 5 wt.-% of
pramipexole or a salt thereof; (b) 0.25 to 25 wt.-% of anionic
water swelling polymer(s); (c) 10 to 75 wt.-% of water swelling
polymer(s) other than (b); and (d) to 100 wt.-% of further
excipients.
12. An extended release tablet formulation comprising pramipexole
or a pharmaceutically acceptable salt thereof in a matrix
comprising: (a) at least pregelatinized starch as water swelling
polymer and optionally excipients, the resulting tablet providing a
pH-independent in vitro release characteristic in the range from pH
1 to 7.5, or (b) at least pregelatinized starch as water swelling
polymer, a water swelling anionic polymer, and optionally
excipients, the resulting tablet providing a pH-dependent release
characteristic with a faster release characteristic in the range of
pH<4.5, and a slower and further on pH-independent release
characteristic in the range from pH 4.5 to 7.5.
13. The extended release tablet formulation according to claim 6,
wherein the water swelling polymer which is not pregelatinized
starch or an anionic polymer is hydroxypropyl methyl cellulose,
hydroxypropyl cellulose, carboxymethyl cellulose sodium, or sodium
alginate.
14. The extended release tablet formulation according to claim 12,
wherein the matrix comprises hydroxypropyl methyl cellulose and
excipients, wherein the amount of hydroxypropyl methyl cellulose
ranges from 10 to 75% by weight and the amount of excipients ranges
from 25 to 90% by weight.
15. The extended release tablet formulation according to claim 12,
wherein the matrix comprises hydroxypropyl methyl cellulose and
excipients, wherein the amount of hydroxypropyl methyl cellulose
ranges from 25 to 65% by weight and the amount of excipients ranges
from 35 to 75% by weight.
16. The extended release tablet formulation according to claim 1,
wherein the anionic polymer is an acrylic acid polymerisate.
17. The extended release tablet formulation according to claim 16,
wherein the acrylic acid polymerisate is present in the range of
0.25 to 25% by weight.
18. The extended release tablet formulation according to claim 17,
wherein the acrylic acid polymerisate is present in the range of
0.5 to 15% by weight.
19. The extended release tablet formulation according to claim 18,
wherein the acrylic acid polymerisate is present in the range of I
to 10% by weight.
20. A method of manufacturing the extended release tablet
formulation by a direct compression process comprising the steps
of: (1) producing an active ingredient trituration wherein the
active ingredient is pramipexole or a pharmaceutically acceptable
salt thereof by preblending it with a portion of water swelling
polymer(s) and/or excipient(s) in a mixer, wherein pramipexole or
the pharmaceutically acceptable salt thereof is milled prior to
use; (2) premixing the active ingredient trituration of step (1),
the main portion of the water swelling polymer(s), and/or
excipients in a mixer to obtain a pre-mixture; (3) optionally dry
screening the pre-mixture through a screen in order to segregate
cohesive particles and to improve content uniformity; (4) mixing
the pre-mixture of step (2) or (3) in a mixer, optionally by adding
remaining excipients to the mixture and continuing mixing; and (5)
tabletting the final mixture by compressing it on a suitable tablet
press to produce matrix tablets.
21. The method according to claim 20, wherein the pramipexole or
the pharmaceutically acceptable salt thereof is peg-milled prior to
use in step (1).
22. A method of manufacturing the extended release tablet
formulation by a wet granulation process comprising the steps of:
(1) producing an active ingredient trituration wherein the active
ingredient is pramipexole or a pharmaceutically acceptable salt
thereof by blending it with a portion of the excipients in a mixer,
wherein pramipexole or the pharmaceutically acceptable salt thereof
is milled prior to use; (2) granulating the active ingredient
trituration of step (1) by adding the granulation liquid; (3)
drying the granules of step (2) in a fluidized bed dryer or a
drying oven; (4) mixing the dried granules of step (3) with the
water swelling polymer(s) and/or excipients in a mixer to obtain
the final mixture; (5) tabletting the final mixture of step (4) by
compressing it on a suitable tablet press to produce matrix
tablets.
23. The method according to claim 22, wherein the pramipexole or
the pharmaceutically acceptable salt thereof is peg-milled prior to
use in step (1).
24. The method according to claim 22, wherein the granulation
liquid of step (2) is water.
25. A method of manufacturing the extended release tablet
formulation by a dry granulation process comprising the steps of:
(1) mixing the active ingredient pramipexole or a pharmaceutically
acceptable salt thereof with either a portion of the fillers or all
the excipients in a mixer, wherein pramipexole or the
pharmaceutically acceptable salt thereof is milled prior to use;
(2) compaction of the mixture of step (1) on a suitable roller
compactor; (3) reducing the ribbons obtained during step (1) to
small granules by suitable milling or sieving steps; (4) optionally
mixing the granules of step (3) with the remaining excipients in a
mixer to obtain the final mixture; and (5) tabletting the granules
of step (3) or the final mixture of step (4) by compressing it on a
suitable tablet press to produce matrix tablets.
26. The method according to claim 25, wherein the pramipexole or
the pharmaceutically acceptable salt thereof is peg-milled prior to
use in step (1).
Description
RELATED APPLICATIONS
[0001] This application claims priority to European Application No.
04019248.6 filed Aug. 13, 2004, which is hereby incorporated by
reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to an extended release
tablet formulation containing pramipexole or a pharmaceutically
acceptable salt thereof, method for manufacturing the same, and use
thereof.
BACKGROUND OF THE INVENTION
[0003] Pramipexole is a known dopamine D2 receptor agonist. It is
structurally different from the ergot-derived drugs, e.g.,
bromocriptine or pergolide. It is also pharmacologically unique in
that it is a full agonist and has receptor selectivity for the
dopamine D2 family of dopamine receptors.
[0004] Pramipexole is designated chemically as
(S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole and has
the molecular formula C.sub.10H.sub.17N.sub.3S and a relative
molecular mass of 211.33. The chemical formula is as follows:
##STR1##
[0005] The salt form commonly used is pramipexole dihydrochloride
monohydrate (molecular formula C.sub.10H.sub.21Cl.sub.2N.sub.3OS;
relative molecular mass 302.27). Pramipexole dihydrochloride
monohydrate is a white to off-white, tasteless, crystalline powder.
Melting occurs in the range of 296.degree. C. to 301.degree. C.,
with decomposition. Pramipexole is a chiral compound with one
chiral center. Pure (S)-enantiomer is obtained from the synthetic
process by chiral recrystallization of one of the intermediates
during synthesis.
[0006] Pramipexole dihydrochloride monohydrate is a highly soluble
compound. Water solubility is more than 20 mg/mL and solubility in
buffer media is generally above 10 mg/mL between pH 2 and pH 7.4.
Pramipexole dihydrochloride monohydrate is not hygroscopic, and has
a highly crystalline nature. Under milling, the crystal
modification (monohydrate) does not change. Pramipexole is very
stable in the solid state, yet in solution it is light
sensitive.
[0007] Pramipexole immediate release (IR) tablets were first
authorized in the USA in 1997, followed over the course of the next
years by marketing authorizations in the European Union (EU),
Switzerland, Canada, and South America as well as in countries in
Eastern Europe, the Near East, and Asia.
[0008] Pramipexole IR tablets are indicated in the EU and US for
the treatment of signs and symptoms of either early Parkinson's
Disease or advanced Parkinson's Disease in combination with
levodopa. The IR tablets have to be taken 3 times a day.
[0009] From the pharmacokinetic point of view, pramipexole IR
tablets are rapidly and completely absorbed following oral
administration. The absolute bioavailability is greater than 90%
and the maximum plasma concentration occurs within 1 to 3 hours.
The rate of absorption is reduced by food intake but not the
overall extent of absorption. Pramipexole shows linear kinetics and
a relatively small inter-patient variation of plasma levels. The
elimination half-life (t.sub.1/2[h]) varies from 8 hours in the
young to 12 hours in the elderly.
[0010] As commonly known, modified release of active ingredient(s)
allows simplification of the patient's administration scheme by
reducing the amount of recommended daily intakes, improves
patient's compliance, and attenuates adverse events, e.g., related
to high plasma peaks. Modified release pharmaceutical preparations
regulate the release of the incorporated active ingredient or
ingredients over time and comprise formulations with a controlled,
a prolonged, a sustained, a delayed, a slow or an extended release,
so they accomplish therapeutic or convenience objectives not
offered by conventional dosage forms such as solutions or promptly
dissolving dosage forms.
[0011] A modified or extended release of active ingredient(s) from
a pharmaceutical preparation may be accomplished by homogeneously
embedding the active ingredient(s) in a hydrophilic matrix, being a
soluble, partially soluble or insoluble network of viscous,
hydrophilic polymers, held together by physical or chemical
entanglements, by ionic or crystalline interactions, by complex
formation, by hydrogen bonds or van der Waals forces. The
hydrophilic matrix swells upon contact with water, thereby creating
a protective gel layer from which the active ingredient(s) is (are)
slowly, gradually, continuously released in time either by
diffusion through the polymeric network, by erosion of the gel
layer, by dissolution of the polymer, or by a combination of these
release mechanisms.
[0012] However, it has proved difficult to formulate a tablet
having a suitable combination of modified, extended or
sustained-release and handling properties, where the drug is one
having relatively high solubility, as in the case of pramipexole
dihydrochloride.
[0013] There are a number of approaches described in prior art to
provide sustained release tablet compositions of pramipexole.
[0014] WO 2004/010997 describes a sustained-release pharmaceutical
composition in a form of an orally deliverable tablet comprising a
water-soluble salt of pramipexole, dispersed in a matrix comprising
a hydrophilic polymer and a starch having a tensile strength of at
least about 0.15 kN cm.sup.-2, preferably at least about 0.175 kN
cm.sup.-2, and more preferably at least about 0.2 kN cm.sup.-2, at
a solid fraction representative of the tablet. The disclosure
thereof is concentrated to provide a composition with sufficient
hardness yield during a high-speed tabletting operation, in
particular to resist erosion during application of a coating layer.
According to a preferred embodiment it is provided a pharmaceutical
composition in a form of an orally deliverable tablet having a core
comprising pramipexole dihydrochloride monohydrate in an amount of
about 0.375, 0.75, 1.5, 3, or 4.5 mg, dispersed in a matrix
comprising (a) HPMC type 2208 in an amount of about 35% to about
50% by weight of the tablet and (b) a pregelatinized starch having
a tensile strength of at least about 0.15 kN cm.sup.-2 at a solid
fraction of 0.8, in an amount of about 45% to about 65% by weight
of the tablet; the core being substantially enclosed in a coating
that constitutes about 2% to about 7% of the weight of the tablet,
the coating comprising an ethyl cellulose-based hydrophobic or
water-insoluble component and an HPMC-based pore-forming component
in an amount of about 10% to about 40% by weight of the ethyl
cellulose-based component.
[0015] Furthermore, WO 2004/010999 discloses an orally deliverable
pharmaceutical composition comprising a therapeutically effective
amount of pramipexole or a pharmaceutically acceptable salt thereof
and at least one pharmaceutically acceptable excipient, the
composition exhibiting at least one of (a) an in vitro release
profile wherein on average no more than about 20% of the
pramipexole is dissolved within 2 hours after placement of the
composition in a standard dissolution test; and (b) an in vivo
pramipexole absorption profile following single dose oral
administration to healthy adult humans wherein the time to reach a
mean of 20% absorption is greater than about 2 hours and/or the
time to reach a mean of 40% absorption is greater than about 4
hours. However, in practical use, it appears that any formulation
having an extended or controlled release profile designed for a
once daily application would meet the above requirements for which
a general teaching how to adjust such a profile is missing.
[0016] It is an object of the present invention to provide a
controlled release tablet composition of pramipexole or a
pharmaceutically acceptable salt thereof that is suitable for
once-daily oral administration. It is a further object to provide a
tablet composition comprising pramipexole or a pharmaceutically
acceptable salt thereof that provides a day-long therapeutic effect
and will allow patients to treat their symptoms with a single daily
dose, which makes it possible to adjust the release profile of the
active ingredient according to a selected release profile dependent
or independent from the pH values. Furthermore a method of
manufacturing the tablet formulation shall be provided.
DESCRIPTION OF THE INVENTION
[0017] Surprisingly, it has been found that pramipexole or a
pharmaceutically acceptable salt thereof may be used in
formulations as once daily extended (or slow) release tablets and
two alternative formulation principles allow different release rate
types dependent or independent from the pH value.
[0018] One embodiment of the present invention relates to an
extended release tablet formulation comprising pramipexole or a
pharmaceutically acceptable salt thereof in a matrix, the matrix
comprising at least two water swelling polymers, wherein one of the
polymers is pregelatinized starch, and wherein another one of the
polymers is an anionic polymer.
[0019] Preferably the invention relates to an extended release
tablet formulation, wherein the anionic polymer is selected from
the group of optionally crosslinked acrylic acid polymers,
methacrylic acid polymers, alginates and carboxy methyl
cellulose.
[0020] Also preferred is an extended release tablet formulation,
wherein the anionic polymer is a crosslinked acrylic acid polymer
and wherein the content of the optionally crosslinked acrylic acid
polymer in the matrix is from about 0.25 wt.-% to about 25 wt.-%,
and preferably from about 0.5 wt.-% to about 15 wt.-%, and
preferably from about 1 wt.-% to about 10 wt.-%.
[0021] Also preferred is an extended release tablet formulation
further comprising a water swelling polymer which is not
pregelatinized starch or an anionic polymer and which is preferably
selected from hydroxypropylcellulose or hydroxypropyl methyl
cellulose.
[0022] Particularly preferred is an extended release tablet
formulation, wherein the water swelling polymer which is not
pregelatinized starch or an anionic polymer is hydroxypropyl methyl
cellulose and wherein the content of hydroxypropyl methyl cellulose
in the matrix is from about 10 wt.-% to about 75 wt.-%, and
preferably from about 25 wt.-% to about 65 wt.-%.
[0023] Particularly preferred is an extended release tablet
formulation, wherein the matrix comprises about: [0024] (a) 0.05 to
5 wt.-% of pramipexole or a salt thereof; [0025] (b) 0.25 to 25
wt.-% of anionic water swelling polymer(s); [0026] (c) 10 to 75
wt.-% of water swelling polymer(s) other than (b); and [0027] (d)
to 100 wt.-% of further excipients
[0028] Another embodiment of the present invention relates to an
extended release tablet formulation comprising pramipexole or a
pharmaceutically acceptable salt thereof in a matrix comprising:
[0029] a) at least pregelatinized starch as water swelling polymer
and optionally excipients, the resulting tablet providing a
pH-independent in vitro release characteristic in the range from pH
1 to 7.5, or [0030] b) at least pregelatinized starch as water
swelling polymer, a water swelling anionic polymer, preferably an
acrylic acid polymerisate, and optionally excipients, the resulting
tablet providing a pH-dependent release characteristic with a
faster release characteristic in the range of pH<4.5, and a
slower and further on pH-independent release characteristic in the
range from pH 4.5 to 7.5.
[0031] The extended release formulations according to the present
invention intended for oral administration allow to select and
estimate which in vitro release characteristic and timing of a
formulation is most suitable to achieve the desired in vivo plasma
profiles preferably with a once daily application. Therefore, two
different formulation principles have been developed for a single
unit matrix tablet, i.e., two formulation principles having
different release rate types are provided and a different pH
dependency is available. These alternative formulations are
beneficial to patients as the extended release drug delivery will
allow patients to treat their symptoms with a single daily dose,
thereby increasing patient convenience and compliance.
[0032] The term "in vitro release characteristic" as used
hereinbefore or hereinafter is directed to a release characteristic
as obtained in a kind of normally used liquid medium for in vitro
experiments wherein the release of active ingredient from the
extended release formulation can occur, i.e., for example, in in
vitro dissolution media, but also in body fluids or simulated body
fluids, more in particular in the gastrointestinal fluids.
[0033] In the frame of the present invention the term "extended"
release should be understood in contrast to an immediate release,
the active ingredient is gradually, continuously liberated over
time, sometimes slower or faster, dependent or independent from the
pH value. In particular, the term indicates that the formulation
does not release the full dose of the active ingredient immediately
after oral dosing and that the formulation allows a reduction in
dosage frequency, following the definition for extended release,
interchangeable with slow release. A slow or extended release, used
synonymously with prolonged action, sustained release, or modified
release, dosage form is a dosage form that allows at least a
reduction in dosing frequency or a significant increase in patient
compliance or therapeutic performance as compared to that presented
as a conventional dosage form (e.g., as a solution or an immediate
drug-releasing, conventional solid dosage form).
[0034] A release characteristic which is pH-independent indicates
that the release characteristic is virtually the same in different
pH media.
[0035] According to the teaching of the present invention two types
of extended release tablet formulations are available showing
different in vitro release profiles.
[0036] The extended release tablets of the present invention apply
a swelling and partly eroding polymer matrix leading to a square
root of time to exponential in vitro release characteristic,
formulation a) is widely independent from the pH value in the range
from pH 1 to 7.5, and formulation b) is (slightly) faster in
simulated gastric juice having a pH<4.5 but is independent from
the pH value in the range from 4.5 to 7.5. A faster release in
simulated gastric juice versus slower release in the intestinal
fluid can be advantageous in cases where a loading dose effect from
the dosage form is desired, whereas a widely pH independent release
profile can be advantageous to reduce the risk of dose dumping and
food effects.
[0037] According to the present invention under "formulation a)" is
understood the tablet formulation wherein the matrix comprises the
composition as above-defined under a) and under "formulation b)" is
understood the tablet formulation wherein the matrix comprises the
composition as above-defined under b).
[0038] The water swelling polymer present in both alternate tablet
formulations a) and b) of the present invention represents at least
pregelatinized starch as one hydrophilic water swelling polymer
constituting the extended release matrix which slowly releases the
pramipexole or its salt as active ingredient. The polymer swells
upon contact with aqueous fluid following administration, resulting
in a viscous, drug release regulating gel layer.
[0039] Examples of polymers present in the formulation of the
invention in addition to pregelatinized starch are water swelling
substantially neutral polymers or water swelling anionic
polymers.
[0040] The term "water swelling substantially neutral polymers" of
the present invention comprises alkylcelluloses, such as, methyl
cellulose; hydroxyalkylcelluloses, for example, hydroxy methyl
cellulose, hydroxyethyl cellulose, hydroxypropylcellulose and
hydroxybutyl cellulose; hydroxyalkyl alkylcelluloses, such as
hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose;
carboxyalkylcellulose esters; other natural, semi-synthetic, or
synthetic di-, oligo-, and polysaccharides such as galactomannans,
tragacanth, agar, guar gum, and polyfructans; methacrylate
copolymers; polyvinyl alcohol; polyvinylpyrrolidone, copolymers of
polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl
alcohol and polyvinylpyrrolidone; polyalkylene oxides such as
polyethylene oxide and polypropylene oxide and copolymers of
ethylene oxide and propylene oxide, preferably cellulose ether
derivatives such as hydroxypropyl methyl cellulose and
hydroxypropyl cellulose, most preferred hydroxypropyl methyl
cellulose.
[0041] The term "water swelling anionic polymer" of the present
invention comprises acrylic acid polymerisate, methacrylic acid
copolymers, alginates, carrageenans, acacia, xanthan gum, chitin
derivates such as chitosan, carmellose sodium, and carmellose
calcium, preferably acrylic acid polymerisate.
[0042] Different viscosity grades of hydroxypropyl cellulose and
hydroxypropyl methyl cellulose are commercially available.
Hydroxypropyl methyl cellulose (HPMC) preferably used in the
present invention has a viscosity grade ranging from about 3,500
mPa.s to about 100,000 mPa.s, in particular ranging from about
4,000 mPa.s to about 20,000 mPa.s and most in particular a
viscosity grade of about 6,500 mPa.s to about 15,000 mPa.s
(apparent viscosity of a 2% aqueous solution at 20.degree. C.),
e.g., hypromellose 2208 or 2206 (DOW, Antwerp, Belgium). HPMC type
2208 contains 19-24% by weight methoxy and 4-12% by weight
hydroxypropoxy substituents.
[0043] Hydroxypropyl cellulose having a viscosity higher than 1,500
mPa.s (apparent viscosity of a 1% aqueous solution at 20.degree.
C.) is preferred, in particular hydroxypropyl cellulose having a
viscosity in the range from about 1500 to about 3000 mPa.s,
preferably from 4000 to 6500 mPa.s (2% aqueous solutions), e.g.,
the KLUCEL.RTM. series such as KLUCEL.RTM. M (Hercules, Wilmington,
USA).
[0044] Without wishing to be bound by theory, there are believed to
exist three main mechanisms by which pramipexole or a salt thereof
can be released from a hydrophilic matrix: dissolution, erosion and
diffusion. Pramipexole or its salt will be released by the
dissolution mechanism when it is homogeneously dispersed in a
matrix network of a soluble polymer. The network will gradually
dissolve in the gastrointestinal tract, thereby gradually releasing
its load. The matrix polymer can also gradually be eroded from the
matrix surface, likewise releasing pramipexole or its salt in time.
When pramipexole is processed in a matrix made up of an insoluble
polymer, it will be released by diffusion: the gastrointestinal
fluids penetrate the insoluble, sponge-like matrix and diffuse back
out loaded with drug.
[0045] Therefore, the water swelling polymers constituting the
matrix, mainly provide for the controlled pharmacokinetic release
profile of the preparation. Depending on the amount of water
swelling polymer(s) processed in the preparation, the release
profile can be tuned, i.e., larger amounts of swelling polymer lead
to a more pronounced sustained release effect and vice versa.
Preferably, the amount of water swelling polymer in the present
formulation ranges from about 30 to about 99% by weight.
[0046] In addition, when using a combination of polymers, the ratio
of the polymers also influences the release profile of the
preparation. A combination of different polymers offers the
possibility of combining different mechanisms by which pramipexole
is released from the matrix. Such combination facilitates control
of the pharmacokinetic release profile of the preparation at will.
For example, when using one or more water swelling polymers, in
particular hydroxypropyl cellulose and hydroxypropyl methyl
cellulose, the weight percentage of hydroxypropyl methyl cellulose
preferably ranges from 25 to about 62%; the weight percentage of
hydroxypropyl cellulose preferably ranges between about 0% and
about 16%.
[0047] Release of pramipexole or a salt thereof from a matrix
containing hydroxypropyl cellulose and hydroxypropyl methyl
cellulose occurs by a combined set of release mechanisms. Due to
the higher solubility of hydroxypropyl methyl cellulose compared
with hydroxypropyl cellulose, the former will gradually dissolve
and erode from the matrix, whereas the latter will more act as a
sponge-like matrix former releasing the active ingredient mainly by
diffusion.
[0048] The extended release tablet formulation according to
formulation a) is pH-independent. Therefore, the disadvantage that
food related dose-dumping may be encountered is avoided. The
problem of food related dose-dumping in fed patients can be
attributed to a lot of factors such as the mechanical forces that
are exerted by the stomach on its content and thus on an ingested
preparation as well as the different pH regions of the
gastrointestinal tract. Since the pH values encountered in the
gastrointestinal tract vary not only with the region of the tract,
but also with the intake of food, an extended release formulation
preferably also has to provide an extended release profile and in
particular has to avoid dose-dumping regardless whether the patient
is in fasted or fed conditions.
[0049] According to the present invention the oral extended release
formulation a) may retain its pharmacokinetic release profile along
its way through the gastrointestinal tract so as to avoid
undesirable fluctuations in drug plasma concentrations or complete
dose-dumping, in particular avoids dose-dumping in different
regions of the gastrointestinal tract.
[0050] Beside pramipexole or a salt thereof, and the water swelling
polymers, the formulation of the present invention may also
optionally comprise further excipients, i.e., pharmaceutically
acceptable formulating agents, in order to promote the manufacture,
compressibility, appearance and taste of the preparation. These
formulating agents comprise, for example, diluents or fillers,
glidants, binding agents, granulating agents, anti-caking agents,
lubricants, flavors, dyes, and preservatives. Other conventional
excipients known in the art can also be included.
[0051] The filler may be selected from soluble fillers, for
example, sucrose, lactose, in particular lactose monohydrate,
trehalose, maltose, mannitol, sorbitol, inulin, and from insoluble
fillers, for example, dicalcium or tricalcium phosphate and talc.
Different grades of lactose can be used. One type of lactose
preferably used in the present invention is lactose monohydrate 200
mesh (DMV, Veghel, The Netherlands). Another lactose monohydrate,
lactose monohydrate of the type DCL 11 (DMV, Veghel, The
Netherlands), can also preferably be used. The notation DCL refers
to "Direct Compression Lactose". The number 11 is a reference
number of the manufacturer. In case of a water soluble active
ingredient, like the one described in this invention, more
preferably water insoluble fillers, such as starch and starch
derivates, microcrystalline cellulose, dibasic calcium phosphate
dihydrate, and anhydrous dibasic calcium phosphate, can be used in
addition or instead of the water soluble fillers. The total weight
percentage of filler ranges between about 5% and about 75% by
weight.
[0052] A glidant can be used to improve powder flow properties
prior to and during tabletting and to reduce caking. Suitable
glidants include colloidal silicon dioxide, magnesium trisilicate,
powdered cellulose, talc, tribasic calcium phosphate, and the like.
Colloidal silicon dioxide is preferably included as a glidant in an
amount up to about 2%, preferably about 0.2% to about 0.8%, by
weight of the tablet.
[0053] A lubricant can be used to enhance release of a tablet from
apparatus on which it is formed, for example by preventing
adherence to the face of an upper punch ("picking") or lower punch
("sticking"). Suitable lubricants include magnesium stearate,
calcium stearate, canola oil, glyceryl palmitostearate,
hydrogenated vegetable oil, magnesium oxide, mineral oil,
poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate,
sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc,
hydrogenated vegetable oil, zinc stearate, and the like. In one
embodiment, magnesium stearate is included as a lubricant in an
amount of about 0.1% to about 1.5%, preferably about 0.3% to about
1%, by weight of the tablet.
[0054] Among the optional formulating agents that further may be
comprised in the matrix formulation there may be mentioned agents
such as polyvidone; copovidone; starch; acacia; gelatin; seaweed
derivatives, e.g., alginic acid, sodium and calcium alginate;
cellulose, preferably microcrystalline cellulose, cellulose
derivatives, e.g., ethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, having useful dry or wet binding
and granulating properties; and antiadherents such as talc and
magnesium stearate.
[0055] According to a preferred embodiment of the present invention
the matrix of the extended release tablet formulation of
alternative a) comprises or essentially consists of pregelatinized
starch, hydroxypropyl methyl cellulose and excipients. The amount
of pregelatinized starch is preferably in the range from 10 to 75%,
particularly preferred from 25 to 65% most preferred from 45 to 55%
by weight. The amount of hydroxypropyl methyl cellulose is
preferably in the range from 10 to 75%, particularly preferred from
25 to 65% most preferred from 35 to 55% by weight. The amount of
further excipients is preferably in the range from 0 to 30%,
particularly preferred from 0.5 to 20%, most preferred from 1 to
10% by weight. Optionally carboxymethyl cellulose sodium may
additionally be present preferably in the range from 5 to 50,
particularly preferred from 10 to 40, most preferred from 15 to 30%
by weight.
[0056] The expression "consisting essentially" is understood in the
sense that it does not in principle exclude the presence, in
addition to the mandatory components mentioned, of other
components, the presence of which does not affect the essential
nature of the formulation.
[0057] In case of formulation b) of the present invention it is
provided a pH-dependent release profile, the release of pramipexole
or its salt from the tablet and subsequent the absorption into the
blood stream can vary during the passage of the dosage form along
the gastrointestinal tract. Thus, it is provided a pH-dependent
release characteristic wherein the release characteristic in the
range of pH<4.5 is faster and a slower and further on
pH-independent release characteristic in the range from
4.5.ltoreq.pH.ltoreq.7.5.
[0058] The above details for the water swelling polymer and
selection and type of optional excipients apply to formulation b),
too.
[0059] Moreover, an anionic water swelling polymer, preferably an
acrylic acid polymerisate, is mandatorily present in formulation
b), which is preferably selected from carbomer or CARBOPOL.RTM.
series, known acrylic acid polymerisates having high molecular
weights. Particularly preferred are, for example, carbomer 941
(CARBOPOL.RTM. 71 G, CARBOPOL.RTM. 971) and carbomer 934
(CARBOPOL.RTM. 974). The acrylic acid polymerisate is preferably
present in the range of 0.25 to 25% by weight, particularly
preferred 0.5 to 15% by weight, most preferred 1 to 10% by weight.
The pH dependency of formulation b) results form the presence of
acrylic acid polymerisate which intends to swell in a greater
extent in the acid pH range above pH 4.5 and in the alkaline pH
range. An increasing amount of acrylic acid leads to a decrease of
the release rate. Therefore, adjusting the amount of acrylic acid
polymerisate makes it possible to further tune the dissolution
profiles as desired. To adjust the amount of acrylic acid
polymerisate in the preferred range from 0.25 to 25% by weight
provides the further advantage that the desired, resp. matching,
dissolution profiles can be adjusted, resp. maintained, for a
variety of formulations composed of different amounts and/or types
of gel-forming agents, water swelling polymers, fillers, and dry
binders.
[0060] According to a preferred embodiment of the present invention
the matrix of the extended release tablet formulation of
alternative b) comprises or essentially consists of pregelatinized
starch, hydroxypropyl methyl cellulose acrylic acid polymerisate
and excipients. The amount of pregelatinized starch is preferably
in the range from 10 to 75%, particularly preferred from 25 to 65%
most preferred from 45 to 55% by weight. The amount of
hydroxypropyl methyl cellulose is preferably in the range from 10
to 75, particularly preferred from 25 to 65, most preferred from 35
to 55% by weight. The amount of acrylic acid polymerisate is
preferably as abovementioned. The amount of excipients is
preferably in the range from 0 to 30 particularly preferred from
0.5 to 20, most preferred from 1 to 10% by weight. Optionally
carboxymethyl cellulose sodium may additionally be present
preferably in the range from 5 to 50, particularly preferred from
10 to 40, most preferred from 15 to 30% by weight.
[0061] As active ingredient, pramipexole or a pharmaceutically
acceptable salt thereof, may be present in the formulation
according to the present invention in any amount suitable for the
desired treatment of a patient. A preferred salt of pramipexole is
the dihydrochloride salt, most preferably in the form of the
monohydrate. Usual amounts are from about 0.1 to about 5 mg
pramipexole salt. According to a particularly preferred embodiment,
e.g., 0.750 mg pramipexole dihydrochloride monohydrate,
corresponding to 0.524 mg anhydrous base, is used in the extended
release tablet formulation according to the present invention.
However, any other amount of active ingredient suitable for
treatment may be used with the only proviso that the amount of
pramipexole or salt is sufficient to provide a daily dose in one to
a small plurality, for example one to about 4, of tablets to be
administered at one time. Preferably the full daily dose is
delivered in a single tablet. An amount of pramipexole salt,
expressed as pramipexole dihydrochloride monohydrate equivalent, of
about 0.1 to about 10 mg per tablet, or about 0.05% to about 5% by
weight of the composition, will generally be suitable. Preferably
an amount of about 0.2 to about 6 mg, more preferably an amount of
about 0.3 to about 5 mg, per tablet is present. Specific dosage
amounts per tablet, e.g., include 0.375, 0.5, 0.75, 1.0, 1.5, 3.0,
and 4.5 mg pramipexole dihydrochloride monohydrate. The amount that
constitutes a therapeutically effective amount varies according to
the condition being treated, the severity of the condition, and the
patient being treated.
[0062] An extended release tablet formulation according to the
present invention, has preferably the following composition: [0063]
0.05 to 5% by weight of pramipexole or a salt thereof; [0064] 10 to
75% by weight of pregelatinized starch; [0065] 10 to 75% by weight
of other water swelling polymer(s); [0066] 0 to 25% by weight of
acrylic acid polymerisate; and [0067] to 100% by weight of optional
excipient(s).
[0068] Therefore, a particularly preferred extended release tablet
formulation of the present invention consists of: [0069] 0.1 to 2%
by weight of pramipexole or a salt thereof; [0070] 25 to 65% by
weight of hydroxypropyl methyl cellulose; [0071] 0 to 40% by weight
of carboxymethyl cellulose sodium; [0072] 25 to 75% by weight of
pregelatinized starch; [0073] 0 to 15% by weight of acrylic
polymerisate, preferably carbomer 941; and [0074] 0.5 to 50% by
weight of further excipients, preferably selected from the group
consisting of colloidal silicon dioxide, magnesium stearate,
lactose monohydrate, mannitol, microcrystalline cellulose, dibasic
anhydrous calcium phosphate, hydroxypropyl cellulose, povidone,
copovidone, talc, macrogols, sodium dodecylsulfate, iron oxides,
and titanium dioxide.
[0075] A starch having a tensile strength of at least about 0.15 kN
cm.sup.-2 at a solid fraction representative of the tablet as
claimed according to WO 2004/010997 is not necessary to practice
the present invention.
[0076] It is particularly preferred that no coating is present on
the tablet formulation according to the present invention. However,
the extended release tablet of the invention may comprise a
nonfunctional coating. A nonfunctional coating can comprise a
polymer component, for example HPMC, optionally with other
ingredients, for example one or more plasticizers, colorants, etc.
The term "nonfunctional" in the present context means having no
substantial effect on release properties of the tablet, and the
coating serves another useful purpose. For example, such a coating
can impart a distinctive appearance to the tablet, provide
protection against attrition during packaging and transportation,
improve ease of swallowing, and/or have other benefits. A
nonfunctional coating should be applied in an amount sufficient to
provide complete coverage of the tablet. Typically an amount of
about 1% to about 10%, more typically an amount of about 2% to
about 5%, by weight of the tablet as a whole, is suitable.
[0077] The tablets of the present invention can be of any suitable
size and shape, for example round, oval, polygonal or
pillow-shaped, and optionally bear nonfunctional surface markings.
According to the present invention it is preferred that the
extended release tablets are white to off-white and of oval or
round, biconvex, shape.
[0078] Tablets of the invention can be packaged in a container,
accompanied by a package insert providing pertinent information
such as, for example, dosage and administration information,
contraindications, precautions, drug interactions, and adverse
reactions.
[0079] The present invention is further directed to the use of the
extended release tablet formulation according to the present
invention for preparing a medical composition for the treatment of
Parkinson's Disease and complications or disorders associated
therewith.
[0080] Furthermore, the present invention is preferably directed to
a method of manufacturing the extended release tablet formulations
via a diret compression process comprising the steps of: [0081] (1)
producing an active ingredient trituration wherein the active
ingredient is pramipexole or a pharmaceutically acceptable salt
thereof by preblending it with a portion of water swelling
polymer(s) and/or further excipient(s) in a mixer, wherein
pramipexole or the pharmaceutically acceptable salt thereof is
milled, preferably peg-milled, prior to use; [0082] (2) premixing
the active ingredient trituration of step (1), the main portion of
the water swelling polymer(s) and/or excipients in a mixer to
obtain a pre-mixture; [0083] (3) optionally dry screening the
pre-mixture through a screen in order to segregate cohesive
particles and to improve content uniformity; [0084] (4) mixing the
pre-mixture of step (2) or (3) in a mixer, optionally by adding
remaining excipients to the mixture and continuing mixing; and
[0085] (5) tabletting the final mixture by compressing it on a
suitable tablet press to produce matrix tablets.
[0086] Therefore, the tablets are manufactured via a direct
compression process which applies to both types of pramipexole
extended release matrix tablets. To achieve adequate content
uniformity in this low drug load formulation, the active ingredient
is preferably peg-milled. Preferably the particle size distribution
of the peg-milled drug substance, as determined by laser
diffractometry using a dry dispensing system, is characterized by
particle fraction of 90% (V/V) being smaller than 100 .mu.m, most
preferably a particle fraction of 90% (V/V) being smaller than 75
.mu.m in diameter.
[0087] Also other processes can be applied to the manufacturing of
pramipexole extended release tablets, like conventional wet
granulation and roller compaction. In case of wet granulation,
preferably pramipexole is granulated with suitable fillers, like,
e.g., starch, microcrystalline cellulose, lactose monohydrate, or
anhydrous dibasic calcium phosphate, and wet binding agents, like,
e.g., hydroxypropyl methyl cellulose, hydroxypropylcellulose,
povidone, copovidone, and starch paste, leading to a active
ingredient concentrate, which after drying and dry screening is
mixed with the main fraction of gel forming excipients, like all
the above described retarding principles. In case of roller
compaction, or in other words dry granulation, either a premix of
pramipexole with part of the excipients used in the direct
compression process, or the complete mixture containing all
excipients, is processed through a conventional roller compactor to
form ribbons, which are thereafter screened down to granules which
are further finally mixed with other excipients, like glidants,
lubricants, and antiadherents.
BRIEF DESCRIPTION OF THE DRAWINGS
[0088] FIG. 1 is a flow diagram illustrating a preferred embodiment
of the direct compression manufacturing process according to the
present invention;
[0089] FIG. 2 is a graph illustrating the dissolution profiles of a
matrix tablet formulation according to the present invention which
contains 4% by weight CARBOPOL.RTM. in 3 different pH media;
and
[0090] FIG. 3 is a graph illustrating the dissolution profiles of 3
matrix tablet formulations according to the present invention which
contain 0%, 1%, and 4% by weight of CARBOPOL.RTM.,
respectively.
[0091] FIG. 1 illustrates a preferred embodiment of the
manufacturing process with reference to a flow diagram wherein the
manufacture of the extended release tablets of Examples 1 and 2 are
exemplarily shown. FIG. 1 shows the detailed process steps and the
in process controls performed.
[0092] Process step (1) is directed to the active ingredient
trituration, i.e., in the present case a salt of pramipexole,
pramipexole dihydrochloride monohydrate, in peg-milled quality, is
preblended with a portion of the water swelling polymer, in this
case pregelatinized starch, in a commonly known mixer. In the flow
chart a TURBULA.RTM. free-fall mixer or blender is used. The mixing
time is several minutes, in the present case preferably 10
minutes.
[0093] In process step (2) according to the flow chart, a premixing
is performed, wherein the active ingredient trituration and the
main portion of the water swelling polymer(s) and excipients are
premixed for several minutes to obtain a pre-mix. In the present
case hydroxypropyl methyl cellulose (hypromellose), the main
portion of pregelatinized starch, carbomer 941 and colloidal
silicon dioxide are premixed for 5 minutes in the abovementioned
TURBULA.RTM. mixer or blender.
[0094] According to the following process step (3), a dry screening
may optionally take place. The pre-mixture may be manually screened
through a screen, for example a 0.8 mm mesh size screen, in order
to segregate cohesive particles and to improve content
uniformity.
[0095] In the subsequent process step (4), the main mixing step is
performed according to which the components are mixed for several
minutes, preferably 5 minutes in the TURBULA.RTM. mixer after
screening. Optionally further excipients may be added at this time,
in the flow chart the component magnesium stearate is added to the
main mixture, and further mixing for several minutes, e.g., 3
minutes, in the TURBULA.RTM. mixer is performed (final mixing) to
obtain the final mixture.
[0096] Process step (5) of the process according to the present
invention is the tabletting. The final mixture is compressed on a
suitable tablet press to produce, for example, oblong shaped matrix
tablets (extended release tablets or ER tablets). In order to
control and maintain the required quality the obtained matrix
tablets are subjected to the following in-process controls: tablet
mass, hardness, tablet height, and friability.
[0097] The obtained pramipexole extended release tablets of the
present invention may then be filled, for example, into High
Density Polyethylene (HDPE) bottles. The bottles are closed tightly
with screw caps and appropriately labeled, whereby all packaging
and labeling activities are performed according to cGMP
regulations. Alternatively, a blister type packaging can be used,
e.g., using aluminum/aluminum foil blisters.
[0098] FIG. 2 represents a graph illustrating the dissolution
profiles of a matrix tablet formulation according to the present
invention. The matrix tablet contains 4% by weight CARBOPOL.RTM.,
the detailed composition is given in Example 2 and corresponds to
the abovementioned formulation according to the present invention.
The release characteristics of the matrix tablet in 3 different pH
media are shown, i.e., in 0.05 M phosphate buffer, pH=6.8, n=x, in
simulated gastric juice, pH=1.2, n=x, and in Mcllvaine buffer,
pH=4.5, n=x; (x . . . represents the number of units tested). The
value percent of released active ingredient is plotted against the
time (hours).
[0099] FIG. 3 represents a graph illustrating the dissolution
profiles of 3 matrix tablet formulations according to the present
invention. The matrix tablets contain no CARBOPOL.RTM., 1% or 4% by
weight CARBOPOL.RTM., respectively, the detailed compositions are
given in Examples 1, 2, and 4. The medium is a 0.05 M phosphate
buffer, pH=6.8. The value percent of released active ingredient is
plotted against the time (hours).
[0100] FIGS. 2 and 3 show a pH-independent in vitro release
characteristic in the range from pH 1 to 7.5 in case CARBOPOL.RTM.
is not present and a pH-dependent release characteristic wherein
the release characteristic in the range of pH<4.5 is faster in
case CARBOPOL.RTM. is present. An increase of the amount of
CARBOPOL.RTM. leads to a decreased releasing rate.
[0101] The advantages of the present invention are manifold:
[0102] According to the present invention extended release tablets
containing pramipexole or its salt are available showing different
in vitro release profiles. It is possible to select a tailor-made
release characteristic for patient's needs, symptoms, and clinical
picture observed.
[0103] The primary indication for pramipexole, Parkinson's Disease,
is an affliction that becomes more prevalent with advancing age and
is often accompanied by decline in memory. Therefore, the matrix
tablets according to the present invention providing an extended or
slow release of pramipexole or a salt thereof allows to simplify
the patient's administration scheme by reducing the amount of
recommended daily intakes and improves patient's compliance,
particularly relevant for elderly patients. The inventive extended
release tablet formulation provides a daily dose preferably
administered at one time.
[0104] Furthermore, the tablets of the present invention may be
manufactured via a direct compression, wet or dry granulation
process which applies to both types of extended release matrix
tablets.
[0105] The invention described will now be illustrated by the
Examples which follow various other embodiments and will become
apparent to the skilled person from the present specification.
However, it is expressly pointed out that the Examples and
description are intended solely as an illustration and should not
be regarded as restricting the invention.
EXAMPLES
[0106] According to the present invention pramipexole extended
release tablets have been manufactured. The tablets of the Examples
are white to off-white, 14.times.6.8 mm oblong shaped, biconvex
tablets. The tablets are intended to be administered orally, and
shall not be divided into halves. The pramipexole tablets in the
Examples contain 0.75 mg of pramipexole dihydrochloride
monohydrate, corresponding to 0.524 mg of pramipexole free,
anhydrous base.
Example 1
[0107] One embodiment of the qualitative and quantitative
composition of pramipexole extended release tablets according to
the present invention is shown in Table 1. TABLE-US-00001 TABLE 1
Qualitative and Quantitative Composition of Pramipexole Extended
Release Tablet mg per 0.75 Reference to Ingredient mg tablet
Function Standards Pramipexole dihydrochloride 0.750 Active
Corporate monohydrate, peg-milled ingredient standard Hypromellose
2208 157.500 Swelling Ph.Eur./USP (Methocel K 15 M) agent
Pregelatinized starch 185.100 Filler Ph.Eur./NF (Starch 1500)
Carbomer 941 3.500 Gelling Ph.Eur./NF (CARBOPOL .RTM. 71 G) agent
Colloidal silicon dioxide 1.400 Glidant Ph.Eur./NF Magnesium
stearate 1.750 Lubricant Ph.Eur./NF Total 350.000
Example 2
[0108] A further embodiment of the qualitative and quantitative
composition of pramipexole extended release tablets according to
the present invention is shown in Table 2. TABLE-US-00002 TABLE 2
Qualitative and Quantitative Composition of Pramipexole Extended
Release Tablet mg per 0.75 Reference to Ingredient mg tablet
Function Standards Pramipexole dihydrochloride 0.750 Active
Corporate monohydrate, peg-milled ingredient standard Hypromellose
2208 157.500 Swelling Ph.Eur./USP (Methocel K 15 M) agent
Pregelatinized starch 174.600 Filler Ph.Eur./NF (Starch 1500)
Carbomer 941 14.000 Gelling Ph.Eur./NF (CARBOPOL .RTM. 71 G) agent
Colloidal silicon dioxide 1.400 Glidant Ph.Eur./NF Magnesium
stearate 1.750 Lubricant Ph.Eur./NF Total 350.000
Example 3
[0109] The batch formula for the two pramipexole tablet
formulations of Example 1 and 2 is shown in Table 3. The batch size
of the final mixture corresponds to a batch size of 2000 tablets.
TABLE-US-00003 TABLE 3 Composition per Batch of Pramipexole 0.75 mg
ER Tablets Grams per Grams per batch batch Ingredient Example 1
Example 2 Pramipexole dihydrochloride 1.500 1.500 monohydrate,
peg-milled Hypromellose 2208 315.000 315.000 Pregelatinized starch
370.200 349.200 Carbomer 941 7.000 28.000 Colloidal silicon dioxide
2.800 2.800 Magnesium stearate 3.500 3.500 Total Mass 700.000
700.000
Example 4
[0110] The following Example shows a pramipexole tablet formulation
which corresponds to formulation a) providing a release
characteristic independent in the pH range of 1 to 7.5.
TABLE-US-00004 TABLE 4 Constituents mg/tablet Pramipexole
dihydrochloride 0.750 monohydrate, peg-milled Hypromellose 2208
(Methocel K 100 M) 175.000 Pregelatinized starch 170.400 Colloidal
silicon dioxide 2.100 Magnesium stearate 1.750 Total weight matrix
tablet 350.000
* * * * *